Genetic Causes of Mr

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The British Journal of Developmental DisabilitiesVol. 49, Part 1, JANUARY 2003, No. 96, pp. 29-44

MENTAL RETARDATION:

A REVIEW OF THE GENETIC CAUSES

Birgitta Winnepenninckx, Liesbeth Rooms and R. Frank Kooy

Birgitta Winnepenninckx, Ph.D.Postdoctoral Fellow, Department of Medical Genetics, University of Antwerp, Universiteitsplein

1, 2610 Antwerp, BelgiumLiesbeth Rooms, M.Sc.Ph.D. Student, Department of Medical Genetics, University of Antwerp, Universiteitsplein 1,2610 Antwerp, Belgium

*R. Frank Kooy, Ph.D.Senior Lecturer, Department of Medical Genetics, University of Antwerp, Universiteitsplein 1,2610 Antwerp, BelgiumTel: +32 (0)3 8202630 Fax: +32 (0)3 8202566 E-mail: [email protected]

* For Correspondence

Introduction

Unravelling the genetic causes ofmental retardation is one of the greaterchallenges of molecular genetics for the

next decade. Mental retardation, definedas a failure to develop a sufficientcognitive and adaptive level, is one of themost common human disorders. Mentalretardation is either the only consistenthandicap (called non-syndromic mentalretardation) or is combined with otherphysical and/or behavioural abnormalities(called syndromic mental retardation).According to estimates, 1-3% of thehuman population (Curry et al., 1997;

Roeleveld et al. , 1997; Croen et al., 2001)has an IQ below 70 and suffers fromlearning and adaptive disabilities. It is anunrivalled lifelong burden that has apredominating impact on the life of thepatient, his relatives and even on societyas a whole.

The causes of the impairment areextremely heterogeneous and although acause for mental retardation has beendiagnosed in only half of the cases, it has

been estimated that half of all cases aredue to environmental factors and half togenetic factors (FIGURE 1). Environmentalfactors include prenatal exposure of thefoetus to toxic substances (e.g., alcohol,drugs), environmental contaminants,radiation, infection, malnutrition, illness ofthe mother (e.g. exposure to rubella,cytomegalovirus) etc. In addition, multipleproblems during or after birth may causemental retardation. Although any unusualstress during birth may cause brain

damage, especially premature birth andlow birth weight may predict mentalretardation. During childhood, factorssuch as disease (e.g. measles), a blow onthe head, environmental toxins, etc. maycause irreparable damage to the brain andthe nervous system. Genetic factors



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FIGURE 1

Overview of causes of mental retardation. The prevalence is adapted from Curry et al., 1997.

Subtelomericabnormalities

6%

Fragile X syndrome1%

Other knownsyndromes and

conditions3%

Metabolic causes3%

Unknown causes,presumed genetic

25%

Chromosomalabnormalities

12%

Environmental causes25%

Unknown causes,presumed

environmental25%

TABLE IOverview of the types of genetic causes of mental retardation

Chromosomal abnormalities

Numerical chromosome abnormalities

Partial chromosome abnormalities

Cytogenetically invisible microdeletions

Interstitial deletions

Subtelomeric deletions

Monogenic causes

Autosomal dominant

Autosomal recessiveX-Linked

Polygenic causes

Mitochondrial disorders



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include chromosome abnormalities,monogenetic disorders and polygenicfactors (TABLE I).

As the impact of mental retardation onlife is so dramatic, determination of the

cause of the disease is of uttermostimportance. Only if the cause of thedisease is known, a prognosis of thedisease, a risk assessment and, if needed,a prenatal diagnosis is possible. Thecurrent paper summarizses the progressachieved in identifying the genetic causesof mental retardation and shortly issues onsome diagnostic and therapeutic methods.

Identified Genetic Causes

Chromosomal abnormalities

Chromosomal abnormalities areresponsible for up to 28% of all mentalretardation cases (Curry et al., 1997).

Chromosomal abnormalities includenumerical chromosome abnormalities,

partial chromosome abnormalities andmicrodeletions.

