Inherited Disorders in Danish Cattle -...

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SUPPLEMENTUM NO. 122, VOL. 115, 2007 Inherited Disorders in Danish Cattle by Jørgen S. Agerholm Department of Veterinary Pathobiology Faculty of Life Sciences University of Copenhagen Bülowsvej 17 DK-1870 Frederiksberg C Denmark Blackwell Munksgaard 2007

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SUPPLEMENTUM NO. 122, VOL. 115, 2007

Inherited Disorders in Danish Cattle

byJørgen S. Agerholm

Department of Veterinary PathobiologyFaculty of Life SciencesUniversity of CopenhagenBülowsvej 17DK-1870 Frederiksberg CDenmark

Blackwell Munksgaard 2007

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This dissertation is based on the following 10 original articles, which are referredto in the text by their roman numerals (I–X):

I: Agerholm JS, Houe H, Jørgensen CB, Basse A. Bovine leukocyte adhesiondeficiency in Danish Holstein-Friesian cattle. II. Pathoanatomical descrip-tion of affected calves. Acta Vet Scand 1993;34:237–43.

II: Agerholm JS, Lund AM, Bloch B, Reibel J, Basse A, Arnbjerg J. Osteogen-esis imperfecta in Holstein-Friesian calves. J Vet Med A 1994;41:128–38.

III: Agerholm JS, Hafner A, Olsen S, Dahme E. Spinal dysmyelination in cross-bred Brown Swiss calves. J Vet Med A 1994;41:180–8.

IV: Agerholm JS, Andersen O. Inheritance of spinal dysmyelination in calves. JVet Med A 1995;42:9–12.

V: Agerholm JS, Bendixen C, Andersen O, Arnbjerg J. Complex vertebral mal-formation in Holstein calves. J Vet Diagn Invest 2001;13:283–89.

VI: Agerholm JS, Arnbjerg J, Andersen O. Familial chondrodysplasia in Holsteincalves. J Vet Diagn Invest 2004;16:293–8.

VII: Agerholm JS, Bendixen C, Arnbjerg J, Andersen O. Morphological variationof ‘‘complex vertebral malformation’’ in Holstein calves. J Vet Diagn Invest2004;16:548–53.

VIII: Agerholm JS, Andersen O, Almskou MB, Bendixen C, Arnbjerg J, AamandGP, Nielsen US, Panitz F, Petersen AH. Evaluation of the inheritance ofcomplex vertebral malformation syndrome by breeding studies. Acta VetScand 2004;45:133–7.

IX: Leifsson PL, Agerholm JS. Familial occurrence of bovine dilated cardiomyo-pathy in Denmark. J Vet Med A 2004;51:332–5.

X: Rude H, Agerholm JS, Maddox-Hyttel P, Christensen K, Flagstad P. Renallipofuscinosis in Danish slaughter cattle. J Comp Pathol 2005;132:303–12.

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APMIS Suppl. 122: Vol. 115, 2007 C 2007 The AuthorsPrinted in Denmark . All rights reserved

Journal Compilation C 2007 APMIS

ISSN 0903-4641

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Symbols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Danish designations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Names of institutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2. Danish cattle breeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3. Labelling of sires for inherited disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4. Estimation of disease extent 1971 to 2005 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

5. Inherited disorders in Danish cattle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195.1. Chondrodysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195.2. Complex vertebral malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215.3. Osteogenesis imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225.4. Syndactylism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235.5. Acroteriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245.6. Congenital paralysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.7. Bovine progressive degenerative myeloencephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.8. Spinal muscular atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275.9. Spinal dysmyelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.10. Syndrome of arthrogryposis and palatoschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295.11. Ichthyosis foetalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.12. Epitheliogenesis imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.13. Hereditary zinc deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325.14. Renal lipofuscinosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335.15. Hereditary dilated cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335.16. Bovine leukocyte adhesion deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.17. Congenital erythropoietic porphyria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365.18. Rectovaginal constriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385.19. Chromosomal aberrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405.20. Defects of spermatozoa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

7. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

8. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

9. Sammendrag (summary in Danish) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

10. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

11. Appendix 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

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JØRGEN S. AGERHOLM

Preface

My research on bovine inherited disorders be-gan in January 1989 when I started my PhDstudies at the Royal Veterinary and AgriculturalUniversity in Copenhagen, Denmark (now Fac-ulty of Life Sciences (LIFE), University of Cop-enhagen). These studies focused on the occur-rence of inherited diseases and congenital mal-formations in Danish cattle, and formed thebasis of my postgraduate education within thefield of veterinary special pathology and re-search methodology. After this period, the cattlebreeding associations continued to finance myfurther research during my employment at theDanish Veterinary Institute (now National Vet-erinary Institute, Technical University ofDenmark) (1992–2000) and from 2000 at theRoyal Veterinary and Agricultural University.Although I have studied other areas of veterin-ary pathology, genetic disorders in cattle be-came my primary research area, and throughoutthe years I have devoted my time to this subject.Now – 18 years after my introduction to in-herited disorders and after publication of a PhDthesis and 24 international publications on thatsubject – I have written my dissertation. I haveselected 10 articles as the basis. These articlesfocus on my main contribution to the subject:the morphology of inherited disorders, their in-heritance, and the identification of affectedbreeding lines. The aim is to summarise the re-sults of my research and to provide an updatedreview of inherited disorders in Danish cattle,focusing on the above areas. Other researchershave published comprehensive international re-views of inherited disorders in cattle, and it isnot my intention to compete with their substan-tial contributions. My work is rather meant tobe complementary to these reviews, and theyshould be consulted for aspects not includedhere. It is my hope that this dissertation willprovide valuable information for veterinary sur-geons, scientists, and breeding associations, andinspire others to enter this important and inter-esting field.

The diversity of my research has brought meinto contact with many people, to whom I

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should like to express my gratitude. Many de-serve to be mentioned, but I must confine my-self to the few. First of all, I thank Axel Basse,who originally introduced me to veterinarypathology and infected me with his unlimitedenthusiasm. I should also like to express my sin-cere thanks to my co-workers throughout theyears: Knud Christensen for inspiring dis-cussions and invaluable help with statistics, JensArnbjerg for interpreting the radiographs, andOle Andersen for his continuing collaborationand support.

It would not have been possible to conductthese studies without the help of the breedersand veterinarians who submitted animals forexamination, or without the help of the cattleadvisers and technicians who provided pedi-grees, breeding data, and other valuable infor-mation. Many thanks are due to my colleaguesand the technical staff at the former DanishVeterinary Institute, and at LIFE, for theirtremendous assistance. I also wish to thank thescientists and laboratory staff at the formerDanish Institute of Agricultural Sciences fortheir cooperation and for providing results onparentage control and genotyping. DanishCattle and the breeding associations are ac-knowledged for their collaboration and for theirfinancial support. Sincere gratitude is extendedto the management of Danish Cattle, the breed-ing associations, the former Danish VeterinaryInstitute, and the Department of Veterinary Pa-thobiology, LIFE, especially Henrik Nygaard,Thorkild Lykke, Knud Børge Pedersen, Helge V.Krogh, Thomas Krogh Nielsen, Henrik ElvangJensen and Christian Friis, for making thestudies possible.

Last – but certainly not least – I should liketo express my heartfelt thanks to my wife Suz-anne and to my sons Rasmus and Morten forhaving listened patiently to exhausting storiesof dead calves throughout the years.

Jørgen S. AgerholmCopenhagen, June 2007

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INHERITED DISORDERS IN DANISH CATTLE

Abbreviations

The use of abbreviations for inherited syn-dromes has been limited to Chapter 5, whereabbreviations are used when appropriate in thesections referring to specific disorders. The ab-breviations are defined at the beginning of eachsection. Elsewhere, designations have been writ-ten in full to achieve a greater degree of readerfriendliness.

Country abbreviations are used attached toherd book numbers to indicate the nationalityof the animal. The following abbreviations areused:

Symbols

M Homozygous normal maleS Homozygous normal femaleM Homozygous normal individual of

unknown sexM Heterozygous male� Heterozygous female� Heterozygous individual of unknown sex

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CAN: CanadaD: GermanyDK: DenmarkF: FranceNLD: The NetherlandsI: ItalyS: SwedenUS/USA: United States of America

H Homozygous affected maleO Homozygous affected femaleH Homozygous affected individual of un-

known sex.... Animals of similar sex and genotype as the

previous animals* Within a symbol refers to an animal of un-

registered descent

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Danish designations

Several inherited disorders found in Danishcattle have been given designations in Danish.These names often refer to the clinical manifes-tation of the disorder. Such descriptive desig-nations have been used to facilitate communi-cation between veterinarians, breeding associ-ations and breeders. To make this dissertationmore useful for readers without a veterinaryeducation and to avoid confusion betweenDanish and English terms, a list of Danish des-ignations is given.

Names of institutions

Names used for institutions in this thesis are re-ferring to their names before January 1st 2007when the Royal Veterinary and AgriculturalUniversity merged with the University of Cop-enhagen and the Danish University of Pharma-ceutical Sciences and became the Faculty of LifeSciences, University of Copenhagen. Simul-

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Bovine progressive degenerative myeloencephal-opathy: weaversyndromet

Chondrodysplasia: bulldogkalvCongenital paralysis: medfødt arvelig lamhedIchthyosis foetalis: fiskeskælsygeProgressive posterior paralysis: staldkrampeRenal lipofuscinosis: oksens sorte nyrerSpinal dysmyelination: medfødt lammelseSpinal muscular atrophy: liggekalvesyndrometSyndactylism: muldyrfod

taneously the Danish Institute of AgriculturalSciences merged with the University of Aarhusand became the Faculty of AgriculturalSciences, University of Aarhus and the DanishInstitute for Food and Veterinary Researchmerged with the Technical University ofDenmark and a number of other institutions.

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INHERITED DISORDERS IN DANISH CATTLE

1. Introduction

Inherited disorders are of interest in all animalspecies. However, the intensive use of individualsires in cattle breeding and the structure of bo-vine breeding programmes make this speciesespecially vulnerable to the effects of undesir-able traits. The use of insemination and devel-opment of methods for dilution and conser-vation of semen has established the necessarybasis for extensive exploitation of sires with asuperior genetic constitution. Such elite siresmay produce huge numbers of progeny. Gener-ally, sires used for artificial breeding produceprogeny in numbers of hundreds to severalthousands depending on the size of the breedand the superiority of the bull. But individualsires may be exploited even more, with insemi-nation numbers above 1 million. It is obviousthat such extensive use of individual sires maylead to dissemination of undesirable geneswithin a breed.

Sires for breeding purposes are often pro-duced by mating of males and females with asuperior genetic background. In this way, fam-ilies of closely related elite sires are created andundesirable recessive genes may be transmittedthrough the generations. Although close in-breeding is not performed, the extensive use ofgenetically related sires may lead to a build upof disease alleles in the population and the sub-sequent occurrence of diseased animals in rela-tively large numbers. An unrecognised spread ofthe allele for bovine leukocyte adhesion de-ficiency occurred in this way for several decades,which subsequently led to an estimated preva-lence of 0.46% affected calves in the US Hol-stein population (156).

Inherited disorders in cattle are mostlycaused by autosomal recessively inherited genes.It is characteristic that the action of autosomalrecessive genes only becomes expressed as a dis-eased phenotype if present in both loci. There-fore, autosomal recessively inherited disordersare of greater concern in cattle breeding thanare disorders with dominant inheritance or re-cessive X-linked inheritance. As dominant or re-cessive X-linked genes are expressed in thephenotype of males, sires carrying such genesare mostly omitted from breeding. However, if

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the defective allele produces a desirable pheno-type in heterozygous individuals, such animalsmay be used for breeding. A classic example ofthis is the Dexter breed, in which heterozygousindividuals constitute a desirable compactphenotype, while homozygous dominant indi-viduals are aborted due to severe chondrodys-plasia (304). In sires, dominant inherited defectsmay also be present only in a certain proportionof spermatozoa due to gonadal mosaicism.Such sires are phenotypically normal but pro-duce defective progeny in segregation patternsnot consistent with simple Mendelian inherit-ance. Bovine cases of osteogenesis imperfectaare probably the result of this phenomenon (64,II).

Before the development of freezing pro-cedures for semen, cattle breeding was per-formed by natural breeding or by the use offresh semen. The geographical distances, infra-structure and means of transportation thuslimited the use of individual sires. Consequently,the occurrence of inherited disorders was most-ly a local or regional phenomenon. Despitethese limitations, international spread of unde-sirable traits with breeding sires did occur. Anearly example of this is the skeletal malfor-mation acroteriasis. The gene for this defect wasspread in Swedish cattle through the Holsteinsire Gallus M. 77 (born 1890), which was im-ported to Sweden and founded an importantbreeding line (309). With the development ofmethods for semen conservation, inherited dis-orders changed from mainly having a local ef-fect to having an international effect. This widerperspective means that inherited disorders incattle have attained international importance.

The methods used in cattle breeding and theirimplications for the spread of unfavourablegenes make surveillance of inherited disordersan important part of bovine health pro-grammes. Such programmes have existed formany years and have widened our knowledge ofinherited bovine diseases considerably (10, 180).They are generally based on passive surveil-lance, which depends on recognition of sus-pected cases in the herds. Consequently, theidentification of inherited disorders is often

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JØRGEN S. AGERHOLM

positively associated with an increasing genefrequency in the population. Passive surveil-lance is therefore less able to identify low preva-lence disorders. The aim of the surveillance sys-tem is to identify some of the consequences ofthe breeding strategy, but prevention of inbreed-ing relies on the efficiency of the breeding sys-tems. If an active surveillance program was usedthis could include examination of progeny ob-tained through breeding between closely relatedindividuals, which at least should include thehighest-ranking breeding sires. Such testing ofvaluable sires is controversial and is generallynot used by breeding associations due to theeconomic implications of identifying recessivelyinherited disease genes. It is important to re-member that most individuals are assumed tobe carriers of recessively inherited disorders(204, 216) and to realize that most recessivelyinherited diseases occur as a result of inbreedingrather than by the mere presence of diseasegenes in the population.

In addition to the problems related to identi-fying disorders of low prevalence, passive sur-veillance is compromised by the ability to recog-nise certain disorders in herds. Disorders thatare obvious to the breeder or veterinarian aremore likely to be recognised than diseases thatrequire detailed examination to be diagnosed.Generally, skeletal malformations, severe neuro-logical disorders, and diseases of the skin arereadily recognised, while defects of the internalorgans are less obvious and are sometimes onlyidentified accidentally. This is exemplified by thebovine leukocyte adhesion deficiency syndrome,which was not identified by surveillance systemsalthough it occurred in several countries. Thislethal syndrome of immunodeficiency was infact diagnosed by coincidence in a study onmastitis (156), although previous observationshad indicated the presence of a familial im-munological disorder in Holsteins (275). In ad-dition, passive surveillance is compromised bythe age of the animal as an association betweenclinical signs and a genetic aetiology is morelikely to occur in calves than in adult cattle.Also defects causing embryonic or foetal mor-tality are difficult to recognise although they areprobably rather prevalent (298). Nevertheless,genetic disease programmes have documentedtheir value for breeding associations despite thelimitations of passive surveillance. This is

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mainly due to the established cooperation be-tween breeding associations and researchers,which has formed a solid basis for reducing theprevalence of specific inherited defects.

The prevalence of a recessively inherited dis-order is mostly reduced by culling or limitingthe use of sires that are heterozygous for thedefect. Heterozygous individuals can be iden-tified by different methods. Examination ofaffected progeny by clinical examination or nec-ropsy is a classic method, which in Denmarkhas been used to identify carriers of, for ex-ample, spinal muscular atrophy (8) and spinaldysmyelination (III). Although this method re-quires several years of progeny examination, itis effective and can identify a wide range of dis-orders. However, it has a major disadvantage inthat the genotype of a sire cannot be determineduntil progeny are born and reach the age of dis-ease development. The time span can be re-duced if the disorder is expressed in the foetus,as, for example, in syndactylism and the arachn-omelia syndrome (124, 167). Meanwhile, testingof sires by examination of foetuses is only appli-cable on a small scale. Therefore, eradication ofinherited disorders by progeny examination isfor the most part slow. Another method isidentification of animals expressing a hetero-zygous genotype. Some inherited enzyme defi-ciencies may allow discrimination betweengenotypes by analysis for enzyme activity inblood. However, due to variation of enzyme ac-tivities in animals, differentiation between car-riers and normal individuals may not always bepossible (143). A third method is genotyping ofanimals by genomic analysis. Recent develop-ments within molecular biology and geneticshave made possible efficient and rapid identifi-cation of heterozygous animals by this ap-proach. Different methods have been used inDanish cattle, including genetic markers (226)or testing for a causal base mutation in a gene(149, 279, 280). The Danish breeding associ-ations have efficiently reduced the prevalence ofbovine leukocyte adhesion deficiency, complexvertebral malformation, and spinal dysmyelin-ation based on results obtained by thesemethods, thus demonstrating their superiorityto progeny examination.

Due to the severe impact of inherited dis-orders on breeding programmes and the econ-omic consequences for breeders and breeding

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associations, intervention must be based onhigh quality research. Critical evaluation of re-search results by external reviewers, i.e. by pub-lication in well-reputed international scientificjournals, provides the reliability demanded bythe breeding associations. Providing this infor-mation must have the highest priority in bovinegenetic programmes and is the most importantreason for collaboration between scientists andbreeding associations. Three fundamental as-pects of inherited disorders must be described:1) the morphology, 2) the inheritance, and 3)the breeding lines affected. The research onwhich this dissertation is based (I–X) has fo-cused on these three aspects.

Determination of the mode of inheritance isan important goal when studying possible in-herited disorders. The mode of inheritance isoften indicated by the occurrence in a familialpattern, the sex of affected calves, and the par-ental phenotypes. Occurrence of defective pro-geny of both sexes following breeding betweengenetically related and phenotypically normalanimals indicates an autosomal recessive modeof inheritance. However, such an occurrence ofa disorder could be due to other causes, i.e. tera-togens, and it must be emphasised that such ob-servations are only indicative and must be con-firmed. It must also be emphasised that breed-ing between genetically related animals is socommon in cattle that even several cases of adisorder can occur by coincidence in a breedingline. Such an example is provided by researchinto the complex vertebral malformation syn-drome of Holstein calves. The initial studiesshowed that 17 malformed calves were genetic-ally related to two widely used sires (A: Carlin-M Ivanhoe Bell (US1667366); B: Pawnee FarmArlinda Chief (US1427381)) (V). Later, molecu-lar genotyping determined that only Carlin-MIvanhoe Bell was a carrier of complex vertebralmalformation (280). This example clearly dem-onstrates that interpretation of inbreeding re-quires great caution.

Analysis of segregation patterns is a classicmethod for evaluation of inheritance. The ratiobetween affected and unaffected animals can bedetermined by experimental breeding trials. Anexample would be experimental breeding be-tween a sire and his daughters. However, it isoften possible to select animals from the generalpopulation, thus avoiding experimental mating.

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A prerequisite for this is registered pedigreesand matings in addition to a relatively highnumber of carriers in the female population.The inheritance of several disorders in Danishcattle has been studied in this way by analysingthe segregation following breeding between aheterozygous sire and daughters of another het-erozygous bull (224, IV, VIII). Such studies areless expensive than breeding trials, and, as thenecessary number of pregnant females is oftenavailable in the population, a result can be ob-tained within a short period of time. However,it is essential that the progeny is available forexamination. Increased intrauterine mortalityamong affected progeny, as seen in, for ex-ample, the complex vertebral malformationsyndrome (VIII), is devastating for a study, asaborted foetuses mostly remain unexamined.Analysis of segregation patterns for non-con-genital disorder may also be problematic.Calves may die due to dystocia or neonatal in-fections before lesions have developed, or ani-mals may have to be maintained for a longperiod for lesions to develop. Spinal muscularatrophy (8), renal lipofuscinosis (X) and heredi-tary dilated cardiomyopathy (IX) are examplesof such disorders. Introduction of moleculargenotyping in breeding studies may reducesome of these problems, as segregation ratiosamong genotypes can be determined in the neo-natal animals.

The effective interventions made possible bymolecular genotyping can rapidly reduce thenumber of diseased calves in a population. Ifheterozygous sires are totally removed from abreeding population, defective calves will onlybe born for an additional 9 months, corre-sponding to the length of the gestation periodin cattle. This effectiveness is a compromisingfactor for further research into the defect, as ad-ditional cases must be produced experimentally.Experimental production is expensive due to thelong gestation period of cattle and as cowsusually only give birth to a single calf. Breedingbetween homozygous affected animals is effec-tive as all progeny are diseased. However, this isonly possible for non-lethal defects or if treat-ment of affected animals is possible, as for her-editary zinc deficiency (193). Superovulationand embryo transfer may reduce the number ofhomozygous affected parents needed, as hasbeen applied to syndactylism (124) and in-

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herited congenital myoclonus (128). Breedingbetween heterozygous animals is another way toproduce affected progeny. If parents with con-firmed heterozygous genotype of an autosomalrecessive gene are used, a segregation ratio be-tween phenotypically normal and affectedcalves of 3:1 is expected. Consequently, a ratherhigh number of pregnant animals are needed toproduce a sufficient number of defective pro-geny for further studies. Sophisticated labora-tory techniques, such as cloning and genotypingof embryos, may prove useful as homozygousaffected embryos can be selected, thus reducingthe number of cows needed. Due to the econ-omic implications, research into many inheriteddisorders has relied on the availability of defec-tive animals from the general population andhas been performed only over a short period oftime. Consequently, many aspects have not beenadequately examined. This is not satisfactoryfrom a scientific point of view, but from a breed-ing point of view the implications are limited,as the lack of affected animals is reflecting aproblem that has been solved.

Although the prevalence of a recessively in-herited disorder is significantly reduced andmay approach zero, the abnormal gene may per-sist in the population and remain unrecognisedfor a long period of time. It is thus possible thatalready characterised defective genes in thecourse of time can re-enter the population ofbreeding sires and, unless the sires are testedsystematically, an initially concealed increase ingene frequency may develop. The persistence ofrecessive genes in the female population for dec-ades and the re-occurrence of defective calvesfollowing the use of breeding sires that turned

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out to be carriers has been observed inDenmark. Calves affected by hereditary zinc de-ficiency (10) or chondrodysplasia (7) (Fig. 1)have appeared in this way. Therefore, persistentsurveillance and testing of breeding sires isnecessary.

