Clinical and pathological case of

J. Neurol. Neurosurg. Psychiat., 1966, 29, 500

Clinical and pathological study of a case ofcongenital muscular dystrophy

S. S. GUBBAY, JOHN N. WALTON, AND G. W. PEARCE

From the Departments of Neurology and Pathology, Newcastle General Hospital,Newcastle upon Tyne

The classification of disorders giving rise to general-ized hypotonia of the skeletal musculature in infancyhas been discussed previously by Walton (1956,1957) who suggested that these cases can be separa-ted into three categories, namely, infantile spinalmuscular atrophy, symptomatic hypotonia, andbenign congenital hypotonia. Congenital musculardystrophy is one of the least common causesof symptomatic hypotonia in infancy and a reviewof the literature by Short (1963) revealed sevenreported cases with necropsy information, to whicha further case presenting with congenital hypo-tonia was added. Banker, Victor, and Adams(1957) have described the clinico-pathologicalfindings in two male sibs with congenitalmuscular dystrophy: the initial clinical picture inone of them was of arthrogryposis multiplex con-genita, whereas the other had hypotonic flaccidweakness without contracture at birth. Greenfield,Cornman, and Shy (1958) listed congenital or earlyinfantile muscular dystrophy of Batten amongstthe different conditions of muscle which can producethe clinical syndrome of weakness and hypotoniaat birth or in the early weeks of life.The following case report with biochemical,

histological, and electron microscopic findings isof a 5i-year-old child with congenital hypotoniaand weakness who also showed multiple contracturesgiving the appearance of arthrogryposis multiplexand in whom muscle biopsy has shown the histo-logical changes of progressive muscular dystrophy.It is thought worthy of record because of theapparent rarity of this condition.

CASE REPORT

H.T., a girl, was born at full term by normal delivery on5 October 1960 at the General Hospital, Bishop Auck-land, with a birth weight of 6 lb. 7 oz. Her mother, whowas 29 years of age at the time, had mild hyperemesisfor the first seven months of gestation and in the lastfew days before delivery her blood pressure becameelevated. The foetal movements which were observedduring pregnancy were thought to be unremarkable.

This was the mother's second pregnancy, the first beingcomplicated by toxaemia, and surgical induction threeweeks before term resulted in the stillbirth of a 3 lb.12 oz. female infant following prolapse of a non-pulsatingumbilical cord. No obvious abnormality was apparenton external examination of the stillborn child. Therehave been no subsequent pregnancies.The onset of respiration in the patient was immediate

after delivery although for the next two days she wassaid to have been very 'chesty'. Within the first week itwas noticed that she held her hands clenched in a fullypronated position and there was a paucity of movementin both upper limbs. These characteristics persisted andwere associated with a generalized floppiness of thelimbs and head and bilateral talipes deformities of thefeet. By the age of 6 months she had achieved onlyprecarious head control and had an ever-open mouthwhich gave the impression of mental defect. At oneyear it was evident that there was gross retardation ofmotor development, although judging by her generalbehaviour and attempts at speech mental developmentseemed normal. She was unable to roll over or sit un-supported and could not raise her arms above her head,although she was able to put her hands to her mouthwhen eating. At this stage the child was seen by one of us(J.N.W.) who found a generalized muscle weakness andhypotonia with marked weakness and wasting of proxi-mal muscles but no fasciculation of the tongue and nodefinite weakness of the chest wall musculature. All thedeep tendon reflexes excepting the knee jerks wereabsent. The differential diagnosis entertained at thisstage was between a non-progressive spinal muscularatrophy, congenital muscular dystrophy, and benigncongenital hypotonia.The patient was admitted to the Babies' Hospita[,