Numerical chromosome abnormalities

A numerical chromosome abnormalityis caused by additional (=polyploidy) ormissing (=monosomy) chromosomes fromthe normal set of 46. Aberrations in thenumber of chromosomes are easy to detect

by counting the chromosomes in spreadsobtained from blood cells under amicroscope. Reported live-born autosomalchromosome polyploidies are restricted totrisomy 13 (Patau’s syndrome), 18(Edwards’ syndrome) and 21 (Downsyndrome). Though the former two arerare, trisomy 21 (=Down syndrome) is themost frequent cause of mental retardation,

affecting on average 1 in 1500 but the risk increases exponentially with the age of themother. Patau’s syndrome and Edwards’syndrome share many features incommon. Patients are always severely

mentally retarded and most affectedchildren die during the first weeks after

birth. The fact that chromosome 13, 18 and21 are among the three gene-poorestchromosomes of the human genome(www.ncbi.nih.gov), may explain whyonly these polyploidies are viable.Monosomy of any autosomal chromosomeis invariably lethal at the earliest stage ofembryonic life. Numerical sexchromosome abnormalities are morecommon than numerical autosomalabnormalities, but not necessarilyassociated with mental retardation. Turnersyndrome (females possessing only one Xchromosome) and Klinefelter patients(XXY males) may be intellectually normal.However, once the number of X-chromosomes exceeds two, such as in the

triple X syndrome, patients are alwaysmentally retarded.

Partial chromosome abnormalities

Deletions, insertions, inversions,translocations etc. may occur on any partof any chromosome. Translocations canremain without clinical consequences aslong as they are balanced, without loss orgain of genetic material and do notinterrupt an important gene. A well-

known example is the Robertsoniantranslocation, which results from the

breakage of two acrocentric chromosomes(13, 14, 15, 21 or 22) at or close to theircentromeres followed by a fusion of thelong arms. The resulting hybridchromosome consists of two long arms offor instance chromosomes 14 and 21. Asthe short arm of these acrocentric



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chromosomes contains abundantribosomal sequences only, the carrier ofthis Robertsonian translocation remainsunaffected. However, the progeny of sucha patient may inherit an extra copy of the

long arm of chromosome 21 on top ofchromosome 14 and suffer from Downsyndrome, or may inherit an extra copy ofthe long arm of chromosome 14 and not

be viable.Deletions may cause diverse

phenotypes, depending on both the sizeand location of the deletion, but almostinvariably including mental retardation.As a general rule, deletions spanning morethan 2% of the total genome are notviable. Deletions with a minimum size ofroughly a single chromosome band, or 5-15 Mb, can be detected under amicroscope on chromosome spreads madeof blood cells. Examples of suchcytogenetically visible deletions includecri-du-chat syndrome, characterised bymental retardation and cat-like crying in

childhood. Upon karyotype examinationof patients, a deletion of varying size of

the short arm of chromosome 5 (or even atotal truncation), but invariably including the region 5p15.2-p15.3, may be identified.

Cytogenetically invisible microdeletions

Interstitial microdeletions

However, not all deletions are

cytogenetically visible. Some deletions aretoo small to detect under a microscope. Bydefinition, such so-called submicroscopicdeletions involve the loss of only a limitedchromosomal segment, taking away a fewgenes only and causing so-calledcontiguous gene syndromes. Suchdeletions do not occur at random positionsin the genome but tend to cluster in

specific regions. A submicroscopic deletioninvolving a segment on chromosome7q11.23 causes Williams-Beuren syn-drome, associated with mental retardationin combination with recognisable pheno-

typic features and an asymmetriccognition profile. Another contiguousgene syndrome is the Smith-Magenissyndrome, in which a deletion of a portionof 17p11.2 is associated with a striking phenotype including psychomotor andgrowth retardation, and behaviouralproblems. In addition, the velocardiofacialsyndrome, caused by a 22q11 micro-deletion, is characterised by cleft palate,cardiac anomalies, typical faces, andlearning disability. Such deletions are notroutinely detected by karyotype analysis,

but may be detected by fluorescence insitu hybridisation (FISH) with probesspecific for that chromosomal region uponrequest by an experienced clinician.