Fig. 1. Genealogical diagram showing the genetic re-lationship between five cases of chondrodysplasia inthe Danish Red Dairy breed. Four cases in generationIV and V were reported in 1974, while the case ingeneration VIII was found 15 years later. Sire A: ThySkov; B: NOF Kel; C: NØ Gerber; D: NOF Lød; E:HV Flid; F: 060480-00463.

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2. Danish cattle breeds

The Danish cattle population has been decreas-ing during the study period (1989–2005), from atotal of 2.2 million animals (1990) to around 1.6million (2004). The number of calvings in dairyheifers/cows decreased from 769,000 to 569,000,while the number of calvings in suckler heifers/cows increased from 86,000 to 102,000. Most nu-merous are Danish Holsteins (375,000 cows in2003/2004), followed by the Jersey breed (62,000cows), Danish Red Dairy breed (44,000 cows),crossbreeds (35,000 cows), and Danish RedHolstein (5,000 cows). A wide range of beefbreeds is represented in Denmark, but generallythe numbers are low. The most prevalent beefbreeds are the Limousine and Hereford breeds(around 8,300 and 4,800 purebred cows, respec-tively (2004 figures)) (61).

Most genetic diseases in Danish cattle havebeen found in Holsteins and the Danish RedDairy breed, thus partly reflecting the breedcomposition of the national cattle population.Besides reflecting the number of animals, theseobservations may also be due to other con-ditions, such as differences in breeding strategies,inbreeding levels, and value of calves. However,the findings may also be due to two factors thatgreatly influence the ability to recognise inheriteddisorders. The awareness of the breeder is prob-ably the most important single factor. If breedersare informed about inherited disorders, cases arelikely to be found. This situation developedamong breeders of the Danish Red Dairy breedwhen information on bovine progressive de-generative myeloencephalopathy was given. Thisled to a high level of producer awareness, whichsubsequently resulted in the recognition of twoother inherited neurological diseases: spinalmuscular atrophy (121) and spinal dysmyelin-ation (III). So there is a self-perpetuating effectof identifying an inherited disorder within a spe-cific breed, as this leads to an increased aware-ness. The herd size is the other important factor.This is especially the case when natural breedingis used as the sire is often used in a single herdonly. As many disorders have an autosomal re-cessive mode of inheritance and as the mean herdsize of beef cattle herds in Denmark is only 11 pu-rebred/hybrid animals (61), affected animals gen-

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erally occur in low numbers unless there is severeinbreeding. This combination of small herd sizeand low number of affected calves makes recog-nition of inherited disorders in suckler cattle inDenmark difficult, as most herds will only en-counter one or very few cases. So unless thefarmer submits the first case and this turns outto have a documented inherited defect, cases willremain unrecognised. Consequently, the identi-fication of inherited disorders primarily withinthe Holstein breed and the Danish Red Dairybreed does not necessarily indicate that inheriteddefects are more common in these breeds than inother breeds in Denmark.

The genetic composition and names of cattlebreeds in Denmark have changed over time.When reviewing the literature on inherited dis-orders in cattle in Denmark, uncertainty mayarise as to which breeds are actually affected be-cause of the varying use of breed designations,i.e. Holstein, Holstein-Friesian, Danish Holstein-Friesian, Black Pied Danish Cattle of Friesiandescent, Black and White Danish Dairy breed,Black and White Danish Milk breed, and Sort-broget Dansk Malkerace. To avoid confusion, asingle designation is used for each breed, i.e.Danish Holstein breed. This simplification is notcorrect from a breeding point of view, as the con-stitution of the animals may have varied overtime due to fluctuation in the genetic compo-sition of the breed. However, such simplificationis acceptable within the scope of this dissertation.The Danish nationality of the breed is generallyincluded in the name. This has been done for con-venience to facilitate reference to the occurrenceof disorders in Denmark. Nevertheless, inheriteddisorders in cattle clearly often have an interna-tional perspective. In this respect, national cattlepopulations do not constitute separate breedsand the designation Danish in this dissertationsimply refers to the physical presence of the ani-mal in Denmark, even thought it may have a pre-dominantly foreign genetic background. A simi-lar approach has been carried out for cattlebreeds in other countries, especially for Holste-ins. A recent study has in fact demonstrated thatthe global population of Holstein cattle can beconsidered as one single population unit (315).

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3. Labelling of sires for inherited disorders

Sires that are used for insemination in Denmarkare labelled for certain hereditary disordersbased on their descent or test results. Fourlabels are used. A sire can be labelled as non-carrier, confirmed carrier, likely carrier, or poss-ible carrier of a specific disorder. The labellingpolicy is based on the following general criteria:

O A sire can be labelled ‘‘non-carrier’’ if thiscan be proved, i.e. by genotyping of the ani-mal itself or by progeny examination in cer-tain breeding combinations, of which far-ther-daughter matings are often used.

O A sire is labelled as ‘‘confirmed carrier’’ ifthis has been documented, i.e. by genotypingor by the occurrence of at least two affectedprogeny. It is a demand that the diagnosis inprogeny has been confirmed by an approvedmethod and that parentage has been con-firmed.

O The label ‘‘likely carrier’’ is used if only oneaffected progeny has been found. Diagnosisand parentage must be confirmed as for‘‘confirmed carrier’’ and the label has mostlybeen used when a genotyping test was un-available.

O The label ‘‘possible carrier’’ applies to ani-mals that are genetically related to a con-firmed carrier within the last three gener-ations. This label is mostly used when geno-typing methods are unavailable.

Females can be labelled in a similar way, butlabelling is mostly based entirely on descent.Labelling of sires in Denmark is performed bythe breeding associations, and is controlled andregulated by the Danish Veterinary and FoodAdministration. Information on the disease sta-tus of sires is publicly available.

By the end of 2005, labelling for the followingdisorders was used in Denmark: bovine leuko-cyte adhesion deficiency, complex vertebral mal-formation, chondrodysplasia in Holsteins, syn-dactylism, congenital paralysis, bovine pro-gressive degenerative myeloencephalopathy,spinal muscular atrophy, spinal dysmyelination,hereditary zinc deficiency, and rectovaginal con-striction. Labelling has been based on genotyp-

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ing of sires by molecular methods (complex ver-tebral malformation and bovine leukocyte ad-hesion deficiency), progeny examination (spinalmuscular atrophy, hereditary zinc deficiency,and rectovaginal constriction), or both (syndac-tylism, chondrodysplasia in Holsteins, bovineprogressive degenerative myeloencephalopathy,and spinal dysmyelination). Labelling of somesires has been adapted from foreign breeding as-sociations and the exact basis is not known.Similarly, no detailed basis for labels given tosires prior to 1989 is accessible. Labelling of sir-es for spinal muscular atrophy and spinal dys-myelination is based on extensive progeny ex-amination, which included necropsy of almost500 calves (Table 1). Genotyping has been per-formed at the former Department of AnimalGenetics, the Royal Veterinary and AgriculturalUniversity, Denmark, at the former Danish In-stitute of Agricultural Sciences, and at foreignlaboratories.

A list of sires diagnosed as carriers of heredi-tary diseases until 31 December 2005 is given inAppendix 1. Sires labelled as ‘‘likely carriers’’have been included in the ‘‘confirmed carriergroup’’. Labelling of sires as ‘‘likely carriers’’mostly refers to spinal muscular atrophy andspinal dysmyelination. However, as all ‘‘likelycarriers’’ of these defects are genetically linkedto ‘‘confirmed carriers’’, they can beyond anydoubt be regarded as true carriers.

A number of additional inherited disordershave been recognised in Denmark. Familial pat-terns of occurrence have been recognised andcases have been genetically linked to each other.Pedigree analyses have identified a number ofsires that most likely are carriers. These are alsoshown in Appendix 1 to provide the basis forthe estimations made in Chapter 4, and to en-sure that future cases can be genealogicallycompared to them. Nevertheless, it must be em-phasised that parentage analysis has not beensystematically performed.

Programmes to control inherited disordersmostly rely on the ability to identify hetero-zygous sires. It is therefore of interest to analysethe extent to which heterozygous sires have beenidentified. For disorders inherited in an auto-

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TABLE 1. Annual number of confirmed cases of spinal muscular atrophy and spinal dysmyelination in 477 DanishRed Dairy calves submitted due to suspicion of an inherited neurological disorder

Year Spinal muscular Spinal Other disorders.

atrophy dysmyelination1989 28 2 181990 27 5 251991 33 4 251992 19 15 151993 4 21 21994 12 60* 331995 8 14 271996 5 13 131997 7 4 71998 1 1 111999 0 1 72000 0 1 32001 0 0 12002 1 0 22003 1 0 12004–2005 0 0 0Total 146 141 190

.Disorders associated with recumbency in the Danish Red Dairy breed.*Including 21 cases examined as part of a breeding study.

somal recessive manner, this can be clarified byanalysis of disease status in sons of confirmedcarriers, as heterozygous and homozygous nor-mal sires must segregate 1:1, if it is assumed thattheir dams are homozygous normal and thatthere is no selection for or against specific geno-types. If it is hypothesized that all carriers havebeen detected (sires labelled ‘‘confirmed/likelycarrier’’), then the remaining sires must behomozygous normal (sires labelled ‘‘free/poss-ible carrier’’). Testing of observed numbers ofsires affiliated to these two categories againstthe 1:1 hypothesis by the chi-square test showsthat significantly fewer heterozygous sires thanexpected have been identified (Table 2). Thefigures for bovine leukocyte adhesion deficiencyand the complex vertebral malformation syn-drome were analysed further to evaluate a poss-ible bias in the observed numbers. Labelling forthese diseases differed from the other disordersas it was based on genotyping and as a largegroup of sires with unknown genotype wasfound. An initial analysis including only geno-typed sires showed a persistent highly significantlack of carriers, thus excluding a major biasfrom the sires with unknown genotype as thecause (data not shown). A comparison between

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genotype and year of birth showed that the twogenotypes segregated 1:1 until 1991 for bovineleukocyte adhesion deficiency and until 2000 forcomplex vertebral malformation syndrome(Fig. 2), thus demonstrating that heterozygousmales did not enter the breeding program foryoung sires after genotyping had become avail-able, and thereby created a bias.

It is important to note that identification ofcarriers by progeny examination depends on thegene frequency in the female population.Consequently, the efficiency with which carriersare detected is lower during the initial spread ofa disease gene and at the end of an eliminationcampaign, thus compromising the data ob-tained through these periods.

The results show that identification of siresbased on passive surveillance is an inefficientway of identifying carriers and that othermethods should be used. The inability to effec-tively identify all carriers in the initial breedingscheme causes a delay in reducing the preva-lence of diseased calves. However, heterozygoussires that pass undetected through the initialbreeding scheme will probably be identifiedlater on if used extensively.

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TABLE 2. Observed and expected genotype of sires that are sons of confirmed heterozygous sire and are used forinsemination in Denmark

Observed numbers Expected numbers2 Chi-squareHomozygous Heterozygous Homozygous Heterozygousvaluenormal/unknown genotype normal/unknown genotype

genotype genotypeComplex vertebral malformation 1054 (454/600) 286 670 670 440.17***Syndactylism 23 (8/15) 4 13.5 13.5 13.37***BPDME1 68 (2/66) 7 37.5 37.5 49.61***Spinal muscular atrophy 181 (4/177) 50 115.5 115.5 74.29***Spinal dysmyelination 85 (4/81) 30 57.5 57.5 26.30***Hereditary zinc deficiency 67 (0/67) 6 36.5 36.5 50.97***Bovine leukocyte adhesion deficiency 616 (270/346) 141 378.5 378.5 298.05***Rectovaginal constriction 77 (3/74) 16 46.5 46.5 40.01***1 Bovine progressive degenerative myeloencephalopathy.2 Assuming that the contribution from the dam is similar for both groups and no selection for or against

heterozygous sires.***P�0.001, dfΩ1.

Fig. 2. Annual ratio between homozygous normal sires and sires that are heterozygous for a) complex vertebralmalformation syndrome, and b) bovine leukocyte adhesion deficiency. H Homozygous normal sires; M Hetero-zygous sires.

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4. Estimation of disease extent 1971 to 2005

It is of interest for breeding associations andscientists to know the approximate number ofcalves affected by genetic diseases. These esti-mations can be used by breeding associations tomake decisions regarding intervention in breed-ing programmes, can show the magnitude of adisease problem, and can be used to evaluatethe efficiency of the surveillance programme. Itis important to stress that estimates are simplynumbers calculated based on a hypothesis anda range of precautions, which may increase ordecrease the estimate. It is outside the scope ofthis dissertation to provide a detailed statisticalanalysis of the number of affected calves, andeven if this were done, the influence of a widerange of assumptions could always be disputed.However, with relation to the cattle health pro-gramme it is of interest to know the magnitudeof the problem, and therefore a simple andtransparent approach is used. Consequently,one should not focus on the exact numbers butrather on changes over time and disease levelscounted in hundreds or thousands of animals.A number of precautions are discussed, buttheir exact influence on the estimate is notgiven.

Affected and unaffected animals occur inconsistent patterns if carriers of disorders withsimple Mendelian autosomal recessive inherit-ance with complete penetrance are mated.These segregation ratios can be used to calcu-late an expected number of diseased progeny ifthe genotype of certain individuals in their pedi-gree is known, i.e. if two heterozygous individ-uals are mated then 25% of the progeny will beaffected and 75% unaffected. As most of the in-herited disorders in Danish cattle are inheritedautosomal recessively, they therefore follow pre-dictable patterns.

Danish breeding sires are labelled for severalinherited disorders (see Chapter 3) and as breed-ing data and pedigrees of cattle in Denmark areextensively registered in the Danish Cattle Data-base, data on progeny can be extracted for cer-tain combinations of sires. Data, which includedthe number of calves born (stillborn or viable)from 1 January 1971 to 31 December 2005, wereextracted and analysed for segregation ratios for

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each of the labelled disorders and for congenitalerythropoietic porphyria, hereditary dilated car-diomyopathy, and chondrodysplasia in theDanish Red Dairy breed. The sires that formedthe basis for data selection are shown in Appen-dix 1. The following breeding combinations wereused (see Fig. 3):

O SireII mated to daughters of SireIII, giving asegregation ratio between unaffected andaffected progeny of 7:1.

O SireII mated to females related to SireIV, giv-ing a segregation ratio between unaffectedand affected progeny of 15:1.

O SireII mated to females related to SireV, giv-ing a segregation ratio between unaffectedand affected progeny of 31:1.

The segregation ratios are reached under the as-sumption that the gene frequency was zero indams of the oldest generation (generation III,IV and V, respectively). The number of affectedprogeny from each of these combinations wasadded and analysed annually and in total.

Analysis of segregation ratios in full-term ornear full-term calves is only an applicablemethod if the chance of an affected calf equalsthe chance of an unaffected calf surviving thegestation period. This is not the case for com-plex vertebral malformation (225, VIII). There-fore, the number of embryos (Ntotal) that re-sulted in the observed number of calves (Nobs)had to be calculated. By applying the results ob-tained by Nielsen et al. (225), who determinedthat only 23% of affected foetuses survived togestation day 260, the total number of embryoscould be calculated as:

NobsΩ(PRNormal¿Ntotal)π((PRDefect¿Ntotal)¿23%),

where PRNormal and PRDefect are the prevalenceof normal and defective progeny in the sire com-bination (Fig. 3).

The number of defective embryos can subse-quently be calculated as:

Number of defective embryosΩPRDefect¿Ntotal.

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JØRGEN S. AGERHOLM

Fig. 3. Principles for extracting breeding data and analysing segregation ratios regarding autosomal recessivelyinherited disorders. The father (SireII) of all calves is a carrier of a specific disorder. When mated to daughtersof carriers of the same disorder (SireIII), 12.5% of the progeny will then have the diseased phenotype. Similarly,diseased progeny will be born with prevalences of 6.25% and 3.125% when a carrier (SireII) is mated to femalesthat have a carrier as father to the maternal grandmother (SireIV) or to the great-grandmother (SireV), respec-tively. The numbers of each symbol do not necessarily correspond to the expected ratio. The female populationin the oldest generation in each situation are expected to have a gene frequency of 0.

The number of affected progeny varied con-siderably according to the actual disorder (Table3) and over time (Fig. 4a–f). Of the disordersoccurring in Holsteins, complex vertebral mal-formation was the most numerous, with an esti-mated number of affected embryos around

TABLE 3. Estimated number of affected progeny for some hereditary diseases in Danish cattle grouped accordingto combination of sires in different generations (see text for details)

Number of affected progenySireII¿SireIII SireII¿SireIV SireII¿SireV Total

Complex vertebral malformation1 7,966.7 3,323.9 789.5 12,080.1Bovine leukocyte adhesion deficiency 546.9 84 10.5 641.4Congenital erythropoietic porphyria 20.6 1.5 0 22.1BPDME2,3 28.5 2.7 0.3 31.5Spinal muscular atrophy 1,402.8 371.6 68.5 1,842.9Spinal dysmyelination 432.8 60.8 7.0 500.6Hereditary dilated cardiomyopathy3 98.6 112.4 60.0 271Rectovaginal constriction4 285.5 34.6 3.4 323.51 The number of progeny is given as embryos.2 Bovine progressive degenerative myeloencephalopathy.3 The number represents both males and females. Severe symptoms mostly develop after the usual slaughter

age of males.4 The number represents both males and females, but severe disease is only seen in females.

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12,000. Bovine leukocyte adhesion deficiencywas less numerous, with an estimated numberaround 600 cases. In the Danish Red Dairybreed, animals suffering from spinal muscularatrophy or spinal dysmyelination numberedaround 1,800 and 500 calves, respectively, while

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Fig. 4. Annual number of animals with a diseased phenotype according to year of birth and sire combination fora) complex vertebral malformation, b) bovine leukocyte adhesion deficiency, c) bovine progressive degenerativemyeloencephalopathy, d) spinal muscular atrophy, e) spinal dysmyelination, and f) rectovaginal constriction.Contribution from sire combinations: SireII mated to daughters of SireIII H; SireII mated to females related toSireIV M; SireII mated to females related to SireV , see text and Fig. 3 for details.

bovine progressive degenerative myeloencephal-opathy remained almost insignificant. The esti-mated number of females with rectovaginal con-striction was around 150 (Table 3).

A number of precautions influenced the accu-racy of the estimations. The two most import-ant factors were probably the impact of un-identified heterozygous sires and the quality ofthe data. Data on calves related to unidentifiedheterozygous sires were obviously not includedin the data sets, and consequently the estimatednumbers of affected calves are too low. A sig-nificant lack of heterozygous sires has beendemonstrated (Table 2). The impact of these sir-

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es cannot be determined, but many sires areprobably young sires culled after initial testingbecause of low breeding value. The lack of datafrom such sires might not greatly influence thenumber of defective calves.

The data quality had an important influenceon the estimations. Estimations of the numberof calves affected by syndactylism and heredi-tary zinc deficiency gave only 8 and 15 animals,respectively, while only a single calf of theDanish Red Dairy breed suffering from con-genital paralysis or chondrodysplasia shouldhave been born. Although the number ofaffected calves with these disorders is unknown,

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JØRGEN S. AGERHOLM

an estimated number of only 15 calves with her-editary zinc deficiency appears to be much toolow, as this disorder was considered a majorproblem in Danish Holstein in the 1970s. Thepoor estimations are probably due to lack ofunambiguous identification of cattle untilaround 1983, when unequivocal identificationby ear tags was made compulsory and regis-tration of breeding was computerised. There-fore, estimations based on data through the1970s are unreliable for all disorders, but asmost disorders have been recognised in the1980s or later, the influence on the calculationsis limited for these diseases.

A few additional precautions should be men-tioned, but many others may influence the esti-

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mated number. Errors in registration of parent-age erroneously included some animals and ex-cluded others depending on the disease statusof the correct sire. Erroneous registrations oc-cur with a frequency of 2–2.5% (data from1986–1988). The estimations have not been cor-rected for perinatal mortality, which will reducethe actually observed number of affected calvesfor non-congenital disorders. Similarly, the ac-tual number of affected calves is approximately50% of the estimated number if the disorder issubclinical before the usual culling age of malesof around one year or only of importance inone sex. This is relevant for diseases such as her-editary dilated cardiomyopathy and rectova-ginal constriction.

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5. Inherited disorders in Danish cattle

There has been research on inherited disordersin Danish cattle for around 80 years, but reportsof malformations that later turned out prob-ably to be inherited have been published formore than 140 years. Research focusing on thissubject was started by K. Løje, who in 1930published a review on inherited disorders (192).This was followed by the substantial research ofJ. Nielsen, who in 1950 published his disser-tation on congenital paralysis in the Danish RedDairy breed (217) and established the basis forreducing the prevalence of this disorder throughbreeding measures. Until 1989, when the pres-ent investigation was initiated, several re-searchers and research groups studied a varietyof disorders, including hereditary zinc de-ficiency, congenital erythropoietic porphyria,and defects of spermatozoa. This led to a sub-stantial number of publications in internationalscientific journals and established the scientificbasis for the recognition and control of in-herited disorders in Danish cattle.

Several comprehensive international reviewson inherited disorders in cattle have been pub-lished (65, 135, 180). In addition, a regularly up-dated and internationally acknowledged elec-tronic database, Online Mendelian Inheritancein Animals (OMIA), is available on the world-wide web (http://omia.angis.org.au/) (215). Thereview presented in this dissertation focuses en-tirely on inherited disorders identified in Danishcattle and deals with three fundamental aspectsof inherited disorders: morphology, inheritance,and affected breeding lines. It provides insightinto the causes, pathogenesis, morphology, andpresent occurrence of inherited disorders inDanish cattle. Furthermore, it is the first reviewon this subject in Danish cattle written in Eng-lish, making it available to scientists inter-nationally. The review focuses only on inheriteddisorders with an established or likely geneticaetiology based on single genes. Some disorders,such as, for example, spastic paresis, progressiveposterior paralysis, and segmental aplasia of theWolffian duct in sires, which have been reportedin Denmark (39, 40, 243, 261), have been omit-ted as they do not fulfil these criteria. However,a review of these disorders in Danish cattle has

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previously been provided (7). Syndromes thathave been claimed to have a genetic aetiologybecause of a familial occurrence, but that havenot been thoroughly examined, have also beenomitted. Examples are foetal mummification(192) and a syndrome of pharyngeal swelling,anterior arthrogryposis, and seizure (named Ba-enster syndrome after the Holstein sire Baenster(DK6323)) (218, 219). Such findings have beenevaluated, and it is evident from present scien-tific knowledge that there can be a wide rangeof causes.