Royal Victoria Infirmary, in May 1962 for furtherinvestigation. The haemoglobin was 11-8 g./100 ml.;the total W.B.C. and differential counts and E.S.R.were normal. The serum albumin was 4-6 g./100 ml.and globulin 1-7/g.100ml., andelectrophoresisoftheserumproteins revealed a double beta band. T-waves were some-what flattened in V5 and V6 in the electrocardiogram buta chest radiographwas normalwith no evidence ofcardiacenlargement. The serum aldolase level was raised to 29-7units (Bruns), the S.G.O.T. was 58 units per ml. per min-ute, andtheserumcreatine kinase level 12-6 unitsaccordingto the method of Pearce, Pennington, and Walton (1964)

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Clinical andpathological study ofa case ofcongenital muscular dystrophy

FIG. 1 The patient, note the open mouth, the atrophy ofproximal muscles and contractures of biceps brachii.

(normal upper limit 4 0 units). Electromyography of theright quadriceps muscle using a concentric needleelectrode revealed no spontaneous activity and motorunit discharges appearing on volition were of lowamplitude but did not appear otherwise abnormal.Exploration of the right upper arm and examination ofthe biceps, brachialis, and triceps through a singleincision over the lateral aspect of the right arm wasundertaken on 24 May 1962 when the muscles werenoted to be tough and fibrous and to consist of pale,firm tissue with no resemblance to normal muscle. Abiopsy was taken from the biceps and the histologicalfindings are described below.The child was examined in detail at the age of 3 years

and 5 months on 4 March 1964. She was cheerful andcooperative and weighed 28i lb. with a height of 40inches. Her speech was normal for her age and sheappeared of normal intelligence. Her head floppedforward on to the trunk when unsupported and she tendedto hold her mouth open (Fig. 1). There was moderatebilateral facial weakness and she was unable to roll,sit up on her own, or stand. Widespread and moderatelysevere contractures of limb muscles had developed,especially of the biceps brachii (Fig. 2), long finger andtoe flexors, hamstrings, quadriceps and of the tendons of

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Achilles (Fig. 3). Gross restriction of movement wasnoted at both shoulders and both hip joints. The entirelimb musculature was of tough and fibrous texture,particularly in the calves, and this had been noticed bythe parents since birth. There was moderate wastingof the sternomastoids and shoulder girdle muscles withwinging of the scapulae, marked wasting of biceps,triceps, and deltoids, and slight wasting of forearmmuscles; the lower limbs appeared of normal bulk.Moderate generalized muscular hypotonia was evident.All muscle groups were very weak and, where applicable,were mostly unable to overcome gravity. The deeptendon reflexes were all abolished and the plantarresponses flexor. Sensation was intact and examinationof the cardiovascular and respiratory systems andabdomen was normal. The child has been re-examinedat six-monthly intervals and was last seen on 15 March1966. Muscular weakness has remained virtually un-changed; contractures have increased slightly and whileshe can sit unaided she is still unable to stand.

HISTOLOGICAL METHODS AND FINDINGS

For electron microscopy, three samples of muscle fromthe biopsy of the right biceps brachii were fixed in

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S. S. Gubbay, John N. Walton, and G. W. Pearce

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FIG. 3 Contractures in the lower extremities.

Palade's (1952) osmic fixative for two hours, stainedwith 1% phosphotungstic acid in absolute alchohol,and embedded in prepolymerized methacrylate. Sectionswere cut on an L.K.B. Ultrotome and examined with aSiemens Elmiskop 1 electron microscope. The remainderof the biopsy was fixed in formol calcium and embeddedin paraffin wax for light microscopy.