Subtelomeric deletions

A specific subcategory of cyto-genetically invisible deletions includesdeletions at the end of chromosomes.Chromosomal rearrange-ments involving the ends of chromosomes (telomeres) areemerging as a significant cause ofidiopathic (Flint et al., 1995) as well asfamilial mental retardation (Holinski-Feder et al., 2000). Telomeres arecomposed of a TG rich repeat (TTAGGG)n

which is similar in all vertebrates. This

simple sequence is repeated severalhundred to several thousand times andthe number of repeats is variable betweenindividuals and with age. Immediatelyadjacent to these repeats lie complexfamilies of repetitive DNA that may beshared among several chromosomes(Mefford and Trask, 2002). The function ofthese subtelomeric sequences, which may



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extend over a few hundred kilobases,remains unknown. The high degree ofsequence similarity could cause “cross-talk” between telomeric regions, a processfrom which the rearrangements may arise

(FIGURE 2). The telomeric regions areextremely gene-rich which explains whythe relatively small deletions ofsubtelomeric sequences frequently causemental retardation such as observed inthe Miller-Dieker syndrome (deletion ofthe 17p telomere) and the α-thalassemia/ mental retardation syndrome (deletion ofthe 16p telomere).

Though initial studies reportedidentification of subtelomeric deletions in

5-10% of all cases of idiopathic mentalretardation (Knight et al., 1999) the exactfrequency of these mutations still remainsunknown due to the fact that it is notpossible to detect these cytogenetically

invisible subtelomeric deletions by rou-tine karyotyping. The most frequentlyused technique to detect these rear-rangements is FISH in which fluorescenttelomere-specific probes for each telomereare hybridised to genomic DNA. As this isa laborious technique, relatively fewlaboratories have screened more than aselected series of patients. However,alternative techniques are being de-veloped that make use of a variable

FIGURE 2

Schematic presentation of the structure of a telomere

Homologuepairing

Subtelomeric zone

TTAGGG-repeats

A BChromosome

All human chromosomes end with the (TTAGGG)n sequence repeated hundreds to thousands of times. Adjacent tothese repeats lie various telomere associated repeats (indicated by black and white shaded blocks A-E) with a highdegree of sequence similarity. Each chromosome end contains different subsets of a limited set of subtelomericrepeats (here indicated as A-E). The subtelomeric rearrangements may be a result of the cross talk between thesehighly similar regions.



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mixture of 4-5 fluorescent dyes to label allhuman telomeres with a differentcombination of dyes. The karyotype maysubsequently be visualised with the aid ofa digital camera resulting in images of all

chromosome ends in a different colour.This facilitates the identification ofsubtelomeric deletions in patients, but atpresent the resolution of none of thesetechniques is significantly higher thanlight microscopy. However, in the future,adaptations of these fluorescent tech-niques might enable screening forsubtelomeric deletions on a routine basis.

Molecular methods under develop-ment to screen patients for a large

number of subtelomeric deletions includemultiplex amplifiable probe hybridisation(MAPH), which recovers short amplifiableprobes after hybridisation to genomicDNA. A first set of probes containing allchromosome ends has recently beencompleted (Hollox et al., 2002). In ourlaboratory, we focus on multiplexquantitative PCR reactions to screenapproximately 12 telomeres at the same

time. Quantitativity is assured by thefluodosage technique, measuring theincorporation of fluorescently labelledprimers.

If successful, this technique wouldallow us to screen all telomeres with only4 multiplex sets of primers.

Monogenic causes of mental retardation

Mutations in a single gene may disruptits function and may cause mentalretardation or a variety of phenotypesassociated with mental retardation,depending on the function of the mutatedgene and the impact of the mutation on itsfunction. A subdivision within this group

of disorders is based on the mode ofinheritance.