Inheritance plays a role in many diseases.Disease often develops due to an interaction be-tween a wide range of factors, including viru-lence of an infectious organism, immunity, man-agement, environment, nutritional status, andinheritance. Such diseases occur in Denmark,but are not within the scope of this dissertation,nor are desirable defects such as muscularhypertrophy or genetic defects not associatedwith disease (i.e. abnormal coat colour and poll-edness). The natural subject of this dissertationis diseases due to the effect of single genes pre-dominantly inherited in an autosomal recessivemanner.

5.1. CHONDRODYSPLASIA

Chondrodysplasia (bulldog calves, achondro-plasia, disproportionate dwarfism) is a desig-nation used for a heterogeneous group of con-genital skeletal malformations characterised bydiminished endochondral osteogenesis. Themorphological appearance shows wide vari-ation, but the main feature of all cases is re-duced length of bones with an endochondralgrowth pattern. Some types of chondrodysplas-ia are associated with foetal death and abortion.Others cause semilethal conditions, and severaltypes produce viable but short-legged calves.Chondrodysplasia has been reported in manycattle breeds and at least nine different inheritedtypes have been recorded (135). The aetiologymay be either genetic or non-genetic. The mol-ecular basis for hereditary chondrodysplasia incattle is mostly unresolved, but it is probably

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different for the various types. As the molecularbasis is mostly unsolved, chondrodysplasia isgenerally categorised according to morphology.Although this is a less suitable method, it seemsto be the only way until the molecular basis ofa number of types has been established.

Three morphologically different types ofchondrodysplasia with an established geneticbasis have been recorded in Danish cattle: chon-drodysplasia in the Dexter breed, chondrodys-plasia in the Danish Red Dairy breed relatedto the sire Thy Skov, and chondrodysplasia inDanish Holstein related to the sire Igale Masc.The relation to specific sires (family clusters) isneeded as other types of chondrodysplasiaprobably occur in these breeds. Rasbech (242)claims that chondrodysplasia occurs in allDanish breeds, but no evidence has been pro-vided. A few cases have been examined since1989, but these have been omitted because of anunsolved aetiology.

5.1.1. Chondrodysplasia in the Dexter breedChondrodysplasia in the Dexter breed is a

classic malformation in cattle first reported in1904 (258). It constitutes a prototype for chond-rodysplasia.

Affected calves are aborted, mostly in the 6thto 8th month of gestation. The cows may havehydramnion with associated oedema of thefoetal placenta. The affected foetuses arecharacterised by severe disproportionatedwarfism with prominent shortening of thespine and a compact body. There is a severe dys-plasia of the splanchnocranium with pala-toschisis and doming of the neurocranium,sometimes associated with hydrocephalus. Ex-treme tetramelic shortening of the limbs is seen.Longitudinal sawing of the bones reveals shortdiaphyses with prominent cartilaginous epi-physes. An abdominal defect with eventrationof abdominal organs may be present (Fig. 5) (7,57, 58, 123, 258).

The epiphyses are characterised histologicallyby hyaline cartilage. Distinct epiphyseal growthplates are lacking. Hypertrophied chondrocytesand chondrocyte alignment are irregular and al-most absent. The diaphyses consist of dense, can-cellous bone and compact bone (7, 57, 58, 123).

Inheritance of chondrodysplasia in the Dex-ter breed has been the subject of several studies.Although results have been conflicting, most

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studies have indicated an autosomal dominantinheritance with incomplete penetrance of theheterozygous genotype, maybe influenced byother genes. Aborted chondrodysplastic foe-tuses have a homozygous dominant genotype,while typical short-legged compact Dextercattle have the heterozygous genotype (57, 304,312). Recent genomic analysis of chondrodyspl-astic Australian Dexter cattle has identified amutation (2266insGGca) in the aggrecan geneas the cause of this disorder, although othermutations are present in the gene (51). A genetictest is available for genotyping.

A single case of chondrodysplasia in theDanish Dexter breed has been diagnosed in thestudy period (Fig. 5) (7). However, this disorderhas not been closely monitored and Dexterbreeders have not been contacted separately forsubmission of defective calves. The prevalenceof Dexter chondrodysplasia in Denmark is un-known. The first Dexter cattle were imported in1986 (239) and the breed is a minor breed inDenmark with around 1,000 calvings in 2005.

5.1.2. Chondrodysplasia in the Danish RedDairy breed related to the sire Thy Skov

This type of chondrodysplasia was originallyreported in 1974; four cases were observed in afamilial cluster with the sire Thy Skov(DK28440, born in 1962) as a common ancestor(18). An additional case belonging to the breed-ing line was found in 1992 (7) (Fig. 1).

This defect is characterised as a sublethaltype of chondrodysplasia. Affected calves havebilateral symmetric shortening of the appen-dicular skeleton, mainly of the large bones, withjoint instability and increased width of themetaphyses (Fig. 6). The pelvis and the bonesof the cranial basis are reduced in length. Somecalves have an additional palatoschisis, slighthydrocephalus, or a high interventricular defectin the heart. Only minor histopathologicalchanges are present, mainly consisting of an ir-regular zone of chondrocyte alignment andscanty formation of primary trabeculae (7, 18).

The disorder occurred in a familial patternwith parents of normal phenotype (Fig. 1);findings that are consistent with autosomal re-cessive inheritance. Five heterozygous sires havebeen identified (Appendix 1).

Chondrodysplasia of this type is easily recog-nised by breeders and would probably have

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been reported if it had occurred frequently. Asthis has not happened, it must be assumed thatthis disorder is of low prevalence. However, thedefective allele is probably present in the popu-lation, which may give rise to isolated cases.

5.1.3 Chondrodysplasia in Danish Holsteinrelated to the sire Igale Masc

This specific type of chondrodysplasia wasrecognised in Denmark after the French breed-ing association Sercia France released infor-mation about a defect in progeny of the FrenchHolstein sire Igale Masc (F4493050102, born in1993), which had been used in Denmark. Thedisorder was characterised as chondrodysplasiabased on the examination of four cases inDenmark (VI).

Affected calves were delivered stillborn nearor at term. The body weight was reduced andthe carcasses displayed disproportionatedwarfism with a short and compressed body.The limbs had a bilaterally symmetrical com-pact appearance and a severely reduced length.However, the digits were of almost normal size.The splanchnocranium had severe dysplasiawith palatoschisis, while the neurocranium wasbroad with bilateral exophthalmia and caudaldisplacement of the ears (Fig. 7). Longitudinalsawing of the long bones revealed prominent,non-calcified epiphyses and small irregular di-aphyses, while the vertebrae had extremelyprominent epiphyses, causing spinal cord com-pression. Additional malformations includedumbilical eventration (one case), cardiac hyper-trophy, and pulmonary hypoplasia (VI).

The epiphyseal histopathology was brieflycharacterised by irregular disorganized epiphy-seal plates, which were dominated by hypertro-phied chondrocytes and with almost completeabsence of chondrocyte alignment, while theepiphyses appeared as a homogeneous hyalinecartilage without ossification (VI).

Studies on the inheritance of the defect havenot been published. Genealogical examinationof the Danish cases did not reveal any evidenceregarding the mode of inheritance, but an auto-somal recessive mode of inheritance was a poss-ible explanation for the occurrence of defectiveprogeny (VI). Apparently around 1% of the pro-geny of the sire are malformed. A marker-basedtest, which can test animals related to IgaleMasc, has apparently been developed (136).

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The prevalence of this specific type of chond-rodysplasia in Danish Holsteins is probably lowbecause of the limited number of heterozygoussires used (Appendix 1), and the limited numberof inseminations with semen of these sires.However, the disorder might not be limited tothe Igale Masc family, as a defect with a similarmorphology has been reported in US Holsteins(138).

5.2. COMPLEX VERTEBRALMALFORMATION

The complex vertebral malformation (CVM)syndrome is a congenital lethal malformation,which in late term aborted foetuses and peri-natal calves is characterised by growth retar-dation and bilateral flexure of the carpal andmetacarpophalangeal joints with rotation of thedigits. In addition, most animals have malfor-mation of the vertebrae (∂98%), ribs (∂94%),and arthrogryposis of the tarsal and metatarso-phalangeal joints (∂87%) (Fig. 8). The mor-phology, extent and location of the vertebralmalformations varies between cases, with somehaving few malformed vertebrae, while othershave extensive malformations causing shorten-ing and scoliosis of the spine. Multiple vertebraeof the thoracic spine and posterior part of thecervical spine are misshapen and fused in typi-cal cases (Figs. 9 and 10). A range of other mal-formations has been reported, of which cardiacinterventricular septal defects, possibly com-bined with malformations of the great vesselsand muscular hypertrophy, are the most com-mon (∂53% of cases). The morphological vari-ation of the syndrome has been reported in de-tail (VII).

Analyses of population-based breeding re-sults have demonstrated a significant lack ofcalves born near term, thus indicating frequentintrauterine mortality of homozygous affectedfoetuses (33, 195, 225). Studies of DanishHolstein have shown that the extent of foetalmortality prior to gestation day 260 is approxi-mately 77% (225). This is reflected in a signifi-cantly reduced ratio of CVM-affected calves inbreeding studies (VIII).

CVM occurs in calves genetically related tothe US Holstein sire Penstate Ivanhoe Star(US1441440, born in 1963), often through his

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son Carlin-M Ivanhoe Bell (US1667366). CVMhas only been reported in Holsteins and mostconfirmed cases have been reported fromDenmark (VII). Similar, but genotypically un-confirmed, cases have occurred in the Nether-lands (307, 308). Single cases have been re-ported from the USA (75), United Kingdom(245), Japan (211), and Sweden (33). The fewreports do not reflect the extent to which CVMhas occurred in Holstein cattle. Berglund et al.(33) estimated that 2,200 affected foetuses wereproduced annually between 1995 and 1999 inSweden, while the annual loss in Germany wasestimated to be more than 8,000 foetuses be-tween 1997 and 2000 (160). Similar high figureswere reported from the French region Brittany(195). The defective allele for CVM has beenspread in Holstein populations worldwidethough extensive exploitation of sires that laterturned out to be carriers of the defect. For ex-ample, 13.2% of 957 sires used for inseminationin Germany were diagnosed as carriers of CVM(160), while a prevalence of 31% and 32.5% wasfound in Denmark and Japan, respectively (211,280).

Genomic analysis has identified a single basesubstitution (guanine to thymine) at position559 in the gene SLC35A3 as the cause of CVM.Defective calves have this mutation in both al-leles, thus proving the autosomal recessive na-ture of the disorder. The gene SLC35A3 codesfor a nucleotide-sugar transporter in which thebase mutation is reflected in an amino acid sub-stitution at position 180 (valine to phenylala-nine), thus inhibiting the function of the trans-porter. The nucleotide-sugar transporter playsan essential role in mechanisms controlling theformation of vertebrae from the unsegmentedparaxial mesoderm. Consequently, the defectivetransporter molecule leads to vertebral malfor-mations (280). The genomic analysis hasformed the basis for the development of com-mercially available genotyping tests (31, 150).

Of all the genetic disorders, the CVM syn-drome has probably had the greatest impact onDanish cattle breeding to date. Until 31 De-cember 2005, a total of 544 heterozygous siresused for breeding had been diagnosed (Appen-dix 1) and around 12,000 homozygous affectedfoetuses had been produced (Table 3). The de-velopment of a genotyping test and its strategicuse in selecting breeding sires has effectively re-

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duced the number of affected calves (Fig. 4a)and prevented continued uncontrolled spread ofthe defective allele.

5.3. OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta (OI) is a congenital col-lagenopathy of type I collagen, the most abun-dant and ubiquitous collagen in mammals. Col-lagen type I constitutes an important compo-nent of bone, tendons, ligaments, skin andteeth. The protein is a heterotrimer made of twoa1(I) and one a2(I) chains, which are coded bythe COL1A1 and COL1A2 genes, respectively.The a-chains consist mainly of repeated tripep-tide motifs, which all start with a glycine mol-ecule. This construction is essential for correctformation of the collagen helix structure, butmakes it vulnerable to functional mutations, re-sulting in anomalous chains. Although not allmutations result in abnormal collagen helixstructures, a large number of dominant muta-tions in the COL1A1 and COL1A2 have beenidentified in human cases of OI (59).

OI in cattle is characterised by joint insta-bility due to weakened tendons, ligaments andjoint capsules leading to subluxation or lux-ation. A striking impairment of bone strengthcauses foetal fractures as well as multiple acutefractures in neonatal calves (Figs. 11 and 12).Additionally, the hardness of the dentine is re-duced, predisposing the animals to tooth frac-tures. Reduced strength of skin is not a majorsign in bovine cases. Severely affected calves aregrowth retarded. OI is a lethal disorder (64, 139,277, II). Biochemical changes have been foundin Australian and North American cases, butthe molecular basis has not been identified forany bovine cases (83, 84, 277).

Four familial clusters of OI have been re-ported. Of these, three were in Holsteins in Aus-tralia (64), the USA (277), and Denmark (II),while the fourth cluster occurred in a DanishCharolais herd (139). In addition, an isolatedcase has been reported in a Danish Holstein calf(10).

The bovine clusters of OI have occurred asisolated familial cases. Affected calves havebeen the progeny of a single phenotypically nor-mal sire mated to unrelated normal females andhave occurred with frequencies of 9–50% in the

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herds. Both females and males have beenaffected in equal ratios. Such occurrence doesnot correspond to simple Mendelian inherit-ance, but might be explained by the presenceof a dominant mutation in a certain number ofspermatozoa of the sire, thus displaying testicu-lar mosaicism (64, II). Due to differences in themorphology and biochemistry among cases ofthe four clusters, different mutations of theCOL1A1 or COL1A2 genes are likely to be in-volved.

Sporadic cases of OI are likely to occur inDanish cattle, but the overall prevalence is prob-ably low. Family clusters of OI occur occasion-ally (139, II). So far, these occurrences havebeen in herds using natural breeding. However,if mutations causing OI were to occur in siresused for artificial insemination, considerablenumbers of cases might arise.

5.4. SYNDACTYLISM

Syndactylism (‘‘mulefoot’’) is a congenital mal-formation of the distal parts of one or morelimbs characterised by complete or partial fu-sion or nondivision of the functional digits. Thedisease designation ‘‘syndactylism’’ refers to dis-orders where the digital malformation is theprimary and most important defect. The follow-ing description refers to syndactylism used inthis sense in Holsteins. However, syndactylismalso occurs in other syndromes, such as in thefacial-digital syndrome of Angus cattle, as wellas in other breeds (229, 230).

Syndactylism develops due to fusion or non-division of the foetal anlage of digits III and IV.Horizontal synostosis of the digits may – to agreater or lesser degree – be complete, with syn-ostosis of the second pair of phalangeal bonesas the most common. Additional morpholog-ical abnormalities, such as synostosis, may de-velop in other parts of the distal appendicularskeleton of affected limbs, for example, in meta-carpal/metatarsal bones and carpal/tarsalbones. Concomitant adaptive changes are foundin the muscles, tendons, nerves and vascularsupply of the distal limb (4–6, 102, 124, 186).

Typical cases of syndactylism are externallyrecognised by the presence of a single hoof-likestructure instead of the normally paired claws.A groove may be present in the dorsal midline

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(Fig. 13). The morphological variation reflectsthe underlying skeletal malformation. Thus,cases occur which have a narrow interdigitalcleft and fusion of only the most proximal partof the claw capsules. Such cases may remain un-recognised unless the digits are carefully inspec-ted. Furthermore, genetically affected but clin-ically normal animals are found. The limbs arenot equally affected in diseased animals. Frontlimbs are more frequently affected than hindlimbs, and right legs are more frequentlyaffected than left legs. Both forelimbs are mal-formed in most animals (124, 134, 186).Affected animals are intolerant to high environ-mental temperatures and have developed lethalhyperthermia under experimental conditions(37 æC, 70% humidity) (182).

Syndactylism primarily causes concern in theHolstein breed, but has been recognised in sev-eral cattle breeds (177). The disorder has beena major problem in US Holsteins and has beenspread through export of semen. However,scientific reports of its occurrence outside theUSA are mostly lacking.

The inheritance of syndactylism in Holsteinshas been determined as autosomal recessive bygenealogical examination and breeding studies.However, the genotype has a variable expres-sion, which is reflected in the morphologicalvariation. Furthermore, the penetration of thediseased genotype is reduced, so genetically dis-eased but externally unaffected animals exist(25, 79, 124, 134). Sires have previously beengenotyped by test breeding and progeny exami-nation (124, 140). Initial studies mapped thesyndactyly locus to chromosome 15 (52, 69).Recent studies in Holstein and Angus cattlehave demonstrated several mutations in the lowdensity lipoprotein receptor-related protein 4gene (LRP4) impairing its function in distallimb development (72, 74, 141). Genotyping ofcattle for these mutations is now available andsuch analyses have strongly indicated that theUS Holstein cow Raven Burke Elsie (born 1947)is a common ancestor for a cluster of French,Belgian and US cases of syndactylism (74).

Syndactylism has been known to occur inDanish cattle for more than 150 years. A num-ber of specimens were submitted to the RoyalVeterinary and Agricultural University for in-clusion in the collection of malformations (19–24). The specimen from 1886 had bilateral an-

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terior syndactylism, while the dam had unilat-eral anterior syndactylism, thus indicating aninherited aetiology. Reports of several cases, in-cluding specimens from the collection, havebeen published (42, 237). The breed of these oldcases is unknown. Later, the defect was intro-duced into the Danish Holstein breed by importof semen from the US Holstein sire PineyhillCarnation Star (US1590283, born in 1970) andfurther spread through several of his sons bornin Denmark. Sons and maternal grandsons ofthis sire could only be registered in the Danishherd book if they were bred to at least 30 oftheir own daughters without producing affectedprogeny (238). Other heterozygous sires, includ-ing McCloe-Pond Trent (US17226843, born in1996), have also been used for insemination inDenmark (Appendix 1).

Syndactylism has been diagnosed twice inDenmark in the last 20 years. One case was di-agnosed in 1984 and another in 1989 (223). Thecalves had different sires that were both testedfree of the syndactylism allele by mating to theirown daughters. The genetic basis for these casesis unsolved, and it emphasises that labelling ofsires as carriers based on isolated diseased pro-geny is problematic. Although some cases ofsyndactylism need thorough clinical examina-tion to be diagnosed and might be overlooked,it is expected that typical cases would be recog-nised and reported to the breeding associations.As only very few cases have been reportedthough the last two decades, the prevalence ofsyndactylism in Danish cattle is most probablyvery low.

5.5. ACROTERIASIS

Acroteriasis is a lethal congenital malformationmorphologically characterised by severe facialdysplasia and tetramelic peromelia. Concurrentlesions, such as hydrocephalus and pala-toschisis, are seen. Affected individuals aremostly aborted or stillborn. The disorder is in-herited autosomal recessively as documented bysegregation studies (247, 309).

The defect was originally reported in SwedishHolstein cattle (205, 309) and persisted for sev-eral years (76). The occurrence of this defect inSweden followed importation of the sire GallusM 77 from East Friesland in Germany and in-

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breeding of his descendants. Additional caseswere reported in Holsteins in Holland (100), Is-rael (256), France (172), Germany (247, 314),and the United Kingdom (35). Cases occurringoutside the Netherlands have had Dutch ances-tors.

Details of the occurrence of acroteriasis inDanish Holstein are lacking. Hansen (114) re-ported the occurrence of this defect and statedthat it was introduced by breeding animals. Ras-bech (242, 244) mentions that few cases have oc-curred in Denmark. Information on the numberof affected animals, breeding lines affected, ortheir origin is not available. During the periodwhen reports on acroteriasis were publishedfrom other countries, animals of the Holsteinbreed were imported to Denmark from East

Fig. 5. Chondrodysplasia in the Dexter breed. Abortedfoetus, body weight 4.0 kg (reprinted from 7).Fig. 6. Chondrodysplasia in a one-month-old calf ofthe Danish Red Dairy breed. The calf is geneticallyrelated to the sire Thy Skov.Fig. 7. Chondrodysplasia in a Danish Holstein calfrelated to the sire Igale Masc (reprinted from VI; JVet Diagn Invest 2004;16:293–8 with permission fromthe American Association of Veterinary LaboratoryDiagnosticians).Fig. 8. Complex vertebral malformation in a DanishHolstein calf. Note the short neck and arthrogry-posis of the distal joints (reprinted from V; J Vet Di-agn Invest 2001;13:283–9 with permission from theAmerican Association of Veterinary Laboratory Di-agnosticians).Fig. 9. Malformation of the thoracic vertebrae in acase of complex vertebral malformation in a DanishHolstein calf (reprinted from V; J Vet Diagn Invest2001;13:283–9 with permission from the AmericanAssociation of Veterinary Laboratory Diagnos-ticians).Fig. 10. Radiograph showing malformation of ver-tebrae at the cervicothoracic junction, scoliosis andsynostosis of the proximal part of several ribs in acase of complex vertebral malformation. DanishHolstein calf (reprinted from V; J Vet Diagn Invest2001;13:283–9 with permission from the AmericanAssociation of Veterinary Laboratory Diagnos-ticians).Fig. 11. Osteogenesis imperfecta in a neonatal DanishHolstein calf. Note the severe joint laxity and dimin-ished growth (reprinted from II, J Vet Med A1994;41:128–38).Fig. 12. Acute fracture of the left metatarsus in a caseof osteogenesis imperfecta in a Danish Holstein calf(reprinted from II, J Vet Med A 1994;41:128–38).

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Friesland (Germany), West Friesland (Hol-land), and southern parts of Sweden (299). Thegene for acroteriasis might have been intro-duced by one or more of these imports. At pres-ent, the prevalence of acroteriasis in DanishHolsteins is probably low. No cases were recog-nised between 1989 and 2005.

5.6. CONGENITAL PARALYSIS

Congenital paralysis in calves of the Danish RedDairy breed was originally reported by Løje in1930 (192), but cases had occurred as early as1924 (217). The disorder is characterised bycongenital non-progressive lateral recumbency.Neurological dysfunction is limited to the hindlimbs, which exhibit bilateral spastic extension.Affected calves are able to rise to the sternalposition and are able to walk a few metres byuse of their front limbs if supported by elevationof their hindquarters. The calves mostly die dueto secondary infections, but may survive forsome months if carefully nursed (54, 217). Thereis discrepancy regarding the pathology of thedisorder. Six cases were examined at the RoyalVeterinary and Agricultural University in Cop-enhagen, Denmark, by veterinary pathologistsI. P. Sjolte and A. F. Følger, who were unableto identify any neuropathological changes(217). However, Christensen and Christensen(54) found neuronal atrophy and necrosis in theglobus pallidus and in the reticular substanceof the brain stem, medulla oblongata, and thecervical spinal cord of three calves, two of whichwere around 4-months old.

