Journal of Neurology, Neurosurgery, and Psychiatry, 1972, 35, 435-450
Arthrogryposis multiplex congenitaPart 2: Muscle pathology and pathogenesis
DARAB K. DASTUR, ZOHRA A. RAZZAK, AND E. P. BHARUCHA
From the Neuropathology Unit, J.J. Group of Hospitals, andthe Children's Orthopaedic Hospital, Bombay, India
SUMMARY Pathological findings are reported on 34 specimens from 16 cases of arthrogryposismultiplex congenita (AMC), including initial observations on paraffin sections from 28 muscles, andsubsequent observations on six additional specimens from three of these cases studied both histo-logically and histochemically. Thirteen of the 34 specimens (from 11 cases) were histologicallynormal, probably on account of an unaffected muscle being sampled. The most constant patho-logical feature in the remaining specimens was a disorganization of the muscle fibres and fascicles bysevere fibrosis; only three specimens (from two cases) did not show this. Very thin faintly striatedmuscle fibres embedded in this matrix were encountered in 10 specimens from nine cases. Anattempt at grouping of these atrophic or ill-developed fibres was noticed in four specimens; but thismay not be denervation atrophy. Two specimens (from two cases) showed 'myopathic' features.Repeat biopsy after two to three years was carried out on two affected muscles each from threepatients. Case 3 showed well preserved but uniformly small fibres. Case 4 showed extremely few andscattered small rounded fibres. Case 14 showed pronounced variation of fibre size in both, with bothatrophic and hypertrophied fibres. Normal nerves and spindles were seen in all these six specimensirrespective of the state of the muscle, and excessive fibro-fatty tissue in cases 4 and 14. Histo-chemical examination for oxidative enzymes, ATPase, and phosphorylase in these six specimensrevealed a normal checkerboard pattern and ratio of type I and type IL fibres, in case 3 only. Themuscles of case 4 showed a preponderance of type I fibres. One specimen from case 14, showed thesame fibres reacting for both oxidative enzymes and phosphorylase, suggesting a lack of developmentof fibres. The intrafusal fibres were mainly of type I in all. Two possible pathogenetic mechanismsoperating in early embryonic life, which may lead to the characteristic changes of AMC, are dis-cussed: (1) a defect in the development of the muscle whereby the full recruitment of myoblasts fromthe mesenchyme of the limb-bud does not take place and muscles do not form adequately; (2) a lackof innervation of the muscles on account of arrested growth of anterior horn cells. The combinedoperation of both these mechanisms is also considered. Fibrous tissue replaces the muscle tissuethat is lacking, and contractures and deformities ensue. The evidence gathered on our material, suchas the very thin smooth muscle fibres, the large numbers of well-formed nerves and spindles especiallyin the repeat biopsies, and the above-mentioned histochemical feature, would appear to favour thehypothesis of ill-developed muscles in the production of AMC in the majority; in the rest denerva-tion playing either a major or concurrent role.
A brief review of the literature implicating the observed excessive amounts of fat and connec-joints and the central nervous system in the tive tissue in muscle biopsies and thereforeproduction of arthrogryposis multiplex con- emphasized the myopathic nature of the con-genita (AMC), has already been presented dition, which he called 'myodystrophia foetalis(Bharucha et al., 1972). Changes in the muscle deformans'. Rossi (1947) recognizing the con-have also been held responsible for the deformi- dition to be a clinical syndrome with joint andties. muscle involvement called it 'arthro-myodys-
In 1908, Howard described the condition as plastic syndrome'. Banker, Victor, and Adams'dystrophia muscularis congenita', emphasizing (1957) reported two cases of 'arthrogryposisthe muscular part of the defect. Middleton (1934) multiplex due to congenital muscular dystrophy',
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J Neurol N
eurosurg Psychiatry: first published as 10.1136/jnnp.35.4.435 on 1 A
ugust 1972. Dow
Darab K. Dastur, Zohra A. Razzak, and E. P. Bharucha
where the deformities were considered secondaryto the muscle changes, which were 'identical tothose seen in progressive muscular dystrophy'.Subsequently Pearson and Fowler (1963) re-viewed eight cases (two of their own in sibs) ofmuscular dystrophy with probable arthrogrypo-sis.