Autosomal dominant mental

retardation

As patients with mental retardationrarely reproduce, pedigrees of autosomaldominant mental retardation areinfrequently observed. However, patientswith an autosomal dominant form ofmental retardation may arise as aconsequence of a novel mutation, as is forinstance the case for patients withRubinstein-Taybi syndrome (Petrij et al.,

1995). This disorder, characterised bydevelopmental delay, stature, charac-teristic facial features, and broad thumbsand big toes, is caused by mutations in theCREB gene located on chromosome16p13.3. Milder forms of autosomaldominant mental retardation with variablephenotypic expression may remainhidden if patients are so mildly affectedthat their diagnosis is made only after the

identification of the disorder in a moreseverely affected family member.

Autosomal recessive mental retardation

Autosomal recessive transmission isoften observed in metabolic disorders,where a loss of function of both alleles hasto occur before enzyme levels become toolow to fulfil their function. These deficits

of an enzyme may cause an intracellularstorage of unprocessed substrates, ashortage of their products, a depletion ofcellular energy or the release of excessiveamounts of metabolites, causing all kind ofdisorders. Phenylketonuria (PKU), aninborn error of metabolism resulting froma deficiency of phenylalanine hydroxylase,



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is the most frequent cause of autosomalrecessive mental retardation. As a result ofthe enzyme defect, there is a shortage oftyrosine while phenylalanine accumulates.Another example is the Smith-Lemli-Opitz

syndrome, characterised by mentalretardation and multiple congenitalabnormalities. The disease is caused bymutations in both copies of the steroldelta-7-reductase (DHCR7) gene.

In addition, many isolated cases ofmental retardation may be caused by rareautosomal recessive mutations, though itwas only recently that the first causativegene involved in such isolated cases ofnon-syndromic mental retardation wascloned. A four base-pair deletion withinthe PRSS12 neurotrypsin gene was shownto be associated with mental retardation ina large pedigree with non-syndromicautosomal recessive mental retardation(Molinari et al., 2002). However, little isknown with certainty about the frequencyof such autosomal recessive mutations in

the population.

X-linked mental retardation

X-linked forms of mental retardationare estimated to cause 10-20% of allinherited cases of mental retardation and

thus may occur as frequently as 1 in 600males. The relatively high frequency of X-linked mental retardation explains theexcess of males over females observedamong the mentally retarded (Chelly andMandel, 2001; Leonard and Wen, 2002). AsX-linked disorders may be transmitted byunaffected carrier mothers, large X-linkedmental retardation families are occasion-ally observed, facilitating genetic analysisof these disorders (FIGURE 3).

At least 209 different X linked mentalretardation disorders have been described(Chiurazzi et al., 2001). 140 forms ofsyndromic mental retardation arediscerned and causative genes wereidentified for 27 of them. In addition, morethan 87 forms of non-syndromic mentalretardation have been described and

causative genes have been identified in 11

FIGURE 3

Examples of disease transmission in a family (MRX79) with X-linked mental retardation

Circles indicate unaffected females, squares unaffected males. Filled in squares indicate male patients. Carrierfemales, indicated by a circle with a dot in the middle, may transmit the disease to their progeny but are themselvesunaffected. Squares with a diagonal line through represents deceased family members.

1 2

1 2 3 4 5 6 7 8

1 2 3 4 5 6 7

I

II

II I



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non-syndromic forms of mental retard-ation. The localisation of presently clonedX linked mental retardation causing genesis shown in FIGURE 4.

Despite the impressive progression in

unravelling the underlying causes of X-linked mental retardation, diagnosis ofindividual cases remains problematic.Many X-linked mental retardationdisorders have been observed only in arelatively limited number of patients.Moreover, the prevalence of manymutations is so rare, that some familiesalmost seem to have their own, privatemutation. Therefore, none of thesemutations can be considered as candidatesfor routine screening, with the exceptionof the CGG repeat expansion in the fragileX-syndrome and possibly the A140Vmutation in the MECP2 gene (see further).In the future, gene expression analysisusing microarray technology mightsignificantly enhance the diagnosticpossibilities of cases suspected from X-

linked mental retardation. The majority ofknown mutations in X-linked genes are

loss-of-function mutations. Spotting allgenes of the X-chromosome on amicroarray would enable simultaneousscreening of hundreds of loss-of-functionmutations by simply hybridising RNA of apatient to a single grid.