Extensive research into the inheritance andoccurrence of congenital paralysis was per-formed from 1938 to 1948, and was publishedas a dissertation (217). Segregation studies dem-onstrated that congenital paralysis in theDanish Red Dairy breed was inherited auto-somal recessively.

The sire Tjalfe Kristoffer (DK1343, born in1913) was identified as the original source of thedisease-causing allele (192, 217). Many sires, in-cluding elite sires such as Højager (DK2168)and Højager Nakke (DK2400), were identifiedas carriers of the defect as well and during the1940s the estimated prevalence of heterozygoteswas around 20% among elite sires and 15% inthe general female population (217).

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The current prevalence of congenital paral-ysis in the Danish Red Dairy breed is probablylow. A search for inherited congenital neuro-logical disorders in this breed was performedduring the 1990s when the familial occurrenceof spinal muscular atrophy and spinal dysmyel-ination was determined. Almost 500 calves werenecropsied during this period (Table 1), and nocases with lesions similar to those reported byChristensen and Christensen (54) were detected.As clinical signs of congenital paralysis andspinal dysmyelination are considered to be in-distinguishable by inexperienced observers, it isassumed that cases would probably have beenfound if the disorder had been common.

5.7. BOVINE PROGRESSIVEDEGENERATIVE

MYELOENCEPHALOPATHY

Bovine progressive degenerative myeloencephal-opathy (BPDME) (‘‘weaver syndrome’’) is aneurodegenerative disorder, which was initiallyreported in purebred Brown Swiss cattle in theUSA in 1973 (184). However, cases probably oc-curred already in the late 1950s (269).

The disorder is characterised by progressivehind limb weakness, ataxia, and dysmetria de-veloping in calves aged 5 to 8 months. Otherneurological abnormalities are absent. Pro-gression occurs during the following monthsand severe ataxia and markedly diminished pro-prioceptive reflexes have mostly developed in1.5- to 2-year-old animals. The speed of diseaseprogression varies between cases, but recum-bency is manifest before 4 years of age. Pro-gressive muscular atrophy develops and termin-ally affected animals must be euthanised or theywill die due to tympany or infections. Clinicalcases are mostly found in females as males areoften slaughtered before severe clinical signshave developed (68, 233, 270).

Significant gross lesions are absent andneuropathological changes are non-specific.Microscopic lesions are mainly confined to thespinal cord white matter and consist of de-generation and loss of axons and myelin (Wall-erian-like degeneration). Lesions are most con-sistent and pronounced in the thoracic spinalcord, but not confined to specific fasciculi. Oc-casionally, swollen brain stem axons or degener-

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ated or necrotic Purkinje cells of the cerebellarcortex are found (271). Ultrastructural, histo-chemical, and electrophysiological studies havedemonstrated a variety of changes in brain, pe-ripheral nerves, neuromuscular junctions, andmuscles (12, 27, 80, 232, 234, 235, 288). It hasbeen proposed that the neurological lesions aredue to a dying back process, which may befounded in a metabolic defect of enzyme sys-tems involved in energy production or normalintegrity of the nerve cell body and its processes(234).

BPDME occurs in familial patterns consist-ent with autosomal recessive inheritance (27,269). This mode of inheritance has been con-firmed by microsatellite mapping. The locus forBPDME is closely linked to the locus for themicrosatellite marker TGLA116, which makesgenotyping possible (97).

BPDME has been reported in purebredBrown Swiss cattle or their crossbreds in theUSA (184), Switzerland (45), Canada (27), Italy(29) and Germany (68). The disorder has alsobeen recorded in the Danish Red Dairy breedfollowing crossbreeding with American BrownSwiss cattle (10)*

The gene for BPDME was introduced intothe Danish Red Dairy cattle population by im-port of semen from the USA. The defect hasbeen recorded in three breeding lines originatingfrom the sires Nakota Destiny Dapper(US148460, born in 1965), Norvic Larry’s Lila-son (US131528, born in 1957) and Rolley ViewModern Strech (US156458, born in 1969), re-spectively (7). A list of sires labelled with thisdisorder in Denmark is given in Appendix 1.

Four clinically suspected cases were examinedfrom 1989 to 1991. One of these was diagnosedas affected (10). Suspected cases have not beenrecorded since then. Passive surveillance inDenmark is probably ineffective and cases mayhave remained unrecognised as it is difficult todiagnose clinically. However, the disorder is

* Several authors refer to a publication by Hansen(116) as the first description of BPDME inDenmark. However, this publication is a reviewsolely presenting US cases. K.M. Hansen did, infact, diagnose the first case in Denmark and afterthis several cases of the disorder, though the resultsremained unpublished.

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considered to be of low prevalence on accountof breeding measures taken following its identi-fication in the 1980s.

5.8. SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy (SMA) is a neurode-generative disease belonging to the group oflower motor neuron diseases (199). The defec-tive gene causing this disease was imported toDenmark through semen of American BrownSwiss sires and subsequently spread in thepopulation of Danish Red Dairy cattle (121).

The disease affects calves up to 21 weeks ofage, but most cases are found in calves aged 4to 8 weeks. The age at disease initiation is diffi-cult to determine and the speed of progressionvaries. The disorder is congenital in around 10%of cases. The clinical signs are dominated byprogressive muscular weakness leading to re-cumbency and finally death. Muscular atrophydevelops and is especially conspicuous in thehind limbs (Figs. 14 and 15). Most calves sufferfrom bronchopneumonia, possibly as a sequelto aspiration, and lesions associated with re-cumbency, including decubital lesions andchemically induced dermatitis on the ventralabdomen in male calves (8, 81, 267, 294).

Characteristic histological lesions are foundin ventral horn motor neurons of the spinalcord. Lesions are present in all segments, butare generally most severe in the lumbar intumes-cence. The neurons display a progressive de-generation, which is initially characterised byswollen chromatolytic neurons that become suc-cessively necrotic. Finally, neuronophagia oc-curs and the neurons disappear leaving ‘‘emptybeds’’. Focal as well as more widespread micro-gliosis is seen in the ventral horn grey matter(Fig. 16) (8, 81, 267). The cytoskeleton of theneurons disintegrates through this process (131,132). Wallerian-type degeneration of axonswithin the spinal cord white matter, radix ven-tralis and peripheral nerves, briefly character-ised by axonal swelling, loss of axons, infil-tration by macrophages and distension of my-elin sheets, is seen (8, 267, 293). Although SMAis mainly characterised by lower motor neuronpathology, upper motor neuron degenerationhas been found as well (293). Progressive devel-opment of denervation atrophy of the skeletal

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muscles follows the advancing neuronal loss(Fig. 17).

SMA has been found in American BrownSwiss in the USA (81, 293), as well as in severalnational European breeds upgraded withAmerican Brown Swiss. SMA has been diag-nosed in Denmark (7, 121), Germany (66),Switzerland (267), and Austria (305). The firstcase was diagnosed retrospectively in 1980 inthe USA (294). Pedigree information has beenprovided for the Austrian, Danish, and Swisscases, revealing a clear familial pattern with theAmerican Brown Swiss sire Meadow View Des-tiny (US118619, born 1953) as the common an-cestor. A single sire of the Danish Red Dairybreed (VAR Vit-R, DK31894) apparently notgenetically associated with Meadow View Des-tiny has been identified. This might reflect thepresence of another affected breeding line, phe-nocopies or be due to erroneous pedigree regis-trations. Pedigrees of the American cases havenot been published in the scientific literature.

SMA occurs in a familial pattern consistentwith autosomal recessive inheritance. This modeof inheritance has been confirmed by breedingstudies (224). Recent molecular studies havestrongly indicated that a missense mutation inthe gene FVT1, coding for 3-ketodihydrosphin-gosine reductase, is the cause of SMA. This en-zyme has housekeeping functions related tosphingolipid metabolism and is crucial for neur-onal development and function. The missensemutation lowers the enzymatic activity of 3–ke-todihydrosphingosine reductase to a level insuf-ficient for survival of ventral horn motor neu-rons, which are selectively affected because oftheir high metabolic rate and extensive trans-port processes along the axons (163). Identifi-cation of the molecular cause for SMA providesthe basis for development of genotyping tests.

SMA was a relatively common disorder in theDanish Red Dairy breed from around 1987 to1995 (Fig. 4d), with an estimated number ofaffected calves of approximately 1,800 (Table 3).The prevalence of the disorder was reduced byextensive pathological examination of calveswith neurological disorders (Table 1) and cull-ing of heterozygous sires (Appendix 1). Thespread of the defective allele was especially dueto the use of heterozygotes, such as MRS Abru(DK81137), RGK Focus (DK81284), Ka-WaWestley (DK32188), and HV Hydro

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(DK32960). The prevalence of SMA in theDanish Red Dairy breed is at present assumedto be low, though this cannot be proved as sur-veillance of calves with neurological disordersbased on necropsy has been declining in recentyears (Table 1) and surveillance based on clin-ical recognition of SMA is unreliable. The re-cent success in molecular characterisation of thedisease should be use to genotype the sire popu-lation.

5.9. SPINAL DYSMYELINATION

Spinal dysmyelination (SD) is a lethal congeni-tal neurological disorder of crossbred AmericanBrown Swiss calves. This disorder was intro-duced into the Danish Red Dairy breed becauseof crossbreeding with American Brown Swiss.

Affected animals show congenital recum-bency, often in a lateral position with opistho-tonos and bilateral symmetric extension of thelimbs (Fig. 18). The head and front limbs havea normal position, but the hind limbs are stillextended if the calves are placed in the sternalposition. Efforts of limb movement and supportare absent when calves are raised manually (Fig.19). Reflexes are either normal or increased. Thecalves are alert until they become debilitateddue to infections (268, III).

Gross lesions are generally absent at nec-ropsy, but some calves may have muscular atro-phy, and the cervical and thoracic spinal cordsegments might seem decreased in size on trans-verse section. Characteristic histological lesionsare present in the gracile funiculus, dorsolateralspinocerebellar tract and the sulcomarginaltract, and consist of bilateral symmetric hypo-and demyelination (dysmyelination) with astro-cytosis, oligodendrocyte necrosis and axonal de-generation (Fig. 20). These lesions are recognis-able until lumbar segment 1, where the charac-teristic dysmyelination of the gracile funiculusdisappears. The tract-associated lesions are nolonger recognisable posterior to lumbar seg-ment 4. Occasionally, a few neurons with centralchromatolysis and swollen axons are seen in thebrain stem. Variable degrees of denervationatrophy may be present in the skeletal muscu-lature (109, III).

SD has been reported in crossbred cattle inGermany (109), Denmark (III), and Switzer-

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land (268). A single case has been diagnosed inthe USA (265).

Cases reported from Germany, Switzerlandand Denmark occur in a familial pattern withthe American Brown Swiss sire White Cloud Ja-sons Elegant (US148551, born in 1966) as thecommon ancestor. Cases in Denmark have oc-curred in a familial pattern consistent withautosomal recessive inheritance (III), and segre-gation ratios consistent with this mode of in-heritance have been found in a breeding study(IV). Genomic analyses have identified the de-fective allele to bovine chromosome 11 in a re-gion flanked by markers BP38 and BMS2569,and a marker-based test for genotyping is avail-able (226). As the lesions reflect an impaired oli-godendrocyte function and maturation (109), acandidate gene should be associated with thesefunctions.

A considerable number of cases occurred inthe Danish Red Dairy breed during the 1990s(Table 3, Fig. 4e) mainly due to sires related totwo sons of White Cloud Jasons Elegant: Ka-WaBalison (US172466) (sire B in III) and Prospect(US173809) (sire C in III). Fifty-seven sires wereidentified as carriers of the defect (Appendix 1).The number of cases was reduced significantlyat the end of the period although the detectionof carriers based on progeny examination wasineffective (Table 2). Although the prevalence ofSD in the Danish Red Dairy breed is probablylow, a significant decline in the number of neo-natal calves suffering from congenital neuro-logical disorders submitted for necropsy in re-cent years (Table 1) has reduced the likelihoodof detection of cases of SD.

5.10. SYNDROME OF ARTHROGRYPOSISAND PALATOSCHISIS

The syndrome of arthrogryposis and pala-toschisis (SAP) is a congenital malformation ofCharolais calves. Affected calves are born atterm but most calves are stillborn or die shortlyafter birth, probably due to respiratory failure.Live born calves have muscular hypotonia(251).

The full morphological variation of this syn-drome is not known. The existence of genetic-ally affected but phenotypically normal ani-mals, and viable slightly affected animals, has

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been postulated (32, 99, 173, 174, 260). Further-more, arthrogryposis and palatoschisis as twoindependent lesions, or in combination, arecommonly recognised in calves (101). Whensuch lesions appear in Charolais calves, it maybe difficult to distinguish SAP from other syn-dromes (181). Typical cases of the syndrome aremorphologically characterised by tetramelic bi-laterally symmetrical arthrogryposis and pala-toschisis (Figs. 21 and 22). A detailed descrip-tion of joint involvement has been published(251). Briefly, flexion of the forelimbs, particu-larly due to flexion of the metacarpophalangealjoints and the carpus, rotation of the digits, andhyperextension of the metatarsophalangealjoints are found, but most joints of the appen-dicular skeleton may show flexion or extension.The extent to which each joint is affected variesconsiderably between cases. Malformation ofthe spine (scoliosis or kyphosis) is found insome cases. Skeletal muscles may be hypotroph-ic or partly replaced by adipose tissue (lipoma-tosis). Lesions in the central nervous system insome cases include cervical hydromyelia andsyringomyelia (137, 178, 251). The basic mech-anisms of this syndrome are not known, but itmay be associated with a disturbed differen-tiation of the central nervous system causing anabnormal stimulation of the lower motor neu-rons. Consequently, an unbalanced muscle tonecould develop, which could subsequently causearthrogryposis (250, 251).

SAP was originally reported in Charolaiscattle in France (171), but was later recognisedin Canada (181), the USA (178), Australia(125), Belgium (122), the United Kingdom (137,190), and Denmark (10). The widespread occur-rence of this syndrome is probably due to ex-port of carriers from France (170).

It is generally accepted that the syndrome isinherited in an autosomal recessive mannerbased on patterns of familial occurrence andsegregation ratios between affected and unaf-fected progeny in Canadian Charolais (214,251). However, different observations regardingthe penetration of the homozygous affectedgenotype have been made. Complete penetra-tion of the affected genotype was observed inone study (214). Other researchers (32, 99, 174)found reduced penetration and proposed theexistence of genetically affected but phenotypic-ally normal individuals. Furthermore, a vari-

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ation in expression of the diseased genotype hasbeen proposed by Lauvergne (170), who claimedthat 30% of the cases have arthrogryposis with-out concomitant palatoschisis. Candidate genesfor SAP have been identified based on compara-tive physiological studies, but need to be exam-ined more closely (73).

Due to uncertainty regarding the morpholog-ical appearance of affected calves, a stringentdiagnostic strategy has been applied in Den-mark based on diagnostic criteria of tetramelic,bilateral symmetric arthrogryposis and pala-toschisis. A single case was diagnosed in 1989in a calf of unregistered descent (Figs. 21 and22) (10). Very few malformed Charolais calveswere necropsied from 1989 to 2005, and therehas been no specific search for the disorder. Theprevalence of the syndrome in Denmark is un-known, but is believed to be low.

5.11. ICHTHYOSIS FOETALIS

Ichthyosis foetalis (IF) is an ectodermal dys-plasia, originally reported in Danish cattle bySand (252). This lethal subtype of ichthyosis ischaracterised by the presence of hyperkeratoticepidermal plates of various sizes covering theentire body and enclosed by inflamed fissures.The presence of coat varies between cases. Ich-thyosis in animals was reviewed by Baker andWard (28) and Huston et al. (135), and ad-ditional cases have recently been published(241).

IF is generally referred to as an autosomalrecessively inherited malformation. This ismainly based on a study by Tuff and Gleditsch(295) in Norwegian Red Poll cattle, demonstrat-ing a familial occurrence following breeding be-tween unaffected cattle and a segregation ratiocorresponding to this mode of inheritance. Lüps(191) reported a familial occurrence of cases inGerman Pinzgauer cattle consistent with auto-somal recessive inheritance. Other cases havemainly been reported as individual cases, omit-ting determination of inheritance. Extrapol-ation from the studies in Norwegian Red Pollcattle and German Pinzgauer cattle to otherbreeds is not advised, as although these casesmay share a common morphology, a differentmolecular basis may mean they have differentmodes of inheritance.

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IF has been observed in two Danish cattlebreeds. According to Rasbech (242), the originalcase (252) was in the Danish Red Dairy breedand a few additional cases were seen in thisbreed and in Danish Holsteins. The exact diag-noses can be questioned, but according to thedescription of the original case, an illustrationpublished by Rasbech (242, 244), and a speci-men seen in the former collection of malfor-mations at the Royal Veterinary and Agricul-tural University in Copenhagen, these casesmost likely suffered from IF.

Cases have not been diagnosed during thisstudy period, and the prevalence in Danishcattle is apparently very low.

Fig. 13. Syndactylism of the anterior limbs in aDanish Holstein calf (reprinted from 223; Dansk VetTidsskr 1990;73:699–701.).Fig. 14. Spinal muscular atrophy in a four-week-oldcrossbred Danish Red Dairy/American Brown Swisscalf. Note the severe atrophy of skeletal muscles andthe bilateral flexion of the anterior distal joints.Fig. 15. Spinal muscular atrophy. Same calf as in Fig.14.Fig. 16. Photomicrograph of the spinal cord ventralgrey matter in a case of spinal muscular atrophy. Anormal neuron (A) is surrounded by two necroticneurons (B) and a chromatolytic neuron (C). Cross-bred Danish Red Dairy/American Brown Swiss calf.Haematoxylin and eosin. BarΩ50 mm.Fig. 17. Photomicrograph of skeletal musculature(musculus semitendinosus) in a case of spinal muscu-lar atrophy. Denervation atrophy characterized bygroups of atrophic fibers and groups of hypertrophicor normal sized fibers. Crossbred Danish Red Dairy/American Brown Swiss calf. Haematoxylin andeosin. BarΩ30 mm.Fig. 18. Spinal dysmyelination in a neonatal cross-bred Danish Red Dairy/American Brown Swiss calf.Note the lateral recumbency, opistothonus and ex-tended hind limbs.Fig. 19. Spinal dysmyelination. Note the absence ofsupport to the body. Same calf as in Fig. 18.Fig. 20. Photomicrograph of the cervical spinal cordin a case of bovine spinal dysmyelination. Note thesymmetric dysmyelination of the gracile funiculus(↓), dorsolateral spinocerebellar tract (») and sulco-marginal tract (↑). Crossbred Danish Red Dairy/American Brown Swiss calf. Luxol fast blue.

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5.12. EPITHELIOGENESIS IMPERFECTA

Epitheliogenesis imperfecta (EI) is a congenitalmalformation characterised by local agenesia ofthe skin. Several types of this disorder areknown (135). The classic form (type 1) is lethaland characterised by lack of skin on the distalparts of the limbs, deformed ears due to auricu-lar epithelial defects, defects in the integumentof the muzzle, and a defective oral epithelium(Figs. 23 and 24). The basic defect may be as-sociated with defective metabolism of fibro-blasts impairing the nutrition of the epithelium(93).

EI type 1 has mainly been reported in Holste-ins (135). Familial occurrence following breedingbetween unaffected parents indicates that somecases are due to an autosomal recessive gene, al-though segregation ratios between affected andunaffected calves differ from expected ratios(107, 108, 135, 179). The inheritance of recentcases in Holsteins is unsolved (60, 311).

Documentation of the occurrence of EI inDanish cattle is insufficient to draw definitiveconclusions. Rasbech (242, 244) claims that afew sporadic cases have been observed, prob-ably in Danish Holsteins and in the Danish RedDairy breed. A case resembling EI type 1 in acalf of the Danish Red Dairy breed has beenphotodocumented by K. M. Hansen (in 242,244). In 1991, EI type 1 was diagnosed in a fe-male Hereford calf originating from a smallherd (Figs. 23 and 24) (7, 10). In addition to thetypical lesions present in the distal parts of thelimbs, the muzzle, nostrils, and oral cavity,lesions were also found at the base of the earand the teats. The ears were not malformed.The calf was the result of natural breeding be-tween unaffected related parents, which is con-sistent with autosomal recessive inheritance, butno definitive conclusion could be reached asonly one affected animal was born in the herd.Additional cases have not been submitted dur-ing the study period, and the prevalence of EItype 1 in Danish cattle is probably low.

5.13. HEREDITARY ZINC DEFICIENCY

Hereditary zinc deficiency (HZD) in Holsteinswas originally reported from Scotland, wherethe disorder had occurred since at least 1951

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(203). However, little attention was paid to thedisorder until the 1970s when it was suddenlyreported in national Holstein populations inseveral European countries, including Denmark(16, 103), Holland (297), Germany (272, 273,282), and Italy (96 – referred in 272). Additionalcases were reported in the 1980s from Ireland(200), the United Kingdom (78, 228), andFrance (254).

Several names have been proposed for thisdisorder. Lethal trait A46 was used by Andresenet al. (16) referring to the nomenclature orig-inally proposed by Lerner (187). Adema diseasewas proposed by Grønborg-Pedersen (103) andreferred to a carrier of the defect, the DanishHolstein sire Hornshøj Adema (DK8177). Des-ignations referring to lesions observed inaffected calves, such as parakeratosis and thy-mic hypoplasia, have been used by others (48,272). The term ‘‘hereditary zinc deficiency’’ re-fers to a fundamental aspect of this disorderand has been used in recent publications (193,276).

HZD is caused by impaired intestinal zinc ab-sorption (85–87) due to abnormal function ofa protein belonging to a family of zinc-uptakeproteins. The molecular basis is a single nucle-otide substitution in the gene SLC39A4 (313).In acrodermatitis enteropathica, a human ana-logue of bovine HZD (50, 303), defects in thegene SLC39A4 have also been identified (166,300).

Affected animals can be reconstituted by con-tinuous administration of supplementary zincgiven at high doses (48, 164, 272, 297). As zincis absorbed by passive diffusion and by a car-rier-mediated process (130, 264), the increasinglevels of zinc in the blood of treated calves maybe due to passive diffusion across the intestinalbarrier.