LIGHT MICROSCOPY The muscle fibres were everywhereembedded in dense connective tissue; they showed greatdiversity of size from considerable hypertrophy toextreme atrophy (Fig. 4). In most areas the fibres weremixed together without regard to size but a few areascomprised mainly atrophic fibres. However, there wasno evidence of grouped atrophy indicating denervation.Localized areas of muscle fibre necrosis and phago-cytosis were present and a group of phagocytes wasseen within the substance of one fibre when sectionedtransversely (Fig. 5).Many fibres were found to be rounded in outline when

cut transversely and centrally situated nuclei werecommon. Most of the muscle fibres were affected by the

disease process but cross-striations were commonlywell preserved. Not infrequently the longitudinal stria-tions formed by the individual myofibrils did not havevisible transverse banding and their parallel arrangementwas often in disarray. Hyaline or floccular degenerationwas seen in some fibres and involved the diameter inwhole or in part. Vacuolation was also seen occasionally(Fig. 6). Two small areas of sarcoplasmic basophiliawere present in the sections and both were surroundingtwo or three large vesicular nuclei containing prominentnucleoli. However, such regenerative activity wasscanty. Blood vessels showed no specific abnormality.One small collection of lymphocytes was present butother cells of inflammatory type were not seen. Thehistological picture was characteristic of progressivemuscular dystrophy at a moderately advanced stage ofthe disease process.

ELECTRON MICROSCOPY The appearance of the myo-fibrils varied from normality to fusion into a homo-geneous mass. The constituent myofilaments of themyofibrils were commonly seen to be lost, particularlyat the periphery, with thinning of the myofibril. Fusionof myofibrils was seen in many atrophic fibres so thatthe array of I and A bands was no longer discernible,but even in these severely damaged areas discrete myo-filaments, especially myosin filaments, could still beseen. The interfibrillar space was obliterated in theseareas but its previous site and the approximate boundar-ies of the fibrils could sometimes be determined by thepresence of short rows of empty vesicles which werechiefly the dilated remnants of the longitudinal sarco-tubular system. In these areas of coagulation necrosismitochondria, glycogen, and other structures usuallycould not be identified. In many sections the sarcolemmawas structurally normal while the external collagen layerwas greatly proliferated and apparently fused with theperiphery of the muscle fibre (Fig. 7). However, thiscase also showed that the sarcolemma could be inter-rupted or even absent when the underlying sarcomereswere relatively intact or showing minor changes only(Fig. 8).

Collagen was not observed actually within the sub-stance of the muscle fibres but it sometimes appearedto erode the fibre superficially from the peripherycausing a reduction in diameter of the fibre. Electronmicroscopical examination of this material has notshown actual macrophage or fibroblastic activity withina muscle fibre but only at its edges even though lightmicroscopy of one muscle fibre cut transversely did shownumerous centrally situated macrophages (Fig. 5);however, this section probably passed through theextremity of an area of segmental necrosis within afibre. Vesicles of various sizes were commonly presentimmediately beneath the sarcolemma or near to theperiphery of a fibre whose myofibrils had fused; manyof these vesicles were interpreted as dilated sarcotubularelements but some were probably mitochondria whichhad lost their internal cristae (Fig. 9). Such vesicles werecommonly found immediately below the sarcolemmaof dystrophic fibres but where the sarcolemma wasdefective or not clearly visible because of adherent

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FIG. 4. Fasciculi of muscle fibres are embedded in a mass of interfascicular connective tissue. Individual musclefibres show marked variations in size and shape, fibre splitting, and separation by strands of connective tissue.Haematoxylin and eosin x 100.

FIG. 5. One muscle fibre shows necrosis with central phagocytosis of necrotic sarcoplasm. This uncommon

appearance is probably explained by the fact that the transverse section passes through the extremity of an

area of segmental necrosis and phagocytosis. Haematoxylin and eosin x 256.

FiG. 6. Musclefibres showingvarying degrees ofnecrosis andfragmentation lie withinprolifera-ted connective tissue. Onefibreshows vacuolar degeneration andanother is undergoingphagocytosis.Haematoxylin and eosin x 256.

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FIG. 7. An electron micrograph showing a relatively normal musclefibre; immediately outside the intact sarcolemma is adense mass ofcollagen. x 27,000. (Z=Z line, My=myofibril, M=mitochondria, S=sarcolemma), i = I,.