Fragile X syndrome, the most commonform of inherited mental retardation

The fragile X syndrome is the mostfrequent and best-studied X-linkedsyndrome, which on its own has aprevalence of 1 in 4000-6000 (Kooy et al.,2000). It is a disorder characterised bymental retardation and typical physicaland behavioural abnormalities. Adultpatients suffer from mild to severe mental

retardation in addition to very specificphenotypic features (macroorchidism, along face, prominent ears, a high-archedpalate, and flat feet). Behaviouralproblems include hyperactivity, eye-

contact avoidance and repetitive speech aswell as autistiform features in a subgroupof patients. On chromosome spreads ofcells grown under specific cell cultureconditions, fragile X patients show a gapor break on the X chromosome, the so-called fragile site FRAXA. At the molecularlevel, the disorder is due to a dynamicmutation caused by the expansion of aCGG repeat located in the promotorregion at the 5’ end of the FMR1 gene(Verkerk et al., 1991). In the normalpopulation, the CGG repeat ispolymorphic, ranging from 5 to 50 copies,

but is stably inherited without sizechanges upon transmission fromgeneration to generation. However, incarrier females, the CGG repeat isenlarged, ranging from 50-200 repeats,

and is unstably inherited. Such anexpanded CGG repeat is longer than in

the normal population but is not diseasecausing. Therefore it is called apremutation. So, although female carriersthemselves are unaffected, upontransmission from mother to progeny theCGG repeat may expand up to 200 repeatsor more, resulting in fragile X syndromeonce this threshold is reached. Such anenormous expansion is called a fullmutation. Upon expansion of the repeatin fragile X patients, the promotor region

of FMR1 becomes hypermethylatedresulting in the transcriptional silencing ofthe gene. Consequently, FMR1 mRNA andprotein is absent in fragile X patients. Infemales carrying a premutation, thepromotor region remains unmethylatedand FMR1 protein is being produced.

In addition to the fragile X syndrome,expansion of a CGG repeat at other fragile



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FIGURE 4

Schematic representation of an X chromosome

G-banded map of the X chromosome showing the localisation of cloned genes responsible for syndromic (MRXS,only genes responsible for ‘pure’ syndromic mental retardation syndromes are shown) and non-syndromic (MRX)X-linked mental retardation. In some cases, different mutations in the same genes (indicated by an asterisk) cancause both syndromic and non-syndromic forms of mental retardation.



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sites has been reported to cause mentalretardation, including FRAXE (Gecz et al.,1996), associated with a milder form ofmental retardation and FRA11B associatedwith Jacobsen syndrome, characterised by

mental retardation and severe malfor-mations (Jones et al., 1995). In addition tothese fragile sites that have been clonedand proven to be associated with mentalretardation, a variety of other fragile siteshas been reported in patients with mentalretardation, including FRA2A, FRA11A,and FRA12A. However, at present it isunknown whether in these cases thefragile sites are also causative of thedisorder.

Mutations in the MECP2 gene may be afrequent cause of X-linked mentalretardation

Mutations in the MECP2 gene causeRett syndrome in females, characterised by

severe neurodevelopmental decay andmental retardation (Amir et al., 1999). Male

patients with Rett syndrome are extremelyrare as the Rett causing mutations in theMECP2 gene are lethal in hemizygousmales. Yet, MECP2 mutations differing from those that cause Rett syndrome wereidentified in as much as 2% of malepatients with non-syndromic mentalretardation (Couvert et al., 2001). Thissuggested that mutations in the MECP2gene might be a frequent cause of mentalretardation. However, this study did not

discriminate between a disease causing mutation and rare polymorphisms and itwas subsequently argued that theobserved variations in the MECP2 gene inmentally handicapped patients are notdisease causing mutations but rather rarepolymorphisms, unrelated to the diseasein the patient (Yntema et al., 2002). So far,the only well established frequent

mutation in the MECP2 gene is the A140Vmutation, recently postulated to be arecurrent mutation with an estimatedprevalence of 1 in 100 in X-linked families(Winnepenninckx et al., 2002).

