Congenital muscular dystrophy with cerebral white matter hypodensity. Correlation of clinical features and merosin deficiency

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Brain & Development1996; 18:53-8

Original article

Congenital muscular dystrophy with cerebral white matter hypodensity. Correlation of clinical features and merosin deficiency Umbertina C. Reed a,*, Suely K. Marie a, Mariz Vainzof b, Paulo B. Salum a, Jos6 Antonio Levy a, Mayana Zatz b, Aron Diament a a Departamento de Neurologia, Hospital das Cllnicas, Faculdade de Medicina, Divisgto Cllnica Neurol6gica, Av. Dr. Eneas de Cart'alhoAguiar, 255, 5° andar, sala 5011, CEP:05403-000, S~o Paulo, SP, Brazil b Departamento de Biologia, lnstituto de Bioci~ncias, Universidade de S~o Paulo, S~o Paulo SP, Brazil

Received 17 April 1995; accepted 2 August 1995

We report clinical and pathological findings in 9 children affected by congenital muscular dystrophy with normal or borderline intelligence and hypodensity of cerebral white matter (CMD-HWM), also frequently called 'occidental or western form of cerebro-muscular dystrophy' (OCMD). Our patients have uniform, distinct, clinical presentation that includes: normal or subnormal intelligence, severe, slowly progressive motor disability, high rate of facial involvement and dysmorphic aspect, increased creatine kinase levels and variable degrees of abnormal, radiographic, cerebral white matter pattern. By comparing our cases with previous reports we suggest that this subtype of CMD is not uncommon in Brazil and it is represented by a particularly severe and homogeneous clinical picture with important motor disability. The immunohistochemical staining for merosin, performed on the muscle biopsy of 6 among 9 patients, showed that all are merosin negative. Keywords: Congenitalmusculardystrophy, non-Fukuyamatype; Occidentaltype cerebro-musculardystrophy; Cerebral white matter hypodensity;Merosin

1. I N T R O D U C T I O N Congenital muscular dystrophy (CMD) is a clinically heterogeneous group of muscular disorders characterized by an autosomal recessive mode of inheritance in the majority of cases, early onset of hypotonia, generalized muscle weakness with joint contractures of variable degree, histopathological muscle changes of dystrophic type and by a possible association with central nervous system (CNS) and eye abnormalities. The course and severity may vary substantially [1-4] from more benign, apparently nonprogressive or slowly progressive forms to severe, rapidly progressive ones. For many years the most useful criterion for the classification of CMDs has been the absence or the presence of the CNS involvement [1,3]. This criterion allowed subdividing the CMD into a 'pure' muscular type and a more complex heterogeneous subgroup associated with CNS abnormalities that included [5]: Fukuyama's CMD (FCMD), cerebro-ocular dysplasia-muscular dystrophy syndrome (COD-MD), CMD with normal or subnor-

* Correspondingauthor. Fax: (55) (11) 852 0063/853 0698/285 6808. 0387-7604/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSD1 0387-7604(95)00098-4

mal intelligence and hypodensity of cerebral white matter on CT scan (CMD-HWM). In addition some forms do not fit into any category. The classification of CMD was discussed at the 22nd European Neuromuscular Consortium-Sponsored Workshop on CMD in Baarn, the Netherlands [6] and 3 subtypes were recognized: type I, without severe impairment of intellectual development; type II, with severe impairment of intellectual development including FCMD; and type III, which includes all 'muscle-eyebrain' syndromes and a number of uncommon forms (e.g., congenital atonic-sclerotic or Ullrich disease). The CMD-HWM has been considered an intermediate form between pure CMD and FCMD, frequently named the 'occidental or western' type of cerebro-muscular dystrophy [7-9] and now, according to the multinational Baarn Workshop [6], is classified as a subtype of type I CMD. Until recently only FCMD, originally described and common in Japan, had been associated with leukodystrophic appearance on CT scan. In Japan, CMD-HWM is sporadic and is preferentially mentioned as non-Fukuyama type of CMD [10,11]. The prevalence of CMD-HWM in western countries is well documented [5,8,9,12-14], but it is remarkable that its occurrence among CMD patients seems to vary in different countries. For example, Topaloglu et al. [8,9] and Cook et al. [14], respectively

U.C. Reed et al. / Brain & Development 1996; 18:53-8

54 Table 1

Clinical findings in 9 patients with CMD-HWM Case

1

2

Sex Age at examination Consanguinity Family history Head control Sit when placed Stand alone Maximal motor ability Congenital hypotonia Joint contractures Areflexia Facial muscle involvement Intelligence Epilepsy Cardiac findings Ophthalmic abnormalities Course Age at final follow-up CK (fold increased) EMG CT MRI