FIG. 8. An electron micrograph showing relatively normal muscle apartfrom some dilated tubules, but the sarcolemma isnot visible throughout and the external collagen is dense, proliferatedand adherent. x 19,500. (C=collagen, V=vesicle.)


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FIG. 9. An electron micrograph showing four lipid bodies lying between the myofibrils; the sarcolemma cannot be seen.x 26,100. (L=lipid body, My=myofibril.)

collagen it may be postulated that some at least couldhave arisen from fibroblastic or phagocytic sourcesexternal to the muscle fibre. However, direct cellularevidence to support this suggestion is lacking and itseems unlikely. Small indentations into the peripheryof a dystrophic fibre have been seen which appear tocarry in collagenous fibres from the exterior but vesi-cular structures have not regularly been seen in relationto these indentations.

Nuclei commonly showed crenation of the nuclearmembrane and an intense coarse granularity whichseems likely to correspond with the hyperchromaticappearance of nuclei found with light microscopy.Collections of fine granules were sometimes concentratedimmediately internal to the nuclear membrane.

DISCUSSION

The clinico-pathological findings and the serumenzyme studies in this patient confirm the diagnosisof congenital muscular dystrophy, and other possi-ble causes of infantile muscular hypotonia and3

weakness have been excluded. This patient showednone of the clinical or histological features ofcentral core disease or nemaline myopathy.

Batten (1910) in his classification of the myo-pathies included a 'simple atrophic type' whichbegan at birth or in infancy, was characterized bygeneralized smallness of bulk, hypotonia, andweakness of muscles, and which was gradually pro-gressive with the formation of muscular contrac-tures. Histological evidence of muscular dystrophyin children with congenital hypotonia has beenrecorded by various authors (Lereboullet andBaudouin, 1909; Councilman and Dunn, 1911;Haushalter, 1920; Turner, 1949; Banker et al., 1957;Lewis and Besant, 1962; O'Brien, 1962; Short,1963). A pathological process in muscle whichappeared to be dystrophic has been described insome cases of arthrogryposis multiplex congenita byUllrich (1930), Middleton (1934), Stoeber (1938),Gilmour (1946), and Banker et al. (1957).


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FIG. 10. An electron micrograph showing a muscle cell nucleus with an extensively folded nuclear membrane and anabnormally granular internal structure. A concentration offine granules isfound imm?diately under several areas of thefolded nuclear mntembrane. The myofibrils are in disarray and numerous dilated tubules are present. The sarcolemma isdefective in parts and slight collagen proliferation is present externally. x 16,500. (N=nucleus.)

In retrospect it is unfortunate that a necropsyexamination was not performed on the stillbornelder sibling of the child described in this report, asthe demonstration of a similar disease process mighthave given further support to the view expressed byShort (1963) that this disease entity may well showan autosomal recessive pattern of inheritance.Roberts (1929) described a congenital deformity inlambs due to a dystrophic muscular disease whichwas inherited as a simple autosomal recessive factor.The reason why enzymes leak from a diseased

muscle fibre into the blood stream is unknown butit is widely assumed that this leak may depend upona defect in the muscle fibre membrane. Such a defectwould explain the raised serum aldolase andcreatine kinase levels found in this and in othervarieties of dystrophy. However, previous electronmicroscopical studies by several workers (see

Pearce, 1964) have demonstrated that in most formsof muscular dystrophy the sarcolemma is oftenremarkably resistant to structural change in spiteof internal damage to the myofilaments and amoderate degree of collagen proliferation outsidethe fibre. The absence of morphological change inthe sarcolemma even at electron microscopicallevel does not necessarily imply normal function,nor does it exclude the possibility that enzymemolecules may yet diffuse to an abnormal degreethrough the membrane. However, our findings inthis case demonstrate that defects in the sarcolemmaor even its apparent absence can be observed in amuscle fibre even when severe sarcomere damageis not present but when the external collagen issubstantially proliferated. The external collagenproliferation appears to be a process occurring earlyin this congenital form of muscular dystrophy, and,