Zinc is an essential trace element. It has astructural role in tissues such as bone, teeth,muscle, and integument, and is involved in themetabolism of proteins, nucleic acids, andcarbohydrates through its role as an essentialpart of many metalloenzymes or as an enzy-matic cofactor (127, 168). Calves are born withnormal levels of zinc, as they are nourishedthrough the placenta during intrauterine devel-opment. Serum concentration of zinc decreasesduring the first weeks of life and precedes devel-opment of lesions and clinical signs. Diarrhoea,

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probably due to disturbed turnover of en-terocytes and deficiency of functional intestinalenzymes, develops prior to other symptoms(193). Well-developed lesions are mainly charac-terised by parakeratosis and dermatitis, and oc-cur in areas of continual skin flexion or in re-gions particularly subjected to abrasion. Hence,lesions are most extensive around the mouth,eyes, base of the ear, joints, and lower parts ofthe thorax, abdomen and limbs (Figs. 25 and26). Parakeratosis and ulceration of the non-glandular part of the intestinal tract occurs andis mostly expressed clinically as stomatitis.Diminished eating ability and growth retar-dation occur (193, 272, 282). Thymus, lymphnodes, and gut-associated lymphoid tissue arehypoplastic, and affected calves are immuno-suppressed due to impaired function of the im-mune system (49, 236). Animals often developbronchopneumonia. Lesions are progressiveand, if left untreated, calves die within 4 to 8weeks after initial symptoms are observed (46,47).

The genetic aetiology of the disorder was pro-posed by McPherson et al. (203), who recog-nised that cases occurred following inbreedingand were segregated in a manner similar to anautosomal recessively inherited defect. Thismode of inheritance was proven by additionalsegregation studies (16, 17). Most reportedcases are of Dutch Holstein origin and genea-logical studies have traced the origin of the dis-ease-causing allele to the Dutch Holstein sireEgbert N.R.S. 13110 (born 1932) (164).

Thirty-five sires used for insemination inDenmark have been diagnosed as carriers ofHZD based on progeny examination (Appendix1). These sires have not been used for at leastthe past 20 years. Pedigree analysis has demon-strated that 28 of the heterozygous sires are gen-etically related to Egbert N.R.S. 13110, whilethe pedigree of the remaining seven sires is in-complete. The prevalence of calves sufferingfrom HZD has been reduced since the 1970s.Bauer et al. (30) state that only one calf wasincluded in their study due to lack of affectedcalves, and Agerholm (7) diagnosed only fourcases, all of which occurred in a single herd dueto inbreeding between a sire (Moesgård Chapel,DK224785) and closely related females. Atpresent, the prevalence of HZD in Danish Hol-steins is probably low.

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5.14. RENAL LIPOFUSCINOSIS

Renal lipofuscinosis (RL), which is also referredto as ‘‘black kidneys’’, is a disorder character-ised by cytoplasmic accumulation of the pig-ment lipofuscin in the renal tubular system, pre-dominantly in the proximal tubular epithelium.Macroscopically, the kidneys have a bilateraldiffuse brown to black discoloration of the cor-tex (Fig. 27) and outer strip of the outer me-dulla. The disorder is mostly diagnosed in cattleaged 3 years or older. The disorder is apparentlynot associated with clinical disease and is gener-ally not diagnosed before slaughter. However,the culling rate differs from that of unaffectedcattle; thus, indicating an adverse effect onhealth or production (X).

Epidemiological studies (X) have shown thatRL occurs in Danish Holsteins and Danish RedDairy cattle and crossbreds, involving at leastone of these breeds, but apparently not in othercattle breeds in Denmark. Cases are recognisedin family clusters and statistical analysesstrongly indicate an autosomal recessive modeof inheritance.

There is a high prevalence of RL in DanishHolsteins and in the Danish Red Dairy breed.The incidence of the disorder in slaughter cattleaged 3 years or older has been calculated to be0.44% and 2.51% for Danish Holsteins and theDanish Red Dairy Breed, respectively (X).

5.15. HEREDITARY DILATEDCARDIOMYOPATHY

Hereditary dilated cardiomyopathy (HDC) is adisease of adult cattle of Canadian Holstein ori-gin. Affected animals are mostly around 3 yearsold, but variation from 2 months to 8.5 years isseen. Disease progression is subclinical, butonce clinical signs have developed, there is rapiddeterioration due to progressive cardiac insuf-ficiency. Signs include severe subcutaneousoedema located ventrally on the body and be-tween the mandibles, ascites and hydrothorax.These symptoms are consistent with right-sidedheart failure. At necropsy, cardiac lesions arecharacterised by diffuse induration of the myo-cardium, cardiomegaly, and dilatation of allcompartments. Lesions due to chronic stasisand hypertension are present macroscopically

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and microscopically in several tissues. Myocar-dial histopathology is characterised by inter-stitial fibrosis, myocyte necrosis, myofibrehypertrophy, and myocyte vacuolation (94, 197,212, 213, 281).

HDC was originally reported from Switzer-land, where the disorder became endemic (197).In addition, cases have been reported from Ja-pan (262), Canada (26), Australia (202), theUnited Kingdom (43, 44, 212), Germany (165),Austria (62) and Denmark (IX).

HDC is likely to be inherited autosomal re-cessively as cases have been reported in familialpatterns consistent with this mode of inherit-ance (26, 94, 253, IX) and breeding studies havedemonstrated the expected segregation ratios(67). Recent studies have shown that the locusfor HDC is located on chromosome 18 (106)When details of genealogy were provided, a gen-etic relationship to the Canadian Holstein sireMontvic Rag Apple Sovereign (CAN155159)born in 1942 or his son A B C Reflection Sover-eign (CAN198998) was found (94, 198, IX). Inmost scientific publications, sires have been re-ferred to by coded names, thus preventing anydetailed insight into the familial occurrence ofthe disorder. However, detailed pedigrees ofDanish cases of HDC have been published (IX).

HDC has been reported in Holsteins and RedHolsteins, as well as in national crossbreeds (62,165, 281). In Denmark, the disorder has beenobserved in the Danish Red Dairy breed, RedHolstein breed and Holstein breed (IX). Thedisorder may have been present in the DanishRed Dairy breed since the 1960s. Five cases ofmyocardial fibrosis were reported in 1964 (110,220). A retrospective examination of archivedmaterials from these cases has demonstratedhistopathological changes consistent with HDC(IX). A genetic basis for this disorder was ap-parently not considered in the original studies.

The prevalence of HDC in Danish cattle isunknown. Fourteen cases were diagnosed dur-ing a 13-year period (1991–2003) (IX). Ad-ditional cases have not been diagnosed sincethen, thus indicating a low prevalence. However,this is most likely erroneous. The diagnosedcases consisted mainly of animals referred to theRoyal Veterinary and Agricultural University inCopenhagen. As animals are mainly referred tothe University from the eastern part ofDenmark, where cattle density is low, the figures

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only reflected a subpopulation of Danish cattle.Furthermore, an estimate of the number ofcases based on pedigree information of onlythese 14 cases revealed that almost 150 caseshad probably appeared (Table 3). As the esti-mate was based on animals acquired almost for-tuitously and mainly from a subpopulation, thereal number of cases may be considerablyhigher. The high number of Danish Red Dairycattle diagnosed with HDC might reflect thatthis breed is most prevalent in eastern Denmarkrather than a higher prevalence of the disorderin this breed than in Danish Holsteins and RedHolsteins. A search for clinical cases was in-itiated in 1994 through a publication in thejournal of the Danish Veterinary Medical As-sociation (175). Only one clinical case, whichturned out to suffer from endocarditis, was re-ferred to the authors. There has been no activesearch for cases since then.

5.16. BOVINE LEUKOCYTE ADHESIONDEFICIENCY

Bovine leukocyte adhesion deficiency (BLAD)is an immunological defect due to a molecularaberration in CD18. CD18 constitutes a part(b-subunit) of the CD11/CD18 glycoproteincomplex located on the surface of neutrophils.Consequently, the three subtypes of CD11/

Fig. 21. Syndrome of arthrogryposis and palatoschisisin a Danish Charolais calf. Note the tetramelic bilat-eral symmetric arthrogryposis (reprinted from 7).Fig. 22. Palatoschisis in the syndrome of arthrogry-posis and palatoschisis. Same calf as in Fig. 21 (re-printed from 7).Fig. 23. Epitheliogenesis imperfecta. Note the ab-sence of epithelium in the distal parts of the limbs,seperation and loss of claw capsules and intense in-flammation of the corium. All four limbs wereaffected to an equal degree. Hereford calf (reprintedfrom 10; Acta Vet Scand 1993;34:245–53).Fig. 24. Epitheliogenesis imperfecta. Extensive loss ofepithelium in the tongue exposing acutely inflamedsubepithelial tissue. Same animal as in Fig. 23.Fig. 25. Hereditary zinc deficiency. Extensive paraker-atosis around the muzzle and the eyes. DanishHolstein. Courtesy of T Flagstad.Fig. 26. Hereditary zinc deficiency. Parakeratosis,dermatitis and alopecia on the distal part of thelimbs. Danish Holstein. Courtesy of T Flagstad.

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CD18 (CD11a/CD18, CD11b/CD18 andCD11c/CD18) are functionally deficient. Theseglycoproteins play an important role in the in-flammatory response to infections as they inter-act with receptors on the vascular endothelium,thus making adhesion between neutrophils andendothelium possible. Such adhesion is mostlya prerequisite for extravascular migration ofneutrophils, and affected individuals thereforelack extravascular neutrophils in most tissues.In addition, functional defects in neutrophilshave been recorded (209). Consequently, suchindividuals are predisposed to recurrent andprolonged mucosal and epithelial infections(155–157, 210).

BLAD is lethal for most calves within oneyear, but individuals may live longer if managedwell and treated properly for infections (3). Theanimals display signs of immunodeficiency, butthe appearance of affected animals varies. Acommon finding is a total leukocyte number ofmore than 40¿109 cells per L blood, but oftenconsiderably higher. The leukocytes are pre-dominantly neutrophils (�80%) (98). Thehaematological changes in combination withstunted growth may be the only clinical sign ofBLAD, at least at certain stages of disease de-velopment (Fig. 28) (I). BLAD-affected calvescontract a range of opportunistic bacterial andfungal infections, and a wide range of lesionsmay consequently be seen. Widespread ulcer-ative and necrotising stomatitis with peri-odontitis, loss of teeth, and alveolar periostitisare frequent lesions in the oral cavity. Extensivedermatophytosis may occur (Figs. 29 and 30).Multifocal chronic ulcerative and necrotisingenteritis, rhinitis and suppurative broncho-pneumonia are frequent additional necropsyfindings. The inflammatory response in the ali-mentary tract, upper respiratory system andskin is characterised by granulomatous in-flammation and a striking absence of infiltrat-ing neutrophils despite their huge intravascularpresence. Granulation tissue is often present dueto the chronic stage of inflammation. In con-trast to these lesions, pathological changes inthe lung are dominated by suppuration to thealveoli as migration across the blood-air barrieris CD11/CD18 independent (1–3, 95, 98, 129,207, 210, 231, 255, 274, 275, I).

BLAD is inherited in an autosomal recessivemanner and occurs in a clear familial pattern.

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The disease is due to a single base substitutionof adenine with guanine at nucleotide 383 in theCD18 gene (ITGB2), which subsequently leadsto replacement of aspartic acid with glycine atposition 128 in the corresponding protein(D128G). The molecular studies have made gen-otyping of animals possible and the USHolstein sire Osborndale Ivanhoe (US1189870,born 1952) has been identified as the commonancestor (259).

The defective allele for BLAD has been spreadto many Holstein populations through wide-spread use of semen of sires genetically related toOsborndale Ivanhoe, i.e. Penstate Ivanhoe Star(US1441440), Ugela Bell (US1920807), and Car-lin-M Ivanhoe Bell (US1667366). Consequently,cases of BLAD have been reported from Austria(255), Denmark (I), Germany (129, 274), Japan(i.e. 210), Netherlands (34, 95), South Africa(263), and the USA (i.e. 98). However, cases haveprobably gone unrecognised or unreported inother countries.

Cases of BLAD in Denmark were reported in1993 (I) and a large number of Holstein sires wereanalysed for the functional mutation in theCD18 gene. This identified 108 heterozygous sir-es used for breeding out of 405 tested sires, in-cluding the extensively used sire NJY Hubert(DK18382) (149). At present, 338 sires used forartificial insemination in Denmark have beenshown to be carriers (Appendix 1). The estimatednumber of BLAD-affected calves in Denmarkhas been calculated to be around 650 (Table 3),with most cases occurring from 1989 to 1992(Fig. 4b). However, the actual number is higher,as 346 sires with an undetermined genotype thatwere sons of a known carrier (Table 2) were omit-ted from the calculations. Fifty per cent of thesewere expected to be heterozygous for the BLADallele. A rapid decline in the number of BLAD-affected calves occurred after the introduction ofsystematic genotyping of sires (Fig. 4b). At pres-ent, BLAD is considered to be of low prevalencedue to the measures implemented by the Danishbreeding associations.

5.17. CONGENITAL ERYTHROPOIETICPORPHYRIA

Congenital erythropoietic porphyria (CEP) incattle is an inherited enzyme deficiency in the

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pathways of haeme biosynthesis. Haeme, whichis a fundamental part of haemoglobin, is syn-thesised by a number of successive enzymaticsteps, starting with the formation of d-aminole-vulinic acid from glycine and succinyl-CoA,which is further metabolised to porphobilinog-en. Porphobilonogen is subsequently syn-thesised to uroporphyrinogen III by the actionof two enzymes, uroporphyrinogen I synthetaseand uroporphyrinogen III cosynthase. CEP iscaused by deficiency of one of these, uroporphy-rinogen III cosynthase (188, 249). An inter-mediary metabolite (hydroxymethylbilane) inthis enzymatic step is converted to uroporphyri-nogen I, some of which may be further metab-olised to coproporphyrinogen I. These porphy-rinogens are oxidised to their end products, uro-porphyrin I and coproporphyrin I, whichaccumulate in the body and are excreted inurine and faeces (151). The excretion of porphy-rins varies and porphyrin metabolites otherthan uroporphyrin I and coproporphyrin I,such as protoporphyrin, are also excreted (56,146, 151, 248, 302). Determination of the ratiobetween urinary coproporphyrinogen isomers Iand III may allow differentiation between unaf-fected homozygotes, heterozygotes and affectedhomozygotes (206).

The molecular basis for CEP in cattle has notbeen investigated. In man, several mutations inthe uroporphyrinogen III cosynthase gene havebeen associated with CEP (310).

CEP is clinically and morphologicallycharacterised by photosensitization, congenitalbrown discoloration of the skeleton and teeth,chronic haemolytic anaemia, and reducedgrowth.

Clinically, the most striking lesion is photo-sensitization, which may cause subepidermalblistering and dermal necrosis of unpigmentedareas (82, 91, 257). These lesions are due to thephotodynamic properties of the porphyrins de-posited in the skin. These porphyrins absorb en-ergy when exposed to ultraviolet light and be-come unstable. When porphyrins return to theground state, energy is released, which in thepresence of molecular oxygen forms free rad-icals (i.e. singlet oxygen), and subsequently cellcomponents are damaged (92, 151). As this pro-cess requires ultraviolet light, lesions are onlyseen in animals housed outdoors and mainlyduring periods of intense sunlight. There are in-

37

dividual differences, probably reflecting the levelof porphyrins deposited in the skin (302). Ingeographical regions with limited exposure tohigh levels of ultraviolet radiation, as inDenmark, photosensitization may be sparse(146).

A characteristic lesion of CEP is diffuse sys-temic brown discoloration of bones and teeth(Figs. 31 and 32). The colour changes affect thecompact and callous bones, and although bothenamel and dentine of teeth are affected, muchhigher concentrations are found in the dentine.Porphyrins are deposited in bands of higher andlower concentration, probably reflecting cyclesof exacerbation and remission of the diseaseduring foetal development (Fig. 33). Bonydiscoloration can be seen in affected foetusesaround the third month of gestation (146, 148,283). Some cases may remain undiagnosed untilslaughter, when systemic brown discoloration ofbones and teeth is recognised. However, discol-oration can be so sparse that inexperiencedmeat inspectors may overlook it. The incorpor-ation of photodynamic substances into the skel-eton and teeth can be visualised by exposingthese structures to ultraviolet light, as with theuse of a Wood’s lamp (Fig. 34). This will resultin a bright red fluorescence even in slightly dis-coloured cases. Abnormal coloration of inter-nal organs may be present due to accumulationof porphyrins or other forms of pigment, i.e.haemosiderin (146–148, 151).

Affected animals are born with haemolyticanaemia and an intense erythrogenic response(152). Anaemia of variable severity persists butmay be subclinical. The erythrocyte survivaltime is reduced and is associated with increasederythrocyte porphyrin content, probably re-flecting porphyrin toxicity (151, 153, 246, 316).

CEP was originally reported in South AfricanShorthorns (90), but most reported cases havebeen of the Holstein breed. However, ancestorsof the Shorthorn breed have been identified insome cases. A few cases have been reported inother breeds, such as Canadian Ayrshire cattle(126). The disorder has been reported in Holste-ins in the USA (194, 246, 301), South Africa(88, 89, 91), and Denmark (145, 147). The casesapparently occur as isolated familial clusters al-though this might be due to incomplete pedi-gree information. Investigations of some clus-ters by analysis of segregation ratios between

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JØRGEN S. AGERHOLM

affected and phenotypically unaffected animalshave demonstrated an autosomal recessive in-heritance (145, 301), while this mode of inherit-ance has been indicated by the presence of in-breeding loops in other clusters (82, 194).

The inheritance of CEP in Danish Holsteinswith ancestors of the Shorthorn breed has beendetermined by breeding studies. Segregation ra-tios demonstrated an autosomal recessive modeof inheritance (145). Jørgensen (145) foundcases in a familial pattern and claimed to haveidentified the common ancestor, which unfortu-nately was only referred to by the code L.W.Additional pedigree analyses were not possible,so the occurrence of this defect in the DanishHolstein and Shorthorn breeds was not com-pletely resolved (148). Although most caseshave been seen in the Shorthorn or Holsteinbreeds or their crosses in Denmark, a single casein a red coloured cow has been reported (240).

Systemic diffuse brown discoloration of theskeleton in cattle has been recognised in Danishcattle for around 100 years. Poulsen (240) men-tions that such disorders are seen once or twicea year at the public abattoir in Copenhagen,while Møller-Sørensen (208) reports that fewerthan 2 cases were found per 20,000 slaughteredcattle on the island of Funen. Regionally, thedisorder became more prevalent during the1950s (145).

During the present study period, seven casesof the Danish Holstein breed with severe photo-dermatosis were examined at slaughter. Ofthese, four cases had brown discoloration ofbones and teeth, displaying bright red fluor-escence when subjected to ultraviolet light.Haematological analyses were not performed.Although these findings are not pathogno-monic, these animals were considered to sufferfrom congenital erythropoietic porphyria.Three animals were progeny of the Holstein sireKlaus 323 (DK 226735), while one animal wasa daughter of T Ingslev (DK 235145). Pedigreeanalyses demonstrated inbreeding and identifiedthe Holstein sires Black 18 (DK 18004) and SKBlack (DK 11516) as likely carriers of the de-fect, with MJY Black (DK 8744) and VE Klaus(DK 15613TL) as possible carriers (Fig. 35).

A further search for cases has recently beenperformed. In a survey of 111,796 cattle, includ-ing 70,199 Danish Holsteins admitted to fourmajor abattoirs from 1 August 2005 to 31 De-

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cember 2005, no cases were detected. This studyis planned to continue until September 2007.Additional Danish bovine practitioners were re-quested to report cases of severe photoderm-atosis in Holsteins in 2003, but no more caseswere found. It can be concluded that CEP oc-curs with low prevalence in the Danish Holsteinbreed.

5.18. RECTOVAGINAL CONSTRICTION

Rectovaginal constriction (RVC) is a connectivetissue disorder associated with modification andexaggeration of normal structures in the wall ofthe vestibulum and the large intestine at thejunction between the rectum and the anus. Inthe anorectal junction, the structure consists ofthe internal anal sphincter muscle and the analfibromuscular coat, which is where the levatorani muscle is inserted into the longitudinalsmooth layer of the rectum. This combinedstructure is ultrastructurally abnormal andforms a fibrous inelastic band around the anus,which can only be distended a few centimetres.In addition, the amount of collagen in the exter-nal anal sphincter is increased and the collagensubtypes may be changed. A fibrous inelastic

Fig. 27. Bovine renal lipofuscinosis.Fig. 28. Bovine leukocyte adhesion deficiency.Growth retardation and unthriftiness in an 8-month-old Danish Holstein calf (reprinted from I; Acta VetScand 1993;34:237–43).Fig. 29. Bovine leukocyte adhesion deficiency. Exten-sive chronic dermatophytosis and unthriftiness.Danish Holstein.Fig. 30. Bovine leukocyte adhesion deficiency. Exten-sive chronic dermatophytosis. Detail of the animalshown in Fig. 29. Danish Holstein.Fig. 31. Congenital erythropoietic porphyria. Diffusebrown discoloration of compacta and spongiosa. Hu-merus, Danish Holstein.Fig. 32. Congenital erythropoietic porphyria. Diffusebrown discoloration of the teeth. Part of the man-dible. Danish Holstein.Fig. 33. Congenital erythropoietic porphyria. Notethe rings of brown discoloration of different intensit-ies. Femur, Danish Holstein.Fig. 34. Congenital erythropoietic porphyria. Pinkfluorescence of teeth exposed to ultraviolet light(Wood’s lamp). Part of the mandible. DanishHolstein.

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Fig. 35. Genealogical diagram showing the geneticrelationship between four Holstein heifers affected bycongenital erythropoietic porphyria (cases 38025-00586, -00592, -00595 and 33551-01584). The siresKlaus 323 (A), T Ingslev (B), Black 18 (C) and SKBlack (D) are likely carriers of the defect as they arepart of an inbreeding loop. The sires MJY Black (E)and VE Klaus (F) might be carriers.

constricting ring is also present in the tunicamuscularis of the vestibulum (63, 201, 286, 292).Furthermore, bilateral stenosis of the milk veins(vena epigastrica cranialis superficialis dexter etsinister) at their penetration site though the ab-dominal wall is found (13). Increased amountof collagen may be present in the head and inthe perineal region (284, 285).