Mitochondrial mental retardation

In addition to errors on the autosomesor sex chromosomes, defects inmitochondrial genes may also causemental retardation. Such pedigrees may

be apparent because of the maternalinheritance.

Polygenic mental retardation

It is generally assumed that polygenic,e.g. forms of mental retardation that arecaused by more than a single gene, are afrequent cause of mental retardation,especially amongst those patients that are

more mildly affected. In contrast to themore severe forms of mental retardation

that are caused by defects in a single gene,mild mental retardation does not follow aclear pattern of Mendelian inheritance. Itis common among descendants with asub-average socio-economic status.Although nothing is known about thegenetic causes of mild mental retardationas yet, it is generally assumed that amultitude of genes neither of which isnecessary nor sufficient for thedevelopment of the phenotype contrib-

utes to the disorder (Plomin, 1999).

The Diagnostic Process

In most cases, a diagnosis begins witha thorough clinical evaluation of thepatient. The clinician tries to obtain some



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insights in the severity of the disease,physical and behavioural abnormalities,family history, prenatal risks to which thepatient was exposed, problems during

birth, developmental milestones of the

patient etc. Based on the outcome of thisclinical evaluation, a diagnostic route is setup for each patient. A first step will be athorough investigation of the chromo-somes of the patient by checking chromosome numbers and the presence ofchromosome abnormalities. If negative,DNA screening for the fragile X syndromewill be performed. Depending on theoutcome of the chromosome and fragile Xscreening and on the clinical evaluation ofthe patient, a further screening formutations in specific genes or for thepresence of specific microdeletions may beperformed. Metabolic testing is performedonly in rare cases.

Therapeutic Intervention

Therapy today . . .

There is no drug interventionpossible for most forms of mentalretardation and therapy is limited to thetreatment of the anomalies or compli-cations accompanying the mentalretardation, such as the correction ofphysical malformations. In addition, it has

become apparent that the mentaldevelopment and the cognitive capacities

of mentally retarded patients may benefitfrom good education and support. Recentstudies have shown that it is possible to

boost the IQ of mentally retardedchildren by changing their environment(Duyme et al., 1999). By well-adaptedprogrammes including socialisation,physical development, language develop-ment and occupational therapies,

mentally retarded people may attain acertain degree of autonomy.

As possibilities for therapy for mentalretardation disorders are still limited atpresent, current strategies focus on

prevention of the disorder. If detectedearly in life, the mental retardation caused

by phenylketonuria can be prevented by alifelong diet without phenylalanine. Thisis why in many countries newborns areroutinely screened for this enzymedeficiency shortly after birth. Anothermental retardation disorder that can beprevented following early diagnosis iscongenital hypothyroidism. This disordercan be treated by thyroid hormonereplacement therapy. In addition, if agenetic cause of the disorder is known,prenatal diagnosis may be offered to thefamily

. . . and in the future

Perhaps due to its high prevalence,most therapeutic studies have focussed

on the fragile X syndrome. Recently, itwas discovered that intellectually normalor minimally affected individuals with anunmethylated full mutation still produceFMR1 proteins (Smeets et al., 1995). It wasconcluded that the silencing of the FMR1gene is caused by the methylationfollowing the repeat expansion and not

by the expansion itself. Inspired by thediscovery of these exceptional individ-uals, demethylating agents were used to

demethylate the expanded repeat inpatients. In vitro reactivation of FMR1expression in lymphoblastoid cells offragile X patients was obtained bytreatment with the demethylating agent5-azadeoxycytidine, which unfortunatelyis toxic for use on humans (Chiurazziet al., 1998). As this experimentdemonstrates the feasibility of restoring



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protein expression at least in culturedcells from patients, one of the futurechallenges is the search for less toxicdemethylating reagents that are specificfor the fragile X gene.