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Clinical andpathological study ofa case of congenital muscular dystrophy

together with widespread fusion of the myofibrils,it presumably accounts for the striking contractures.Electron microscopy of this collagenous materialdemonstrates that not only is it present in sub-stantial amount but it may fuse with and possiblydamage the sarcolemma before definite or relativelyslight internal architectural alteration in the musclefibres is seen. It may be suggested that the interrup-tion or absence of the sarcolemma in these sectionscould be an artefact due to loss of the membraneduring embedding or the preparation of sections.We can only say that similar changes have not beenobserved by us in normal material similarly treatedand only very rarely in many sections of biopsiestaken from patients with muscular dystrophy of theDuchenne type.Our knowledge of the detailed submicroscopic

pathology of muscle fibre atrophy and necrosis andof connective tissue proliferation is incomplete. Inour descriptions of this material emphasis has beenplaced upon the loss and/or homogenization ofmyofilaments, myofibrils and mitochondria, disrup-tion and loss of the sarcolemma, and the collagen-ous proliferation which seems to be fused to theexterior of the fibre but does not directly invade itsinterior. A system of vacuoles without definiteinternal structure is often found congregated at theedge of damaged fibres. The origin of these vacuolesrequires elucidation but the great majority, if notall, appear to have arisen in the muscle fibre itselfand are most likely to be the remnants of dilatedlongitudinal sarcotubular elements.

Electronmicroscopy of this material has notshownevidence of fibroblastic invasion and proliferationwithin the substance of a muscle fibre except at itsextreme periphery where the sarcolemma appears tohave been damaged. Light microscopy shows thatareas of segmental necrosis and phagocytosis whichnot infrequently interrupt the continuity of musclefibres may be associated with local fibrosis; however,we have not seen in electron microscopic sectionscollagenous invasion of any part other than theperiphery of a dystrophic muscle fibre. Collagenproliferation thus exists as a phenomenon restrictedentirely to the surface of the fibre. Electron micro-scopy of the proliferated collagen shows that mostof the collagen fibrils lie in groups and are externaland usually parallel to the sarcolemma; only rarely dothe collagen fibrils lie obliquely to the fibre andthese are then few in number. The limitations ofelectron microscopy and the difficulties of samplingerror as well as those inherent in the interpretationof early changes mean that many more observationsare required upon such cases before the significanceof the pathological changes can be elucidated. Theconnective tissue proliferation observed in this case

was certainly much greater than that generallyobserved in cases of muscular dystrophy of theDuchenne type, and muscular contractures weremore striking clinically at an early stage of thedisease than in patients with other forms of musculardystrophy showing a comparable degree of muscularweakness. We are therefore impressed by thechanges seen in the connective tissue in this rarecondition of congenital muscular dystrophy and bythe apparent damage to the sarcolemma, but manymore observations will be required before we canunderstand their mode of production or assess thepart which they play in the disease process. How-ever, we do not wish to suggest that the collagenousproliferation necessarily plays an aetiological rolein the disease process as the changes observed in themuscle fibres themselves (degeneration, necrosis,phagocytosis, abortive regeneration) are sufficientin our view to indicate that the disease is primarilydue to a dystrophic process involving the musclefibres themselves. Nevertheless, this form of con-genital muscular dystrophy plainly differs in severalimportant respects, both clinically and pathological-ly, from other varieties of the disease.

SUMMARY

We describe the case of a child with congenitalmuscular hypotonia and weakness who also showedprogressive multiple contractures in profoundlyweakened limb muscles. A muscle biopsy revealedchanges similar in appearance to those of progressivemuscular dystrophy and alterations in serum enzymeactivity were consistent with a dystrophic process.It is concluded that this patient is suffering from therare condition of congenital muscular dystrophy,giving rise to a clinical picture resembling arthro-gryposis multiplex congenita.