The clinical signs of RVC are primarily as-sociated with the effects of the vestibular andvenous stenoses. The vestibular stenosis causesdystocia, which mostly must be resolved byCaesarean section (183). This is mainly a prob-lem associated with natural breeding, as the dis-order is generally identified if the animal is in-seminated. The stenosis of the milk veins causesstasis and increased intravascular pressure in thevein, which results in udder oedema and isch-aemic necrosis of the udder skin and subse-quently mastitis (13, 14). As the anal stenosis isnot associated with clinical signs, RVC is mainlya disorder of adult females and is only acciden-

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tally diagnosed in males. Several unsuccessfulattempts have been made to develop laboratorymethods for identification of heterozygous indi-viduals (63, 169, 287, 289–291, 296). At present,only breeding trials are reliable.

RVC was first reported in the Jersey breed inthe USA in 1975 (176), but may have occurredmore than 40 years earlier (133). The disorderoccurred in a familial pattern consistent withautosomal recessive inheritance. This was laterconfirmed by breeding studies (185).

RVC was diagnosed in the Danish Jerseybreed in 1984 after Danish veterinary surgeonswere made aware of this disorder (115, 118).Several sires were identified as carriers of thedisorder based on clinical examination ofaffected animals or specimens from them, or aclinical history consistent with the disease andfamilial relation to known carriers (118, 119).Identified heterozygous sires were genetically re-lated to the US Jersey sire The Trademark(US585350) or the Danish Jersey sire RosenfeldtFavorit (DK4250) (119, 266). These sires have acommon ancestor, the US Jersey sire FAV Com-mando (US457631) (7). The prevalence ofaffected animals was reduced though the 1980sby a restrictive breeding policy (144).

Four suspected cases of RVC were examinedfrom 1989 to 1991. One of these was probablyaffected (10). No cases have been examinedsince then. As RVC in females is associated withsevere symptoms and as technicians probablydiagnose the disorder in association with in-semination or pregnancy testing, a lack of re-ports of affected cases probably reflects a lowprevalence of the disorder in the Danish Jerseybreed.

5.19. CHROMOSOMAL ABERRATIONS

Three transmissible chromosomal aberrationshave been diagnosed in Danish cattle: tandemfusion translocation, translocation t(1;8;9)(q45;q13;q26), and translocation 1/29. These defectsreduce the animal’s fertility due to developmentof gametes with unbalanced chromosome num-bers leading to non-viable embryos. Thechromosome aberrations, which are mostlyidentified in cultured blood lymphocytes, can bepresent in one or two copies, designated as het-erozygous and homozygous states, respectively.

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The translocations reduce the number ofchromosomes from the normal 60 to 59 or 58in the heterozygous and homozygous state, re-spectively. The centromere of one chromosomemay be lost during the conjunction of thechromosomes, but the coding DNA is con-served (189). Animals that carry these chromo-some defects are therefore phenotypicallynormal.

5.19.1. Tandem fusion translocationThis translocation is characterised by the fu-

sion of two chromosomes at the free end (op-posite the centromere), with simultaneous lossof one centromere. This aberration was reportedby Hansen (111–113) in the Danish Red Dairybreed, but the chromosomes involved were notidentified. The defect was identified in sires usedfor insemination and heterozygous individualshad a decreased fertility of around 10% meas-ured as 30–60 day non-return to service rate.The prevalence of this defect is at present un-known.

5.19.2. Translocation t(1;8;9)(q45;q13;q26)This is a complicated translocation where

chromosomal segments have been exchangedamong chromosome nos. 1, 8 and 9 (162). Thisdefect was originally found in the AmericanBrown Swiss sire Sunburst Hill Combo Fabian(US184214) (161, 162). Semen of this sire hadbeen used to a limited extent in Denmark.

The t(1;8;9)(q45;q13;q26) translocation has asevere negative influence on fertility, exemplifiedby the observation that 223 inseminations onlyresulted in 11 calves (4.9%). The non-return toservice rate at gestation day 56 was 26%. Com-pared to the usual rate of 65% this demonstratesthat most progeny were lost during early devel-opment (55). The defect was trasmitted to 5 of10 progeny. The prevalence of this disorder isassumed to be low in Danish cattle as the severeimpact on the fertility of affected individualswill normally result in slaughter, thereby inter-rupting transmission of the defect.

5.19.3. Translocation 1/29.Chromosome translocation 1/29 is a centro-

mere fusion of chromosome nos. 1 and 29. Thisdefect is the most common chromosome trans-location in cattle and has been identified incattle breeds worldwide (104, 105). The defect is

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associated with a decreased fertility of 5–10%.This is due to a certain level of spermatozoaand eggs with unbalanced chromosome numberas the separation of chromosomes during mei-osis may be disturbed (77, 104, 105).

Translocation 1/29 has been recognised inDanish Blonde d’Aquitaine, Limousine andDanish Red Dairy breed crossed with AmericanBrown Swiss (55, 117, 221, 222). The prevalencewas highest in the Danish Blonde d’Aquitainepopulation. By combining the results of Ager-holm et al. (10) and Hansen and Hansen (120),who performed their studies around 1990, aprevalence of 28.1% and 0.5% can be calculatedfor heterozygous and homozygous affected ani-mals, respectively. The prevalence of animalshaving a 1/29 translocation in the DanishLimousine population was 12.2% (10). The re-spective breeding associations initiated a pro-gramme to reduce the prevalence of translo-cation 1/29. Samples from animals of thesebreeds have continuously been examined andtranslocation 1/29 seems to be of low prevalence(53).

5.20. DEFECTS OF SPERMATOZOA

Several defects of spermatozoa have been iden-tified in Danish cattle, but an inherited basis hasonly been established for the ‘‘Dag-defect’’ inJersey sires.

The ‘‘Dag-defect’’ is characterised by sperma-tozoa with tails that are strongly coiled, exten-sively folded, or split into fibres, and is presentin at least 25% of the spermatozoa. These ab-normalities inhibit controlled motility. The fer-tility of affected sires reflects the level of abnor-mal spermatozoa. The sires often have severelyreduced fertility, as the percentage of defectivespermatozoa is mostly high (36, 38). A dis-turbed arrangement and lack of central and pe-ripheral fibres in the tail has been observedultrastructurally (38, 158, 317). The tail abnor-malities are not present in the spermatozoa aslong as they are within the testicles, but developduring passage through the epididymidis. Thishas led to the hypothesis that the spermatozoaare normal, but are damaged by an unfavour-able biochemical environment within the tu-bules of the epididymides. It has, in fact, beendemonstrated that sires with the ‘‘Dag-defect’’

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have an elevated semen zinc concentration (41),which may damage the spermatozoa. Thepathogenesis has not been clarified, but may in-volve an inherited biochemical defect in thetubular epithelium of the epididymidis.

The ‘‘Dag-defect’’ was named after theDanish Jersey sire Fåborg Dag (born 1962),which was the first animal identified with thisdefect (37, 38). However, the defect probablyoriginated from a Jersey sire born in 1934, buthis identity has not been revealed. Fifteen bullsdiagnosed as having the ‘‘Dag-defect’’ between1963 and 1979 were maternally and paternallyrelated to this sire, thus demonstrating a fam-

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ilial pattern consistent with autosomal recessiveinheritance (159). A breeding study between anaffected sire and his own daughters revealed asegregation ratio of 6 affected males to 32 unaf-fected males, which is in accordance with theexpected 1:7 ratio (c2Ω0.376, dfΩ1).

Systematic data on the prevalence of the‘‘Dag-defect’’ in sires entering breeding stationsare not available, but laboratory techniciansclaim not to have seen the defect for years (15).The disorder was last reported in 1987 in threeJersey sires (227). The present prevalence of the‘‘Dag-defect’’ is apparently low.

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6. Conclusions

A wide range of inherited disorders has beenidentified in Danish cattle since 1989. However,intervention in breeding plans by culling or re-strictive use of heterozygous sires has success-fully reduced the number of affected progenyand controlled further spread of defective genesfor most disorders. A specific programme to re-duce the spread of hereditary dilated cardio-myopathy has not commenced, but as a con-siderable number of animals may be affected, asurveillance program for this disorder is recom-mended. Hereditary dilated cardiomyopathy isa lethal disorder of adult cattle with rapid de-terioration, which is difficult to differentiateclinically from other causes of right-sided heartfailure. Achieving sufficient cases to survey thedisorder will be expensive and there are practi-cal obstacles that must be overcome before anefficient surveillance programme can be estab-lished. In addition, control of the disorder is ex-pected to be prolonged, especially as the dis-order is not expressed until adulthood. Forthese reasons, development of a molecular testfor genotyping of animals must have high prior-ity. It is also important to confirm initial find-ings that cows with renal lipofuscinosis have anapparently increased risk of early culling. If thedisorder is associated with adverse effects onhealth or production, the economic implicationsmay be considerable due to the high prevalenceof the disorder. Determination of the molecularbasis may be of importance in understandingthe mechanisms leading to lipofuscin accumu-lation and in helping control the disorder.

Although many inherited disorders have beenfound in Danish cattle, it is recognised that anumber of these disorders have also been foundin several other countries, demonstrating theclear international perspective of bovine in-herited disorders. Several reports have beenpublished from Germany, Switzerland, the USAand Denmark, but this does not necessarily re-flect the actual occurrence of specific disorders.Disorders such as complex vertebral malfor-mation and bovine leukocyte adhesion de-ficiency are likely to be distributed worldwideand have probably occurred in most nationalHolstein populations despite there being few

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published reports. Reports of hereditary dis-orders are clearly associated with the distri-bution of certain breeds. However, they areprobably also closely associated with the pres-ence of scientists with an interest in investigat-ing inherited bovine disorders and the capacityto identify and describe such disorders. To pos-tulate that inherited disorders are more preva-lent in the countries mentioned than in othercountries is most probably erroneous.

Inherited disorders in Danish cattle havemostly been found in Danish Holstein andDanish Red Dairy breeds. Although this mightbe associated with breeding strategies and there-fore reflect a higher prevalence of inherited dis-orders in these breeds than in other Danishbreeds, it is more likely due to the high numberof animals in these breeds and especially theawareness of the breeders. In contrast to thesituation in these dairy breeds, few inherited de-fects have been recognised in Danish beef cattle.This may reflect not only the low number of ani-mals but also problems in determination of in-heritance when isolated congenital syndromesoccur in small herds using natural breeding.

Statistical evaluation of the progeny-basedidentification of heterozygous sires showed thatthis method had a low sensitivity as significantlyfewer heterozygous sires than expected wereidentified (Table 2). It is likely that most hetero-zygous sires that passed the initial breedingevaluation undetected – and subsequently wereused more extensively – were identified later onsimply because of a higher number of progeny.Therefore, most extensively used carriers wereprobably detected and any delay in reductionof the prevalence of diseased calves caused byundetected carriers is assumed to be limited.The detection of diseased calves was based onthe farmer’s and veterinarian’s ability to recog-nise an inherited disorder without preceding no-tice. The results indicate the inadequacy of theirability and it is recommended that breeders ofanimals at high risk be informed of a specificinherited disorder, thereby increasing theirawareness. This will probably lead to a higherlevel of carrier detection.

Estimations of the number of progeny

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affected by an inherited disorder showed thatgenerally less than 1,000 calves were diseased.This could be interpreted such that inheriteddisorders were almost insignificant compared toother causes of calf mortality. However, thenumbers must be compared to the breedingpopulation. An example of the significance ofan inherited disorder can be given for spinaldysmyelination in 1994, where 26,600 calvingswere recorded. As 206 defective calves wereborn that year (Fig. 4e), spinal dysmyelinationcontributed 0.77% to calf mortality. This ex-ample demonstrates that inherited disordersmay have significance for a breed even thoughthe total number of defective calves seems low.It is also important to note that the estimationsincluded the effects of interventions in the useof heterozygous sires once the undesirable geno-type was recognised by the breeding associ-ations. The sudden and rapid annual increase inthe number of defective animals that occurredbefore interventions commenced, as seen forseveral disorders (Fig. 4), indicates the serious-ness of these defects and the potential impacton the breeds.

The economic consequences of inherited dis-orders can be significant for cattle breeders.With disorders in the neonatal calf, expenses aremainly related to lost calves, treatment beforethe diagnosis is established, and the cost of re-stocking with females. Other disorders not obvi-ous in neonates, such as hereditary dilated car-diomyopathy and rectovaginal constriction,have a greater impact, and disorders whereabortion is common, such as complex vertebralmalformation, may mean additional losses fromreduced milk production. Estimations of theeconomic impact of inherited disorders havebeen made on a few occasions. British re-searchers estimated the total costs, includinglost milk production and premature culling as-sociated with a case of complex vertebral mal-formation, to be £ 419 (2005 level) (154). Theeconomic impact on Danish breeders can subse-quently be calculated to be around £ 5 millionor DKK 50 million, if it is assumed that thecosts per case are at the same level in Denmarkand that there are around 12,000 cases (Table3). The widespread occurrence of complex ver-tebral malformation and its economic conse-quences emphasises the need for continued sur-veillance to detect inherited disorders of cattle.

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Estimations of the number of defective calveswere performed by a simple and transparentmethod, and documented the disease magnitudeand annual fluctuations in disease occurrence.The most significant contribution to the numberof affected animals was derived from the matingof carrier sires and daughters or granddaugh-ters of heterozygous sires, respectively (Fig. 4).It is recommended that similar estimations bemade when future inherited disorders are recog-nised in Danish cattle, thereby showing thenumber of affected calves over the years and theactual disease extent. Estimations can even bedone before comprehensive genotyping data arepresent as recently demonstrated by Man et al.(196). Such data can be included as part of thebasis for making decisions on intervention inbreeding programs.

The present investigations have shown the im-portance of accurate research and diagnosticmethods. Pathological studies have been an im-portant part of these methods due to the natureof inherited disorders seen in Danish cattle dur-ing recent years. However, many scientificdisciplines, including radiology and molecularbiology, have provided valuable informationand shown that research into inherited disordersof cattle is a multidisciplinary task.

Determining the cause of a disorder may ap-pear straightforward if the disorder shares mor-phology with known inherited disorders. How-ever, the existence of phenocopies indicates thatgreat caution is required regarding such inter-pretations. Examples are the case of syndactyl-ism reported in Danish Holstein in 1990 (223)and cases of malformations indistinguishablefrom the complex vertebral malformation syn-drome (142, VII). Even if cases occur in pat-terns consistent with simple Mendelian inherit-ance, conclusions must be drawn with cautionas such patterns may occur fortuitously (V).Another potential pitfall is the adaptation of re-sults regarding inheritance from one breed toanother or from another species. It is importantto stress that a common morphology does notimply a similar aetiology or mode of inherit-ance. It is well known from human medicinethat a range of mutations can be associated witha shared phenotype and similar observationshave also been made respecting bovine diseases(70, 71), although larger studies of family clus-ters of cattle with shared disease phenotype are

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lacking. In this dissertation such uncertain con-clusions have been minimised as each sectionhas focused on a single breed or family cluster.That breeding associations demand high quality

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research before intervention in breedingschemes is understandable due to the potentialpitfalls and the far-reaching economic impli-cations of erroneous interventions.

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7. Perspectives

This dissertation provides a review and de-scribes the status quo regarding inherited dis-orders in Danish cattle. However, it does notcover the topic exhaustively as obviously it canonly include recognised disorders. It is mostlikely that unrecognised inherited abnormalitieshave occurred and still occur in the cattle popu-lation. Recently, a familial congenital syndromein Danish Holstein calves designated ‘‘brachy-spina syndrome’’ was reported (11). This syn-drome occurs in a familial pattern consistentwith autosomal recessive inheritance. It wasoriginally identified in Denmark, but cases havelater been reported in the Netherlands and Italy,thus demonstrating international perspectivesfor the Holstein breed (9, 278). It is beyonddoubt that other disorders will also be identifiedin the future. Consequently, research on bovineinherited disorders is a ‘‘neverending story’’.

Recognition of inherited disorders and con-genital syndromes in cattle depends on the skillsof the breeder and the veterinary practitioner.These limitations make it necessary for passivesurveillance to focus on disorders that can actu-ally be recognised. These disorders includeskeletal malformations, severe neurological dis-orders, and skin defects. Danish breeders andveterinarians should be requested to report ani-mals suffering from such disorders, with repre-sentative cases being submitted for laboratoryexamination. Functional surveillance is import-ant in order to identify hereditary syndromesin time to prevent a severe impact on livestockeconomy and on animal welfare.

Most sires are probably carriers of one ormore recessive defects (204, 216), so the spreadof defective alleles and the occurrence of defec-tive calves is an inevitable part of modern cattlebreeding. An efficient breeding policy is necess-ary for a remunerative farm economy and forthe availability of dairy products and meat atreasonable prices. High-ranking sires are exten-sively used by breeders and semen suppliers de-spite the simultaneous spread of their defectivegenes. Few semen suppliers and breeders areinterested in knowing which defective genestheir sires spread before a problem is recognisedin the general population. The reason for this is

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an understandable concern regarding the valueof breeding animals and semen once it is knownwhich defective genes the animals carry. Thisphenomenon could be called ‘‘the paradox ofknowledge’’. As all sires are carriers of unfa-vourable recessive genes, would it not be betterto know which undesirable traits a sire spreads,so that the effects can be measured and appro-priate and timely breeding interventions can beinitiated to prevent a severe impact on livestockeconomy and animal welfare, than just to waitand see what happens? It is generally requiredthat negative effects of compounds or pro-cedures are known so that this information canbe included in the overall assessment. Whyshould this not apply to the commercial sementrade? This is, meanwhile, not a scientific matterbut a matter between semen suppliers and se-men buyers. The attitude of several breeding as-sociations towards inherited disorders has pro-gressed towards openness and evidence-baseddecision making. The World Holstein FriesianFederation is an example of an association fa-cing the undesirable effects of intensive cattlebreeding; it states that the full disclosure ofnamed genetic defects in the Holstein popula-tion provides useful information when makingbreeding decisions on farms, giving the oppor-tunity to minimize the impact of any associatedproblems (306). Evidence-based decisions re-quire that the impact on the breed can be meas-ured. However, it does not mean that a sire mustbe culled or used restrictively just because hecarries a recessive inherited disorder.

Testing high-ranking sires for undesirable re-cessive genes would make it possible to developmolecular genotyping tests before the recessivegenes are expressed in the general population inthe form of large numbers of defective progeny.Relevant sires could be genotyped and theprevalence of defective progeny could be meas-ured prospectively by analysis of breeding com-binations using the retrospective method ap-plied in this dissertation (Chapter 4). Thiswould provide a solid foundation on whichbreeders and breeding associations could basetheir decisions. In addition, such an approachwould allow the breeding associations to reduce

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the prevalence of the disorder by introducingbreeding restrictions whenever they wanted andsimultaneously to exploit the superior traits ofthe breeding lines by using homozygous normalsires. Such research projects could be carriedout in a partnership between semen suppliers,breeding associations and research institutions.

Progress in genome mapping and methodsfor genomic analysis has made it possible toelucidate the pathogenesis of inherited dis-orders, and this will lead to increased knowl-edge respecting the action of many genes. Ge-nome analysis is mostly applied when a majordisease problem is recognised, with the aim ofdeveloping molecular tests. However, genomeanalysis should be applied more widely tocharacterise sporadically occurring disorders.

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One of the major obstacles is the lack of DNAfrom such sporadic cases. Researchers and diag-nosticians should be encouraged to publish re-ports on sporadically occurring defects and rou-tinely store tissue or DNA for further analysis.Meanwhile, such stored tissue is often lostwithin a few years due to lack of storage ca-pacity or changes in employment and priorities.Establishment of an international bank for stor-age of DNA from defective animals could solvesuch problems, making it possible to obtainmultiple cases of sporadically occurring defectson which research projects could be based. Asinternational biological banks for microorgan-isms have already been founded, establishing abank for DNA of defective animals appears anachievable objective.

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JØRGEN S. AGERHOLM

8. Summary

Inherited disorders are of great concern in cattlebreeding as the breeding systems and the exten-sive use of genetically related sires predisposeto increased frequency of recessively inheriteddisease genes in the population and subsequent-ly the occurrence of diseased animals. Inheriteddisorders may in this way contribute signifi-cantly to the extent of calf diseases and mor-tality as elite sires may produce hundreds ofthousands of progeny. Furthermore, high num-bers of defective animals may be reached dueto international trade with semen, which linksnational cattle populations together genetically.

Several inherited disorders have been re-corded in Danish cattle, mainly in Danish Hol-steins and the Danish Red Dairy breed. Thesetwo breeds are the first and third most commonbreeds in Denmark, which may partly explainthis observation. The structure of the beef cattleindustry in Denmark – with few purebred ani-mals and many small herds – makes recognitionof inherited disorders in beef cattle difficult.

Sires used for breeding purposes in Denmarkare labelled for specific inherited disorders ifthey are genetically related to known carriers orif they have been genotyped. The labelling sys-tem includes disorders such as complex ver-tebral malformation, bovine leukocyte adhesiondeficiency, spinal muscular atrophy, and spinaldysmyelination. Animals may be labelled asnon-carrier, confirmed carrier, likely carrier orpossible carrier based on, for example, molecu-lar genotyping, progeny examination or pedi-gree information. A complete list of sires thatare carriers of an inherited disorder and havebeen used for breeding in Denmark is provided.

The genotype of sons of heterozygous siresused for insemination was evaluated to deter-mine if all carriers had been detected. Theanalyses demonstrated that labelling of siresbased on examination of diseased progeny re-ported by breeders or veterinarians was insuf-ficient to detect carriers. A targeted search forspecific inherited disorders is therefore recom-mended in the future, i.e. through contact withowners of animals at high risk of developingdisease. Such animals can be picked out basedon breeding and pedigree information, which is

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available from the Danish Cattle Database.Molecular genotyping is an efficient way to dis-tinguish between carriers and non-carriers, butthis method is only applicable once the molecu-lar basis of a disorder has been established.