In addition, fundamental research onthe fragile X mouse model hasdemonstrated that the AMPA receptor ispotentially up regulated in thehippocampus (Huber et al., 2002). TheAMPA receptor is a neurotransmitterreceptor that is activated byneurophysiologic processes and isinvolved in memory and learning. Drugsthat directly interfere with the AMPAreceptor in the brain, called Ampakines™have been on the market for some time,and this has inspired clinicians to start totest whether those drugs may be used toameliorate the condition of a selectedgroup of fragile X patients.

However, speaking in general terms,the development of rational therapies formental retardation disorders is more

difficult than for any other type ofdisorder. This is due to the extreme

genetic heterogeneity. As drug targets willhave to be identified for each diseasegene separately, this would in no rarecases require almost an independentapproach for many individual mentalretardation families. Perhaps a morerealistic approach to develop therapywould be to increase our insights in howmutations in these mental retardationgenes leads to disease. Commonpathways might be involved in more than

a single disorder (Ramakers, 2002).Interfering in such pathways couldperhaps be exploited to ameliorate thecondition of patients suffering from morethan a single mental retardation disorderat once. Therefore, increasing our insightin the molecular causes of the mentalhandicap might lead towards realistic

therapies for mental retardation disordersin the future.

Summary

Mental retardation, defined by anintelligence quotient (IQ) below 70, is themost frequent cause of serious handicapin children and young adults with anestimated prevalence up to 3% of thepopulation. The handicap may be mild tosevere and may occur either as an isolatedphenomenon or in the company of othermaladies. Yet, as the handicap interfereswith the performance of essential skills ateach age, the impact of mental retardationon patient’s life and his environment isalways dramatic. Therefore, mentalretardation is one of the more importanttopics in medical science. The currentpaper summarises the advances made inunravelling the genetic causes of mental

retardation, estimated to be responsiblefor 50% of all cases, and issues on the

current diagnostic and therapeuticpossibilities.

Glossary

5' end of a gene

Definition of the beginning of a gene segment(3' respresents the end of the segment).

Acrocentric

Chromosome in which the centromere is very

near one end.Allele

Alternative form of a gene found at the samelocus on homologous chromosomes.

AMPA

Alpha-amino-3-hydroxy-5-methyl-4-isoxozolepropionic acid (AMPA) glutamate receptor.This neurotransmitter receptor is involved inmemory and learning processes.



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Autosomal

Any chromosome other than a sexchromosome (i.e. not an X or Y chromosome).

Centromere

The point at which two chromatids of achromosome are joined. This region isimportant for separation during theproduction of a new copy.

CGG repeat expansion

Repeated sequence CGG at the DNA level.When the number of repeats increases this isreferred to as an expansion.

Chromosomal regions (p & q, centromere)

A chromosome consists of two parts (arms), along and a short arm that are labelled q and p,respectively that are linked by a region knownas a centromere.

Contiguous gene syndrome disorderA disorder resulting from the deletion ofadjacent genes.

CREB

Activator protein of gene expression.

Cytogenetics

The study of chromosome structure usually bydirect observation.

Cytomegalovirus

A Herpes virus that causes pneumonia,retinitis (an infection of the eyes) and

gastrointestinal disease in immunosuppressedpeople.

Deletions

Loss of a DNA sequence.

Dominant

A trait that is expressed in individuals who areheterozygous for a particular allele.Heterozygotes are individuals who possesstwo different alleles at one particular locus on apair of homologous chromosomes.

Fluorescence in situ hybridisation (FISH)

A method for directly observing regions onchromosomes.

FMR1

Gene that causes fragile X mental retardation ifit is shut down.

Gene-poorest chromosomes

Chromosomes carrying a less than normalnumber of genes (the rest of the chromosomeconsisting of apparently non-coding (non-gene) DNA).