We are grateful to Mr. J. Stewart, Miss M. Jenkinson,and Miss A. Brown for histological work and photo-graphy. This work was aided by research grants fromthe Muscular Dystrophy Associations of America, Inc.,the Muscular Dystrophy Association of Canada and theMuscular Dystrophy Group of Great Britain.

REFERENCES

Banker, B. Q., Victor, M., and Adams, R. D. (1957). Arthrogryposismultiplex due to congenital muscular dystrophy. Brain, 80,319-334.

Batten, F. E. (1910). The myopathies or muscular dystrophies. Quart.J. Med., 3, 313-328.

Councilman, W. T., and Dunn, C. H. (1911). Myatonia: congenita;A report of a case with autopsy. Amer. J. Dis. Child., 2, 340-355.

Gilmour, J. R. (1946). Amyoplasia congenita. J. Path. Bact., 58, 675-685.

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Greenfield, J. G., Cornman, T., and Shy, G. M. (1958). The prognosticvalue of the muscle biopsy in the 'floppy infant'. Brain, 81,461-484.

Haushalter, P. (1920). Sur la myatonie cong6nitale (Maladie d'Oppen-heim). Arch. Med. Enf., 23, 133-144.

Lereboullet, M. M., and Baudouin, A. (1909). Un cas de myatoniecongenitale avec autopsie. Bull. Soc. meid. Hop. Paris, 3 ser.,27, 1162-1166.

Lewis, A. J. and Besant, D. F. (1962). Muscular dystrophy in infancy:Report of two cases in siblings with diaphragmatic weakness.J. Pediat., 60, 376-384.

Middleton, D. S. (1934). Studies on prenatal lesions of striated muscleas a cause of congenital deformity. I. Congenital tibial ky-phosis. II. Congenital high shoulder. III. Myodystrophiafoetalis deformans. Edinb. med. J., 41, 401-442.

O'Brien, M. D. (1962). An infantile muscular dystrophy: Report ofa case with autopsy findings. Guy's Hosp. Rep., 111, 98-106.

Palade, G. E. (1952). Study of fixation for electron microscopy, J.exp. Med., 95, 285.

Pearce, G. W. (1964). Tissue culture and electron microscopy inmuscle disease. In Disorders of Voluntary Muscle, edited byJ. N. Walton, pp. 220-254. Churchill, London.

Pearce, J. M. S., Pennington, R. J., and Walton, J. N. (1964). Serumenzyme studies in muscle disease. Part II-Serum creatinekinase, activity in muscular dystrophy and in other myopathicand neuropathic disorders. J. Neurol. Neurosurg. Psychiat.,27, 96-99.

Pennington, R. J. (1964). Biochemical aspects of muscle disease. InDisorders of Voluntary Muscle, edited by J. N. Walton, pp.255-274. Churchill, London.

Roberts, J. A. F. (1929). The inheritance ofa lethal muscle contracturein the sheep. J. Genet., 21, 57-69.

Short, J. K. (1963). Congenital muscular dystrophy: A case report withautopsy findings. Neurology (Minneap.), 13, 526-530.

Stoeber, E. (1938). (lber atonis-h-sklerotische Muskeldystrophie(Typ Ulbrich). Z. Kinderheilk., 60, 279-284.

Turner, J. W. A. (1949). On amyotonia congenita. Brain, 72, 25-34.Ullrich, 0. (1930). Kongenitale, atonisch-skierotische Muskeldystro-

phie, ein weiterer Typus der heredodegenerativen Erkran-kungen des neuromuskularen Systems. Z. ges. Neurol. Psychiat.,126, 171-201.

Walton, J. N. (1957). The amyotonia congenita syndrome. Proc. roy.Soc. Med., 50, 301-308.

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