The number of animals suffering from arange of inherited disorders was estimatedbased on breeding results, pedigree, and data onthe genotype of sires. It was estimated thataround 12,000 embryos had suffered from com-plex vertebral malformation. The total costs re-lated to these cases came to £5 million (2005level) if estimations of the costs associated witha single case of complex vertebral malformationfrom the United Kingdom were adapted. Spinalmuscular atrophy was the most important dis-ease in the Danish Red Dairy breed with around1,800 cases. The number of animals sufferingfrom inherited disorders during the 1970s orearlier could not be estimated due to poor dataquality. The annual number of affected progenywas determined for each disease and the ef-ficiency of the control measurements im-plemented by the breeding associations wasevaluated. The number of diseased animals hadbeen reduced to around zero for most disorders,but the time span needed to achieve this variedconsiderably. A rapid decrease in the number ofaffected progeny was observed if control meas-urements were based on molecular genotyping,while a prolonged decrease was seen if controlmeasurements were based on progeny examina-tion. The findings demonstrate the superiorityof molecular genotyping to progeny examina-tion in programmes to identify heterozygous sir-es and reduce the negative effects of inheriteddisorders. Estimations of the number of animalssuffering from hereditary dilated cardiomyo-pathy showed that more than 100 cases had oc-curred. Hereditary dilated cardiomyopathy hasonly been diagnosed fortuitously and infor-mation on affected breeding lines is probablyfaulty. The number of cases may therefore beconsiderably higher and increased surveillanceof this disorder is recommended. Renal lipofus-cinosis is highly prevalent in Danish Holsteinsand the Danish Red Dairy breed. Further re-search is needed to evaluate whether the in-

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creased culling rate of affected cows is a real ormerely an accidental finding.

A review of inherited disorders and their pres-ent significance in Danish cattle is given, focus-ing on the morphology and inheritance of thedisorders, and providing information onaffected breeding lines. Other important aspectsof the disorders are described, especially theaetiology and pathogenesis. The review includeschondrodysplasia, complex vertebral malfor-mation, osteogenesis imperfecta, syndactylism,

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acroteriasis, congenital paralysis, bovine pro-gressive degenerative myeloencephalopathy,spinal muscular atrophy, spinal dysmyelination,syndrome of arthrogryposis and palatoschisis,ichthyosis foetalis, epitheliogenesis imperfecta,hereditary zinc deficiency, renal lipofuscinosis,hereditary dilated cardiomyopathy, bovineleukocyte adhesion deficiency, congenital er-ythropoietic porphyria, rectovaginal constric-tion, chromosomal aberrations, and defects ofspermatozoa.

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JØRGEN S. AGERHOLM

9. Sammendrag (summary in Danish)

Arvelige sygdomme er af stor betydning i kvæg-avlen, da avlssystemerne og den udbredte brugaf familiært relaterede tyre disponerer for enøget frekvens af recessivt nedarvede sygdomsge-ner i populationen og deraf følgende forekomstaf syge dyr. Da elitetyre kan få hundredetusindestykker af afkom, kan arvelige sygdomme bi-drage væsenligt til omfanget af kalvesygdommeog -dødelighed. Der kan yderligere optræde etstort antal syge dyr som følge af internationalhandel med sæd, som gør nationale kvægbe-stande genetisk beslægtede.

Adskillige arvelige sygdomme er blevet regi-streret hos kvæg i Danmark, især i dansk hol-stein og rød dansk malkerace. Disse er den hyp-pigste og trediehyppigste kvægrace i Danmark,hvilket delvist kan forklare observationen.Strukturen af den danske kødkvægsindustrimed få renracede dyr og lille besætningsstørrelsevanskeliggør erkendelsen af arvelige sygdommehos denne type kvæg.

Avlstyre, som anvendes i Danmark, markeresi stambogen for specifikke arvelige sygdomme,hvis de er beslægtede med kendte bærere af så-danne, eller hvis de er blevet genotypet. Mærk-ningssystemet inkluderer blandt andet sygdom-mene complex vertebral malformation (CVM),bovine leukocyte adhesion deficiency (BLAD),spinal muskelatrofi (liggekalvesyndromet) ogspinal dysmyelinering (medfødt lammelse). Ba-seret på blandt andet molekylær genotypning,undersøgelse af afkom eller afstamningsoplys-ninger, kan dyr blive markeret som ikke-anlægs-bærer, anlægsbærer, sandsynlig anlægsbærer el-ler mulig anlægsbærer. En komplet oversigt overtyre som er anlægsbærere af arvelige sygdommeog som har været anvendt i Danmark gives iafhandlingen.

Genotypen af sønner af heterozygote insemi-neringstyre blev evalueret for at undersøge omalle anlægsbærere var blevet påvist. Analysen vi-ste, at påvisningen af heterozygote tyre var util-strækkelig, hvis denne blev baseret på undersø-gelse af sygt afkom udpeget af besætningsejereneller dyrlægen. En målrettet søgen efter speci-fikke arvelige sygdomme er derfor anbefalet ifremtiden, for eksempel ved kontakt til ejere afhøj-risiko dyr. Sådanne dyr kan udpeges ud fra

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afstamnings- og avlsregistreringer i kvægdata-basen. Molekylær genotypning er en effektivmetode til at skelne mellem anlægsbærere ogikke-anlægsbærere, men denne metode er kunanvendelig, når den molekylær genetiske bag-grund for en sygdom er kendt.

Antallet af afficerede dyr blev estimeret for enrække arvelige sygdomme baseret på avlsresul-tater, afstamning og tyres genotypningsdata.Det blev estimeret, at omkring 12.000 embryo-ner havde haft complex vertebral malformation.De totale omkostninger forbundet med disse til-fælde udgjorde 50 millioner kroner (2005 ni-veau), hvis estimated blev baseret på om-kostningsberegninger fra Storbrittanien. Spinalmuskelatrofi var den vigtigste sygdom hos røddansk malkerace med omkring 1.800 tilfælde.Antallet af dyr, som havde haft en arvelig syg-dom i 1970erne eller tidligere, kunne ikke bereg-nes på grund af utilstrækkelige data. Det årligeantal afficeret afkom blev beregnet for hver syg-dom, og effektiviteten af kvægavlsforeningernesavlsforanstaltninger blev vurderet. Antallet afsygt afkom var blevet reduceret til næsten nul,men tidsperioden, der var nødvendig til at opnådette, varierede betydeligt. Et fald i antallet afsygt afkom skete hurtigt, såfremt kontrolforan-staltningerne var baseret på molekylær genotyp-ning, mens en langstrakt reduktion sås, hvis for-anstaltningerne var baseret på undersøgelse afafkom. Dette viser, at molekylær genotypninger overlegent i forhold til afkomstundersøgelsetil identificering af heterozygote tyre og til atreducere den negative effekt af arvelige sygdom-me. Estimatet af antallet af dyr, som havde haftarveligt betinget dilateret kardiomyopati viste,at mere end 100 tilfælde var forekommet. Arve-ligt betinget dilateret kardiomyopati var kunblevet diagnosticeret tilfældigt og kendskabet tilafficerede avlslinier er sandsynligvis ufuldstæn-digt. Antallet af tilfælde kan derfor have væretbetydeligt højere og en øget overvågning af den-ne sygdom anbefales. Renal lipofuscinose (ok-sens sorte nyrer) er høj-prævalent hos danskholstein og rød dansk malkerace. Det er nød-vendigt med yderligere forskning for at vurdereom den observerede øgede udsætningsrate af af-ficerede køer er reel eller tilfældig.

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Afhandlingen giver en oversigt over arveligesygdomme og deres nuværende betydning hosdansk kvæg. Der fokuseres på sygdommenesmorfologi og arvelighed, og der gives oplysnin-ger om afficerede avlslinier. Andre vigtigeaspekter ved sygdommene omtales, specieltætiologi og patogenese. Oversigten omhandlerkondrodysplasi, complex vertebral malforma-tion, osteogenesis imperfecta, syndactyli, acro-teriasis, kongenital paralyse, bovin progressiv

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degenerativ myeloencefalopati, spinal muskel-atrofi, spinal dysmyelinering, syndrome of arth-rogryposis and palatoschisis, ichthyosis foetalis,epitheliogenesis imperfecta, arveligt betingetzinkmangel, renal lipofuscinose, arveligt betin-get dilateret kardiomyopati, bovine leukocyteadhesion deficiency, kongenital erytropoietiskporfyri, rektovaginal konstriktion, kromosom-fejl og spermiedefekter.

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11. Appendix 1

This appendix provides a list of sires used forbreeding in Denmark and which have been deter-mined as carriers of an inherited defect. The listis mostly adapted from the labelling of sires in theDanish Cattle Database. This labelling is per-formed by the Danish Cattle Federation or thebreeding associations and the accuracy of thedata is their responsibility. The appendix must beread together with the description of each dis-order in Chapter 5. The appendix is a researchtool. Breeders and breeding associations musthave the status of carriers confirmed by theowner of the sire or the breeding association be-fore taking any action against individual sires orincluding the data as part of the basis for makingany decisions. Data were extracted from thedatabase on January 26th 2006.

The data have been expanded with results ob-tained since 1989 regarding disorders for whichlabelling is not performed. Parentage control

TABLE 4. Carriers of chondrodysplasia in DanishDexter

No registered carriers.

TABLE 5. Carriers of chondrodysplasia in the DanishRed Dairy breed

Danish Original herd Nameherd book no.bookno.28440 THY Skov29559 NØ Gerber29851 NOF Kel29852 NOF Lød32566 HV Flid

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has not been performed in all cases. Sires thathave an unconfirmed paternity to a defectivecalf have only been included if the case occurredin a familial cluster.

As labelling is based on progeny examinationor genotyping (see Chapter 3), heterozygous an-cestors are mostly not included in the appendix.DNA of such ancient animals may not be avail-able or affected progeny may not have been re-corded. However, the identity of ancestors ismostly given in Chapter 5.

The sires are identified by their name andherd book numbers. Foreign sires have a Danishherd book number in addition to their originalnumber. Both numbers have been providedthroughout this appendix to improve the useful-ness of the appendix internationally.

The appendix documents the basis on whichestimations made in Chapters 3 and 4 weremade.

TABLE 6. Carriers* of chondrodysplasia in DanishHolstein

Danish Original herd Nameherd book no.bookno.240726 F4493050102 Igale Masc244129 Igale 891

* The mode of inheritance has not been reported.

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TABLE 7. Carriers of complex vertebral malformationsyndrome

Danish Original herd Nameherd book no.book no.17001 US1667366 Carlin-M Ivanhoe Bell18382 NJY Hubert19804 VE Nelson44293 NLD316419721 Delta Cleitus Jabot82190 US1441440 Penstate Ivanhoe Star82634 US1875896 Lutz-Brookview Bell

Rex-ET82658 US1891196 Nowerland Trifecta82685 US1920807 Ugela Bell.

224302 US1875356 Kashome Bell Jurist-Twin

224515 RGK Jure225200 US1892913 Ca-Lill Belltone226804 US1964484 Southwind Bell of Bar-

Lee227511 VE Thor229874 US1882141 Stan-Bitzie Kirk Bell

Boss230104 T Burma230429 CAN371115 Sunnylodge Sammy230961 US2021095 Paradise-R Roebuck231341 US2065871 Highlight Converse-ET231642 VAR Ute231665 RGK Olie232755 NLD316419721 Delta Cleitus Jabot233579 RGK Parbo233883 T Havndal234036 US2089381 Mar-Bil Command

Geoffry234042 KOL Nixon234113 RGK Pust234277 NLD460942030 Etazon Labelle-ET 528234344 US1912270 Emprise Bell Elton234604 US2071247 De-Su Secret Jetson

Top Gun234898 US1819119 Bossir Glen-Valley

Starlite Al234981 US2080263 Paradise-R Cleitus

Mathie234984 F2989026154 Esquimau235145 T Ingslev235514 US2049679 Heinz Liberty-ET235769 US2094527 Ameldin II Pontiac

Hunter235921 NLD776437936 Havep Marconi236199 US2145234 Londondale Swind

Merv-ET236328 US2154310 Mel-Ham Dixie-Lee

Sand-ET236398 T Klassy236503 NLD319957882 Delta Lava236598 F2290038601 Fatal237017 NLD780180664 Etazon Lord Lily

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TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.237018 NLD790545532 Zandenburger Royal237022 V Amster237314 S44358 Häradsköp237454 T Laluffe237626 V Balling237800 RGK Skalp237865 Var Brint238094 US2076574 Agi Spencer238098 NLD115467480 Sperwer238127 NLD167957274 T Limba238138 NLD864484246 T Monark238139 T Minerva238147 S620327618 T Medox238149 NLD167388690 T Mabelle238150 T Moulder238160 T Mitra238176 VE Domino238246 T Mikado238253 NLD785532529 Holim Stans Tornedo-

ET238270 2014517 Highlight Mr Mark

Cinder-ET238340 F2990000428 Fecamp238349 T Molok238359 D340227796 VE Domonit238392 US2193611 Wells Catalyst-ET238486 V Bolivar238538 RGK Tippe238584 ØDA Lyre238624 T Mogul238626 T Metope238628 T Money238652 VE Demo238654 NLD177526248 VE Dokaan238821 V Bjerg238833 V Bond238837 RGK Telius238839 Rgk Tilst238852 TVM Hole238866 VE Dekan238869 TVM Hugev238876 T Marimba238886 NLD176204639 T Nektar239113 T Norbert239114 T Neptun239116 T Nobilik239120 T Narkisos239128 T Nappa239130 T Negro239177 V Cassini239262 T Neon239321 NLD340964542 T Natan239322 T Nota

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TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.239325 T Nasturia239326 NLD198344197 T Navajo239375 RGK Tao239445 NLD340968994 T Nirman239450 T Nokra239468 V Congo239531 RGK Thure239532 RGK Tusty239561 V Chaplin239563 V Cheng239567 V Cypres239568 V Cognac239570 V Ceres239574 V Ceylon239578 V Crosby239581 V Chile239610 S330250115 T Olle239611 T Oporto239635 VE Elta239671 VAR Dalar239677 RGK Talk239682 NLD168778126 RGK Arnold239690 V Carlton239693 V Claes239699 V Cola239700 V Colbert239701 V Chardon239730 RGK Alan239765 T Ommelund239770 T Ofalia239784 T Otroy239786 T Onzelot239789 NLD206189055 T Osterink239828 VAR Daniel239829 VAR Danilo239830 VAR Danner239918 V Casper239919 V Claude239925 V Caudius239945 RGK Akke239966 V Corola239977 VAR Darwin239978 D577317764 VAR Davis240014 VE Etala240049 NLD173169722 Lord Sunshine 102240051 V Council240059 T Orion240060 T Orolo240065 T Odessa240111 V Clive240112 V Chianti240114 V Cremona240116 V Chirac

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TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.240131 NLD829877874 Holim Boudewijn240134 V Daimler240136 V Dental240174 RGK Alex240179 RGK Amor240182 RGK Agro240187 RGK Alfons240223 T Officer240224 T Oxon240225 T Otto240230 T Orient240237 T Osvaldo240248 ØDA Mild240249 ØDA Leman240272 NLD777133097 Lucky Leo240276 VAR Derek240279 VAR Difko240290 V David240291 V Daniel240292 V Diesel240298 VE Edom240378 ØDA My240404 T Polka240406 D341440527 Fabian240409 Picasso240411 T Pampas240414 T Prins240415 T Puma240418 T Parade240421 T Paxo240491 RGK Alpe240492 RGK Almue240497 V Delta240519 V Direktor240520 V Demand240521 V Depot240523 V Detroit240525 V Dalgas240553 NLD831375195 Holim Apollo240557 VAR Donner240558 VAR Dons240567 VE Epoke240575 T Pingo240628 NLD202428341 T Pajero240631 NLD204399328 V Dacapo240653 T Pedro240669 ØDA Fortun240671 ØDA Altag240714 V Dana240721 V Dissing240727 F5191005833 Gelpro240743 T Paris240744 T Pokal

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TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.240745 HMT Jyde240803 T Panter240806 T Perle240809 D577788833 VAR Dorf240826 D342567647 VE Ell240827 F5497015024 TVM Hapell240875 RGK Alaska240901 V Dirch240933 V Dollar240936 V Dixi240937 V Doge240941 V Duma240943 V Demokrat240948 NLD211251167 V Danton241001 D577691423 No registered name241054 VAR Duncan241063 V Dam241064 V Dairy241069 V Deuntzer241071 V Dekan241074 V Diktator241078 V Djabot241079 V Donau241082 V Diadem241089 VE Elsam241090 VE Elba241094 VE Format241095 D343023474 VE Fro241098 RGK Andre241103 RGK Andrew241104 RGK Auto241124 VAR Dybbøl241136 HMT Jalte241149 T Rebus241151 T Rotor241152 T Retto241155 T Rup241160 T Rasmus241171 VAR Dyb241172 VAR Ebro241187 RGK Bolt241190 V Duet241193 V Decamp241196 V Dexthor241216 HMT Jeppe241228 T Rosen241229 T Røn241231 F4493050135 Italie Mas241233 US2266008 Ricecrest Lantz241234 US2249055 Wa-Del Convincer-ET241318 F5898002010 TVM Hilton241386 D342919848 V Dorky241388 D343085106 V Dalvero

66

TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.241390 V Dingo241393 US2257212 Garjo Elton Gabe-ET

TL241400 V Datal241403 RGK Bøg241410 T Roslev241412 T Reform241414 T Rambo241415 T Ratal241419 T Rocket241423 D578133187 VAR Effen241427 US2261720 De-Su Luke Casino-ET241486 NLD207490198 Homerun241493 V Ecamp241495 V Ege241507 T Rekrut241513 T Repro241556 VAR Eggers241632 NLD112538714 Carrousel Sierra TL241638 RGK Bo241642 RGK Bertel241648 F2998012101 TVM Habon241695 V Elton241697 V Engels241751 T Staun241870 US2253348 Sim-Co Liberty

Chance-ET241917 RGK Ben241920 RGK Bob CV241921 V Ego241936 NLD173319699 V Emsen241939 Var Elmo241949 US2271665 Ladys-Manor El

Temptor-ET241950 US2276216 Wa-Del Elton

Bugleboy-ET241952 NLD856070222 Delta Largo241954 F4494050236 Jarny Jabo242099 V Ero242142 NLD864110860 Gryphus Simon Tl242146 T Stof242160 T Slalom242169 T Spolar242211 US2256388 Cedar-Creek Bergwil-

ET242213 NLD118522472 Bobstar 50 TI242275 US2251487 Regancrest Elton

Dante-ET242293 V Espholm242302 V Esprit242305 V Estragon242309 V Eskholm242347 T Stuntman

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TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.242395 RGK Bodo242436 US2289548 Ricecrest Brett ET242466 V Elan242471 V Emmedsbo242493 VE Fantom242502 NLD141079778 Woudhoeve Russel242511 VAR Estrup242513 D344688449 VAR Ferro242515 D344666684 VAR Filip242554 T Tank242557 T Tebel242559 NLD232807253 T Tucky242562 T Think242570 T Terry242572 T Tesk242585 RGK Dennis242643 VAR Facet242644 VAR Facon242649 D344688473 VAR Falk242755 Ejst Funki242766 V Erotik242772 F Ullits242777 V Eufori242778 F Farsø242785 D344666669 V Epsilon242786 D342409897 V Elamain242793 RGK Dingo242834 V Fix242846 US2289080 Webb-Vue Int Boy

Wonder-ET242861 T Teknik242870 T Tavle242885 VAR Fangel242891 Var Felix242897 NLD129187369 Tolhoek Glory Box Tl243021 Nixon 1008243065 T Tyson243066 T Tenerif243084 RGK Dam243094 NLD219170930 RGK Dumle243096 F Tirsvad243101 HMT Loft243112 US2282520 Peckenstein Elton

Curtis243121 V Facet243124 V Farty243145 Esqui 140243158 NLD149310675 Delta Bentley Tl243219 VAR Folmer243284 T Ugilt243285 T Uldahl243306 V Flint243369 T Urban

67

TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.243372 T Urth243373 T Ullman243374 T Urias243377 T Upolo243381 T Ubiq243382 T Utopia243385 T Ursus243387 T Ubbesen243391 T Uggerhøj243393 NLD265548044 T Uno243459 F5994022699 Jesther243518 NLD167388760 Nab Evert243524 RGK Drille243528 RGK Dumbo243532 V Finbo243533 V Frøy243539 V Frey243545 V Fasmark243549 V Follo243556 V Francis243560 Holin243575 HMT Ludo243673 V Fin243675 V Faris243680 VAR Fregat243681 VAR Fremad243682 VAR Fresko243685 VAR Friso243687 F Halling243705 F Rækby243738 T Uniq243744 T Utah243748 T Unipac243760 T Utica243762 T Ungarn243772 T Ulitsa243781 T Uffe243782 T Uranus243787 Ribe Apoll243795 Pust 1072243817 V Fagale243819 V Fakkel243821 V Flantz243822 V Forky243913 Nixon 2423243914 Rud Pabs243924 VAR Galant243935 V Fence243937 V Funtex243940 HMT Lixon243946 F Bevtoft243972 VAR Gamma243973 VAR Gamst

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JØRGEN S. AGERHOLM

TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.244004 Lund244019 T Urtime244025 T 2000-5244027 T 2000-7244032 T 2000-12244033 T 2000-13244034 T 2000-14244038 T 2000-18244040 T 2000-20244041 T 2000-21244053 V Farma244055 V Foton244060 V Fokus244100 Ø S Rup244117 T 2000-34244120 T 2000-37244121 T 2000-38244170 US17001863 Pride-Of-Iowa Will

Carl-ET244173 T 2000-42244178 T 2000-47244195 Addesqve244214 Søgd Apol244267 NLD263010279 Morpheus244285 Nix Boj244374 US2289624 Whittail-Valley Zest-

ET244393 US17112421 Lylehaven Sand

Gaston-ET244408 DG Convin244421 F1095001791 Lorak244429 RGK Ede244439 S Asmus244440 S Asger244454 Rav Nix244469 Høng Lantz244470 Høn Apollo244476 T 2000-56244493 T 2000-74244499 Klassy1068244539 Døl Klassy244542 Eisson244553 Gyrup Lanz244582 Peter244631 Hovg Huxle244741 Gabe 1797244752 NLD188347542 Horst Maistein244840 Lynggaard244869 Høvet244893 T 2000-112244914 D2261528773 Dancy ET244957 US2250783 Regancrest Elton

Durham-ET

68

TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.244960 NLD170658722 Eemvelder Osmond244961 NLD180884717 Rocker245017 Valtain245018 Val 997245025 Eksport245027 Nimbus245037 Klassy1008245040 NLD194532495 Delta Dacca CV245049 L Lily 899245073 Kozak245103 Hux 2686245105 Convin2723245164 Simon245187 Homo Polle245252 Klassy1030245255 US18040136 Windsor-Manor

Machoman-ET245294 Vand Lily245355 Ecco Storm245358 Houg Webst245359 Houg Bobst245360 Houg Klass245373 US1920807 Ugela Bell.