Genotype

Genetic constitution of an individual.

Hemizygous

Loss of one of the usual two copies of a gene(or multiple genes). This term also refers togenes carried by the X chromosome in maleswhere only one copy of this chromosome ispresent.

Hippocampus

Region of the brain involved in learning,memory and generation of emotions.

Hybridising

A single strand DNA/RNA probe sequencecomplementary to a target single strand DNA/ RNA sequence can hybridize to form a doublestrand. If the probe sequence is labelled insome way, it can be used to detect the target

sequence.Hypermethylated

Methylation is the chemical modification ofDNA (addition of a methyl group). DNAmethylation affects the ability of DNA to directthe production of a protein. Hypermethylated(overmethylation) DNA is often not able toproduce the protein whereas hypomethylated(undermethylated DNA) is.

Idiopathic

A term used in medicine to describe a diseaseor condition for which no known cause can be

identified.

In vitro

Used to describe experiments carried out in thetest tube.

Insertions

The additions of DNA sequences.

Interstitial

Region between two other defined regions.

Inversions

When DNA sequences are excised from thegenome, turned back to front and then

reinstated at the same spot, they are said to beinverted.

Karyotype

The observed pattern of chromosomes in cellsof an individual.

Loss-of-function mutation

A mutation that results in the loss of functionof a gene i.e. the loss of the ability to produce aspecific protein.



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Lymphoblastoid

Dividing cells of lymphocyte (white blood cell)like origin.

Microarray

A matrix consisting of very many spots eachconsisting of one gene sequence that can beused to hybridise to a specific probe or to thelabelled RNA from an individual.

Metabolic

Biochemical reactions required for the synthesisof biopolymers such as proteins or lipids.

Mitochondria

The cells power station, generating energy.

Monogenetic

Only one gene involved.

mRNA

Intermediate copied from DNA and used todirect protein production.

Mulitiplex

Multicomponent reaction.

Neuronal receptor

Receptor on the surface on neurons (cells of the brain).

Neurotrypsin (PRSS12)

Neuronal multidomain serine proteaseneurotrypsin (PRSS12), an enzyme that digestsproteins in the brain.

PCRPolymerase chain reaction, a method to amplifysmall amounts of a gene or gene product.

Phenotypic

Observable characteristics.

Polygenic

Controlled by more than one gene.

Polymorphic

A gene that can exist in many forms or lengths.

Polymorphism

The occurence in a population of two or more

genetically determined forms.

Promoter

Control region of a gene that drives theproduction of a protein.

Recessive

A trait that is expressed in individuals who arehomozygous for a particular allele.Homozygotes are individuals who possess twoidentical alleles at one particular locus on a pairof homologous chromosomes.

Ribosomal

A subcellular structure involved in proteinproduction.

Rubella

German measles.

Sex chromosomeX or Y chromosome, determining gender.

Sterol delta-7-reductase (DHCR7)

An enzyme involved in hormone regulation.

Substrate

The reactant in any enzyme-catalysedreaction.

Subtelomeric

Region just before the end of the chromosome.

Telomere

The end section of a chromosome.

Transcriptional silencing

Turning off of protein production from a gene.

Translocations

Incorrect rejoining of two brokenchromosomes so that genetic information thatis normally located in two different areas becomes juxtaposed.

Trisomy

Three copies of a chromosome, instead of theusual two copies.

Unmethylated

Nonchemically modified form of DNA that ismore likely to be active in directing proteinproduction.

X-linked

Located on the X chromosome.

Acknowledgements

Birgitta Winnepenninckx holds aresearch position of the Fund forScientific Research-Flanders (F.W.O.-Vlaanderen). Mental retardation researchin Antwerp is sponsored by the Fund forScientific Research - Flanders (FWO), theFragile X Research Foundation (FRAXA),a Belgian Interuniversity Attraction Pole(IUAP-V), and the National Organization



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for support of the mentally handicapped(NVSG)/Rotary Club Antwerp.

References

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Genetic Causes of Mr

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