Sheldon (1932) had introduced the concept ofmuscular maldevelopment, through the nomen-clature 'amyoplasia congenita'. He postulatedan aplasia, hypoplasia, or dysplasia of certainmuscle groups leading to an imbalance at joints.Hillman and Johnson (1952) also suggestedmuscular aplasia as the primary lesion inarthrogryposis multiplex congenita. Kite (1955)had further incriminated a failure of embryonicmyoblasts as the first cause of all the changes.Frischknecht, Bianchi, and Pilleri (1960) re-ported cerebral defects, degeneration of pyra-midal tracts and anterior horn cells, and pseudo-myopathic changes in muscles in a family witharthrogryposis which he described under theall-inclusive title of 'neuro-arthro-myo-dysplasiacongenita'. Swinyard and Mayer (1963) reviewed70 cases and felt that the primary pathologicalchange may be in the spinal cord, in the musclesthemselves, or in the connective tissue. Theyexpressed uncertainty about AMC being eithera 'single disease entity' or a 'manifestation ofseveral different aetiologies'.To the best of our knowledge, there is only
one recent histochemical study of the musclesin AMC. Fenichel (1969) in a study of cerebralinfluence on muscle fibre typing includes sevencases with 'arthrogryposis', according to thedefinition of this condition given by Drachmanand Coulombre (1962) that it is 'a non-specificsign of foetal immobilization'. Fenichel con-siders 'arthrogryposis' to be a 'model of skeletalfixation during muscle maturation due toabnormal suprasegmental function'.The main objectives of this study have been
described by Bharucha, Pandya, and Dastur(1972). In the present paper the histologicalchanges observed in the muscles will be describedand our current views on the pathogenesis ofAMC will be presented.
Initially 28 muscle biopsy specimens were availablefrom 14 cases (two specimens each were availablefrom 10 cases and three from two). Paraffin sectionsstained by haematoxylin and eosin (H and E), thepicro-Mallory method for connective tissue, and by
phosphotungstic acid haematoxylin (PTAH) wereexamined in each case. Muscle fibre diameters weremeasured in most by micrometry.
Later, from three of the children who could berecalled, two further muscle biopsy specimens fromeach could be obtained. Fresh frozen sections ofthese were processed for the following histochemicalreactions: succinic dehydrogenase (SDH) andreduced nicotinamide adenine dinucleotide (NADH),for oxidative enzyme activity; myofibrillar adenosinetriphosphatase (ATPase); and phosphorylase forglycolytic enzyme activity. Fibre diameters weremeasured and ratios of type I to type II fibres wereobtained. In addition, fixed frozen and paraffinsections were stained with H and E, picro-Mallory,and PTAH stains. Thus in all 34 muscle biopsieswere studied.Serum creatine phosphokinase (CPK) was esti-
mated in four cases by the method of Hughes (1962).
FIRST EXAMINATION The histopathological ob-servations in all cases biopsied are summarizedin Table 1. The largest pathological group of
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FIG. 1. (NP/E/830b). Very thin muscle fibresembedded in fibrous tissue; two normal sized fibres atthe upper end. H and E, x 265.
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FIG. 2. (NP/E/613a). (a) Ill-defined group of very thinimuscle fibres contrasting withgroup of well-formed fibres,both in fibrous matrix. Noteessentially normal musclespindle in the latter. H anid E,x 105. (b) Same muscle showinigcross-striations on very thinfibres of slightly varying sizePTAH, x 660.
muscle comprising 10 specimens from ninecases, showed a similar type of change, ofgreater or lesser severity in different cases. Thisconsisted essentially of a dense fibrosis withtotal lack of organization of muscle intofascicles together with the presence of very finemuscle fibres embedded in this fibrous tissue.Thus Fig. 1 shows very fine strands of musclefibres in a collagenous matrix, contrastingstrikingly with two much larger normal fibres. Inanother area of the same muscle, fibres of aslightly larger dimension, of varying sizes butstill small, are seen. This was from the quadri-ceps muscle of a 2 year old girl, with an averagefibre diameter of 9-7 . only and a range of5-17 ,u. In this case the biopsy of anothermuscle, the deltoid, showed even less muscletissue in the form of thin straggly fibres.
A clearer contrast between the better preservedand the thin fibres which are now attempting agrouping is seen in Fig. 2a from the deltoidmuscle of an infant aged 15 months; a normalmuscle spindle was also encountered. Even thevery small fibres which average 9 4 ,u in size, incontrast to the normal fibres of 38-1 u, showedclear cross-striations with PTAH staining (Fig.2b). In five muscle specimens from five casesPTAH stain revealed cross-striations even inthin fibre