245383 ÅM Conwi245403 ØH Bojer245423 Curtis 914245448 Klassy245463 Søgd Lantz245582 NLD202428505 Isidorus Icon245591 US122185573 Vison-Gen Ozzie-ET245592 US17188116 Glen-Toctin Pippen-ET245631 St. Conv245712 Ub Boj245719 Hovg Web245782 WebsterBoj245900 NLD168175055 Leroy Abrian Tl245904 Glory 1619245915 961 Hukas245927 L Lil Boj245961 Hovg Deweb245964 Hovg Pasen245966 Hovg Deltw246075 Nixon 1209246250 D340717908 Emil CV246357 Boj Rav246440 FB Laluffe246636 Hovg Summe246678 Lambada 1361246679 Bossen246715 NLD176187525 Morgenster Chuck246751 NLD217851172 De Crob Dynasty246772 Bysk Mars246877 Ting Shall

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TABLE 7 (continued). Carriers of complex vertebralmalformation syndrome

Danish Original herd Nameherd book no.book no.246880 E 2003246965 NLD232136885 Katshaar Kirby246991 Bibi247169 Debel Jock247312 Bathau Do247425 TIR-AN Ridler Sabel

ET247571 F2298044708 Orcival CV247609 Havers Ned247789 Debel Curt247793 Ladin Boj247839 Jurmel 915247841 Curtis 2011247855 Dansire Ridler Rocker247982 Ting Inqui248100 D1401263093 Lucifer CV248131 Curtis Boj248294 Luffe 1491248410 NLD262656584 Holim Rafael248466 Holm Manat248568 NLD232138906 Welser Uruguay CV248587 Manor2186248588 Jest2023248633 S. Svane248634 NLD170943976 Janson248660 Vest248901 Debel Conca248905 US131102143 Bo-Irish Alton ET248928 Svane1914249001 Timer Rit249025 US17093333 Sikkema-Star-W Hi

Metro ET249042 Jensen 5249114 Champ 1157249116 Holme Oman249131 Lkm Lancelot 1249138 Lkm Kimmer 32249139 Lkm Lancelot 2249199 Ølgod Bob249401 No registered name249451 Svane2304249512 Svan1914249592 No registered name. The sire Ugela Bell is registered under two Danish

herd book numbers: 82685 and 245373.

TABLE 8. Carriers of osteogenesis imperfecta

Danish Original herd Nameherd book no.book no.228239 Guldager Fantastic

69

TABLE 9. Carriers of syndactylism

Danish Original herd Nameherd book no.book no.12346 SDJ Kran12361 VE Byg12818 NJY Star13229 HV Puns15425 SDJ Dallas82023 US1590283 Pineyhill Carnation Star82532 US1417290 Rincon Var Skyview

Lad82630 US1590582 Wayne-Spring Fond

Apollo235424 CAN362017 Hurtgen-Vue Marathon240552 NLD456911499 Ulkje Fari’s Wayne 403241592 I908017670 Olmo Prelude Tugolo244667 US17226843 McCloe-Pond Trent244751 NLD175029341 Agus Coolcat

TABLE 10. Carriers of acroteriasis

No registered carriers.

TABLE 11. Carriers of congenital paralysis

Danish Original herd Nameherd book no.book no.28836 VE Leo31221 Syf Fort

Additionally, the identities of a substantial number ofheterozygous sires have been published elsewhere(217).

TABLE 12. Carriers of bovine progressive degenera-tive myeloencephalopathy

Danish Original herd Nameherd book no.book no.32382 ØJY Lynbru32710 ØJY Hans32994 ØJY Højbo33018 US181608 H Brigeen D Lancer81057 US156458 Rolling View Modern

Stretch81087 ØJY Ingbru81116 VAR Brun81206 US171547 Johann Proud Matthew81226 US160195 West Lawn Dorset

Improver81250 US175105 Mort Modern Click81289 US172391 Century Acres Hollys

Answer81303 JMS Søbru81313 US175783 H Brigeen Elegant Lou81314 US175928 Twin Oak Jordan81339 VAR Dobru81601 US175545 Ventures Esp Babaray

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JØRGEN S. AGERHOLM

TABLE 13. Carriers of spinal muscular atrophy

Danish Original herd Nameherd book no.book no.31894 VAR Vit R32188 US177055 Ka-Wa Westley32409 US178634 Fox Trail Anchorman32685 FYN Smid32913 HV Garde32960 HV Hydro33326 JMS Balkan33391 RGK Larm33436 HJ Ager33456 FYN Bio33463 RANO April33473 JMS Calm33486 SYD Knut33491 US182822 Johann Lemmerman33499 RGK Lad33506 ØDA Fidus33531 RGK Luxus33559 SYD Krølle33561 FYN Tem33562 FYN Visir33589 HJ Foca33602 RGK Mouse33606 SYD Kato33607 SYD Kæk33608 SYD Komet33635 SYD Klint33636 SYD Krone33637 SYD Krake33639 FYN Malko33674 JMS Dest33721 US184303 Lone Oak Bvc Desperado33732 FYN Dolfus33749 ØJY Vind33750 ØDA Wold33804 HJ Kvist33838 SYD Lido33842 FYN Hasle33858 RGK Nyt33863 SYD Lyn33898 HJ Day33903 ØJY Buk33917 SYD Muld33937 FYN Best33938 RANO Eg33940 JMS Ekko33957 SYD Mely33970 HJ Kridt33974 ØJY Bob33979 RGK Nermi33986 SYD Mego33992 SYD Mango33999 ØDA Whist34004 SYD Mejle34015 RGK Obo

70

TABLE 13 (continued). Carriers of spinal muscularatrophy

Danish Original herd Nameherd book no.book no.34016 RGK Omak34063 RANO Bæk34091 T Fosen34136 FYN Fjord34157 T Spros34294 T Sneco34297 VEST Plank34338 FYN Lakmus34411 VEST Pil34412 VEST Pup34443 FYN Gejs34541 SYD Cap34551 SYD Carlo34592 ØDA Luton34670 T Vold34785 VEST Sne34865 T Pøst34870 SYD Draken35009 SYD Ebru35047 VEST Tatum35113 T Frisbjer35120 FYN Asger35147 VEST Uno35152 T Knustrup35318 ØDA Idum35843 R Aston FG35917 R Bistro81137 MRS Abru81205 US171713 Johann Evilo Rocket81208 US163153 West Lawn Stretch

Improver81284 RGK Focus81297 FYN Knubru81301 KOL Vilo81352 HV Dur

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TABLE 14. Carriers of spinal dysmyelination

Danish Original herd Nameherd book no.book no.32649 KOL Bali33222 US182072 Towpath Jupiter33434 HJ Kibo33549 ØJY Rim33790 US179303 Rolling View Conductor33995 ØDA Wampyr34013 ØJY Plou34063 RANO Bæk34123 SYD Andy34140 VEST Oli34168 SYD Ajax34178 VEST Old34182 SYD Ali34203 SYD Aks34209 VEST Poker34222 SYD Ahorn34231 SYD Assam34233 SYD Alex34234 SYD Astru34263 VEST Pro34264 VEST Præst34269 T Gærum34283 SYD Aura34292 FYN Erot34294 T Sneco34325 SYD Biki34327 SYD Agn34333 T Reng34335 T Knud34362 ØDA Condor34384 ØDA Jaco34406 T Fred34414 ØDA Empire34421 SYD Bold34423 SYD Bruno34429 ØDA Jevo34479 VEST Point34484 ØDA Cafir34498 ØDA Em-9234553 SYD Como34579 SYD Ceres34656 FYN Pit34662 ØDA Lanza34672 T Lars34718 SYD Cruso34788 T Hejn34826 FYN Taro34864 T Årslev34880 SYD Dito34882 SYD Dylan34942 ØDA Julius34970 Herman34991 T Eng35140 T Moritz

71

TABLE 14 (continued). Carriers of spinal dysmyelin-ation

Danish Original herd Nameherd book no.book no.35230 ØDA Master35595 T Tejo35681 FYN Dandy

TABLE 15. Carriers of syndrome of arthrogryposisand palatoschisis

No registered carriers.

TABLE 16. Carriers of ichthyosis foetalis

No registered carriers.

TABLE 17. Carriers of epitheliogenesis imperfecta

No registered carriers.

TABLE 18. Carriers of hereditary zinc deficiency

Danish Original herd Nameherd book no.book no.7095 Ham Hoorn7097 Hob Agi7136 Hhj August7200 Ska Presid7252 Hhj Odin8177 HHJ Adema8236 RDS Thor8965 KOL Hoff8982 VAR Kæk9105 ØJY Astor9210 Hob Gordon9928 NJY Vim9990 VE Star

10231 VAR Telsta10461 VE Daniel10581 NJY Pel10945 HV Komet11238 KOL Pabst11300 RGK Corr11526 JY Emyl11561 HJ Lars11667 NJY Mark11893 JY Skjold12065 SDJ Løkke13219 RGK Uran13221 RGK Tito13497 NJY Bay13726 NJY Bison15913 VAR Jenle15957 NJY Fritz17090 NJY Golf82134 NLD57700 Niertjes Adema 1282146 NLD60721 Emyl 2 V D Emma-

hoeve

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JØRGEN S. AGERHOLM

TABLE 18 (continued). Carriers of hereditary zincdeficiency

Danish Original herd Nameherd book no.book no.82149 NLD35953 Emyl 33 V D Emmahof82150 NLD57544 Frans Ij 256

TABLE 19. Carriers of renal lipofuscinosis

No registered carriers.

TABLE 20. Carriers of hereditary dilated cardiomyo-pathy.

Danish Original herd Nameherd book no.book no.10326 GJ Oskar11516 SK Black16175 SDJ Eksil33068 SDJ Calmo33288 ØDA Kro33385 SYD Jason33805 ØDA Wopper33852 ØDA Sum34052 FYN Rock34462 Pilg Debut35514 SYD Grease43977 DRK Nego81066 CAN331034 Maplelawn Cincinnati-

Red81177 FYN Banca81181 SDJ Otca81219 ØDA Solo82167 D9010361761 Tejo82168 CAN267150 Rosafe Citation R «RC82270 CAN260008 Romandale Reflection

Marquis82477 CAN198998 A B C Reflection

Sovereign82553 CAN290516 Agro Acres Marquis

Ned *RC84018 CAN326692 Narfa Western Star-

Red84020 CAN311569 Branderlea Citation

Topper-Red84025 CAN331034 Maplelawn Cincinnati-

Red84104 CAN312731 Romandale Royal-Red84112 CAN327403 Mapel Wood Prince-

Red. This table is based on the study by Leifsson and

Agerholm (IX). It includes not only the sire ofaffected animals but also the common ancestorand the sires at the root of the genealogicaldiagram. There is no definitive proof that thesesires are carriers of hereditary dilatedcardiomyopathy, only a strong indication.

72

TABLE 21. Carriers of bovine leukocyte adhesion de-ficiency

Danish Original herd Nameherd book no.book no.14249 NJY Cheri14452 RGK Lori14872 Basse Tvil16046 VE Knop16224 ØDA Sherif17001 US1667366 Carlin-M Ivanhoe Bell17037 HJ Daniel18382 NJY Hubert18582 ØJY Lerche18706 HV Vagon19881 VAR Malu82028 US1512026 Harrisburg Gay Ideal82070 US1719192 Arnold Acres Chief82085 CAN327279 Puget-Sound Sheik82129 US1702759 Penn-Dell Gay Jess82190 US1441440 Penstate Ivanhoe Star82220 US1563453 Willow Farm Rockman

Ivanhoe82266 US1189870 Osborndale Ivanhoe82642 US1842389 Lekker Ivanhoe Bell

Jesse-ET82668 US1954217 Dixie-Lee Ivanhoe

Henry-Et82685 US1920807 Ugela Bell.

82694 US1790625 Potts Southern Man-Twin

82701 US1799693 Arlinda Carl-Twin82715 US1753897 Yard-O-Ute Milu

Bookie82728 US1608425 Arlinda Cinnamon220270 VAR Mikro220415 NJY Ivanho221058 NJY Ibsen222300 US1856904 Thonyma Secret222345 ØDA Busk223083 NJY Karat223241 SK Drøn223303 US1874645 Pond Oak Pappy-ET223355 SDJ Jan223419 ØDA Bech223556 SDJ Jolle223601 CEN Sølv223678 ØDA Bertel223685 HMT Pilot223697 SDJ Jessor223699 SDJ Jubel223816 VE Ronson223818 VE Red223902 CAN369995 Lamport Hawkeye223987 CEN Alber223992 ØDA Ny224126 SDJ Jels224132 SDJ Jaket

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TABLE 21 (continued). Carriers of bovine leukocyteadhesion deficiency

Danish Original herd Nameherd book no.book no.224202 NJY Laks224204 NJY Leopol224207 NJY Loft224234 RGK Jajla224251 ØDA E T224304 US1882797 Ripvalley Na Bell

Troy-Et224337 VAR Pasca224429 FYN Flis224542 VAR Paso224543 VAR Pauli224544 VAR Pelro224833 HV Apon224837 HV Agern224894 HMT Rola224899 VAR Pepsi225010 SK Eli225054 SDJ Kerne225113 RGK Jepsen225192 SK Fregat225245 NJY Mads225246 NJY Mozart225253 NJY Multi225323 HMT Rival225375 SDJ Konto225384 RGK Jolly225398 RGK Jes225481 HV Banjo225500 VAR Pirat225602 US1903604 Relay Arise Swd

Vanguard-ET225633 VAR Pors225700 CEN Stedy225746 KOL Dingo225800 NJY Mobil225850 VAR Rabbi225870 SDJ Klink225976 SDJ Korup225988 JY Dors226154 HMT Shag226156 Per226190 VAR Pårup226202 US1927586 Tikvah Bc Julius-ET226311 RGK Kras226321 US Florida226322 US Alaska226323 RGK Kenja226353 CEN Imbel226365 VE Sonda226384 JY Secre226624 SDJ Lokal226643 US Oregon226671 NJY Makron

73

TABLE 21 (continued). Carriers of bovine leukocyteadhesion deficiency

Danish Original herd Nameherd book no.book no.226724 VE Sella226776 US Illinoi226817 KOL Finale226847 NJY Nexø226982 VAR Ringo227200 RGK Lans227275 VAR Ronson227347 NJY Nihof227349 NJY Nestor227365 SK Glob227379 VAR Rival227586 CEN Cling227787 VAR Salto227895 SDJ Lur227897 D105655294 SDJ Lebøl227926 HV Diskos227950 SK Gokart228067 VAR Sigurd228070 VAR Sirius228131 NJY Ocean228165 ØDA Tay228200 CAN384848 Hanoverhill Stardom228218 VAR Sonny228227 SDJ Milt228262 HV Domi228295 NJY Ole228308 NJY Ozon228326 SK Horn228352 Hess Hub228386 VAR Sober228396 SDJ Mango228398 SDJ Mesa228429 HMT Vidne228430 KOL Nibøl228467 RGK Lunk228576 HV Design228646 HV Depot228685 SDJ Malle228807 Hubert 856228830 CEN Imy228906 HMT Vang228908 HMT Veike228941 SDJ Mode229003 VAR Sultan229006 VAR Svend229009 VAR Tango229013 VAR Tax229035 VE Utopi229036 SK Hof229121 HMT Vagn229123 HMT Vilje229151 RGK Marabu229153 RGK Marv

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JØRGEN S. AGERHOLM

TABLE 21 (continued). Carriers of bovine leukocyteadhesion deficiency

Danish Original herd Nameherd book no.book no.229155 RGK Mamut229158 RGK Mentor229166 SDJ Nap229201 HV Dennis229202 HV Dakota229225 T Amerika229228 T Allegro229235 T Andy229299 Hubert 624229302 ØDA Vakka229311 US1936474 Belmont229332 KOL Viva229335 VAR Tebal229337 VAR Terry229342 VAR Tjep229349 FYN Inka229350 FYN Ir229351 SDJ Nis229352 ØDA Bobcat229353 ØDA Mugge229402 RGK Medusa229430 T Anglia229436 T Ambell229447 Bodils Hub229518 HV Duplo229551 T Alling229553 T Asa229558 T Aris229566 VAR Thomas229586 HMT Vups229609 KOL Key229617 Gun Hubert229628 VAR Tippo229631 VAR Tofte229634 VAR Tolk229637 VAR Tot229648 ØDA Varig229658 SDJ Notat229659 SDJ Nil229662 SDJ Neksø229663 SDJ Nøk229712 RGK Milt229713 RGK Mask229732 HV Ebbe229743 Thor229754 Slots Uhre229780 SDJ Nepal229781 SDJ Njal229785 SDJ Nørup229795 SDJ Nibe229803 T Bio229809 T Barbi229871 Drengs Hub

74

TABLE 21 (continued). Carriers of bovine leukocyteadhesion deficiency

Danish Original herd Nameherd book no.book no.229874 US1882141 Stan-Bitzie Kirk Bell

Boss229893 VAR Tone229972 RGK Mølle229976 RGK Nild229980 RGK Nør230043 ØDA Salom230110 T Blunk230125 SDJ Nivå230169 ØDA Visum230172 RGK Nørst230261 T Bern230284 Gamst Vang230303 FYN Jeppe230363 Højg Wilow230709 HV Ergo230773 Vejr Tong230915 Graum Vang230928 Lerche 645231147 Abs Annan231187 Bor Pontus231191 Møns Centa231289 Hou Hubert231311 Lindsø231402 Uffe231730 Hebo Hub231890 Høstrup231973 Mosl Laust232065 Westh232143 Nyrup 1278232147 Nyrup232219 Stardom702232222 Brøns Vang232268 Ares 491232318 Syd Hawkey232640 Otto 524232654 Otto 1052232665 NLD314390431 Oudkerker Constantijn232718 Bertus232726 Us Herbert232885 Nørg Hub232895 Steines233156 Hub 1618233567 Bit Holm233611 Hub 650233643 Hub 942233854 Bell 431233927 Dum234057 Højager234277 NLD460942030 Etazon Labelle-ET 528234280 Holm 429234290 Astre 1601234344 US1912270 Emprise Bell Elton

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TABLE 21 (continued). Carriers of bovine leukocyteadhesion deficiency

Danish Original herd Nameherd book no.book no.234426 Øst Weis234443 US2038151 Zee-Cal Commotion-

ET234755 Bork Huber234990 Vagn235049 Lun Stardu235224 Aero 582235286 CAN355454 Newlands Detective235593 Stamp Ast235777 Gj Bra235823 US2051549 Blackcrest Karmel-

Red-ET235859 US1626173 Eng-Amer Ivanhoe

Jerry236377 Dane Inspi236444 Birk Mount236503 NLD319957882 Delta Lava236534 Bor Vulcan236598 F2290038601 Fatal236975 Astre 913237028 Moun 720237087 Vej Hubert237428 Hubert 450237429 Hubert 472237569 Lubert237787 D107174081 Sturm237822 Mounspi238056 ØH Juror238446 NLD461308877 Etazon Lutz238647 Eksport238793 F5189001700 Enehould238865 Bellis238891 Thor 625238984 Låstrupgdr239438 F Labelle239726 Vil Fatal239749 Label 1401239946 Dissing 2240190 Fatal 1205240325 Blakihu240387 Ring Fatal240589 Fatal 899240622 Tirs Fatal240636 Eksport240647 Eksport240667 Fatal 1205240808 Høj Burma240957 Eksport241027 Burma 661241061 Lily Holm241265 Søren241375 Fatal 514241376 Fatal 1582

75

TABLE 21 (continued). Carriers of bovine leukocyteadhesion deficiency

Danish Original herd Nameherd book no.book no.241570 Labell241626 Årre L Leo241899 Kær Fatal241907 Ho Labell1241934 US397763 Haldrey Leadership241953 US2271271 Ricecrest Emerson ET242109 Eksport242236 Celsi 1419242266 Fecamp1159242529 Funki 1219243076 Tirs Marty243241 Hovg Boude244142 BGH Roscas244282 Uhre Basar244388 Tirs Emer244441 S Anton244442 S Anker244443 S Aksel244444 S Abel244793 Delta 1958244796 Tønnin Leo244858 V GroovyBL244891 Tirsvad Emerson

Cassius245051 P N Stone245373 US1920807 Ugela Bell.

245457 Houg Emers245509 Tir Fatal246759 Pors Marsh247097 Inquirer 1173247168 Manat 773247233 Tir-An Magna Clapson247716 Hes-Stoneham. The sire Ugela Bell is registered under two Danish

herd book numbers: 82685 and 245373.

TABLE 22. Carriers of congenital erythropoietic por-phyria

Danish Original herd Nameherd book no.book no.11516 SK Black18004 Black 18

226735 Klaus 323

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JØRGEN S. AGERHOLM

TABLE 23. Carriers of rectovaginal constriction

Danish Original herd Nameherd book no.book no.

4205 Onkel Sam4250 Rosenfeldt Favorit4419 SKÆ Trad4420 SKÆ Mark4432 Trademølle4452 HJ Kær4718 HJ Navr4843 Rosenfeldt Oktav4844 Rosenfeldt Fos4973 SKÆ Knap5037 ØDA Lux5095 SKÆ Kaj5339 SKÆ Ling5386 SKÆ Mors5519 SKÆ Bargo5528 Expert5587 ØDA Sambo5785 FYN Noes5829 Kildg Mark5940 Mors 725992 HJ Giv6002 ØDA Alsam6056 Lervang 746134 Østerg Sam6147 MRS Oks6253 SKÆ Fut

45427 FYN Dres45479 Såhøj Lux45491 HJ Tuby45492 HJ Stof45510 ØJY Lopa45635 Søgrd Mark46030 US627500 Sargent Plus83001 US585350 The Trademark

300439 US630261 Mayfield VolunteerBruce Twin

300850 US580714 Tristram Nevada

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TABLE 24. Carriers of tandem fusion translocation

No registered carriers.

TABLE 25. Carriers of translocationt(1;8;9)(q45;q13;q26)

Danish Original herd Nameherd book no.book no.33720 US184214 Sunburst Hill Combo

Fabian

TABLE 26. Carriers of translocation 1/29

Danish Original herd Nameherd book no.book no.68001 F4683132159 Ukrainien

(heterozygous)68005 F6485015667 Agenais (homozygous)

F4786011835 Balthazar(heterozygous)

TABLE 27. Carriers of the ‘‘Dag-defect’’

Danish Original herd Nameherd book no.book no.– Fåborg Dag– Fåborg RU.

. Fåborg Ru is most likely the full-brother to FåborgDag mentioned by Blom (36). Other carriers havebeen diagnosed but their identity is no longeravailable.