F M 2mo 18d ly one sib one sib 11 mo 3 mo 2y 9mo llmo . . . sit sit + + + + + + + + IQ 116 IQ 84 + nl nl . . . sl prog non-prog 10y l l m o 7y 10mo 27 X 14 X myog myog HWM HWM T2 WMHy T2 WMHy

3

4

5

F ly l l m o + 3 sib 9 mo 10mo . sit + + + IQ 83 + nl . non-prog 5y 4mo 7x myog HWM -

F 6y 6mo 9 mo ly 2mo . sit + + + + IQ 81 . . nl . non-prog 8y 3X myog HWM T2 WMHy

M ly 6mo + 10 mo 10mo

6

7

8

F F M ly 8mo ly 10mo 6mo . . . . cousin 8 mo 9mo 5mo 9mo 12mo . . . . sit sit sit sit + + + + + + + + + + + + + + + + + DQ 71 DQ 112 DQ 82 nl . . . . nl nl nl nl . . . . sl prog sl prog sl prog ? 3y 8mo 2y 3mo 3y lmo ly 3mo 5x 4X 3x 42 × myog myog myog myog HWM HWM HWM T2 WMHy T2 WMHy T2 WMHy T2 WMHy

9 F ly 2mo

4mo 8mo sit + + + DQ 111 nl ? 2y 4mo myog HWM T2 WMHy

F: female; M: male; y: years; mo: months; d: days; nl: normal; sib: sibling; sl: slowly; prog: progressive; myog: myogenic; HWM: hypodensity of white matter; WMHy: white matter hypersignal.

in Turkey and in Saudi Arabia, reported a frequency o f 3 0 - 5 3 % , while Leyten et al. [3,15] found that less than 10% of C M D patients had hypodensity on CT scan of the white matter suggesting hypomyelhaation.

The aim of this report is to analyze clinical and pathological findings in 9 Brazilian cases with C M D - H W M , emphasizing that in our country the incidence of this type of C M D appears to be particularly high.

Fig. 1. Case 6 at 22 months of age. Left: severe muscle hypotonia and weakness. Motor developmental delay. Right: MRI findings - diffuse hypersignal on T2-weighted image in supratentorial white matter.

U.C. Reed et al. / Brain & Development 1996; 18:53-8

2. P A T I E N T S A N D M E T H O D S From 1984 to 1994, 9 patients aged 2 months to 6 years met the criteria for diagnosis of CMD-HWM: (1) hypotonia and muscle weakness at birth or during the first months of life, (2) normal or subnormal intelligence, (3) dystrophic changes on muscle biopsy, (4) leukodystrophic appearance on neuroimaging studies. All patients were clinically and neurologically evaluated and had their family history taken. Cardiac examination, ophthalmological examination and electromyography (EMG) were carried out in all children. Psychological tests were performed in 8 patients by means of the BrunetL6zine Scale of Psychomotor Development in 4, the Stanford-Binet Intelligence Scale in 3 and the Wechsler Intelligence Scale for Children (WlSC) in 1 child. For the Brunet-L6zine scale the resulting general developmental quotient (DQ) was calculated excluding the score of the item postural/motor development. Serum creatine kinase (CK) level was determined in 8 patients. Eight patients underwent CT scan using standard equipment. Magnetic resonance imaging (MRI) on GE 1.5 Tesla was performed in 8 patients. All children have been followed up for a period that varied from 9 months to 10 years and 9 months. Muscle biopsy specimens were taken from all patients. Frozen slices were stained with hematoxylin and eosin, modified Gomori, periodic acid Schiff, oil red O, NADH-tetrazolium reductase, succinate dehydrogenase, myofibrillar adenosine triphos-

55

phatase pH = 4.3 and 9.4, alkaline and acid phosphatases and cytochrome c oxidase. The muscle biopsies of 6 patients were subjected to immunocytochemical analysis for merosin. Details of this study are being submitted elsewhere (Vainzof et al.).

3. R E S U L T S The clinical features and the results of laboratory, neurophysiological and radiographic investigations of the 9 children (3 males and 6 females) are summarized in Table 1. In 2 cases the parents were first cousins. Three patients had siblings with similar symptoms of severe muscle involvement, one of them (case 3) with 3 affected siblings. These 5 siblings died during childhood (at 14 months, 15 months, 4 years, 7 years, 7 years), 4 of them without specific neuromuscular evaluation and without any neuroradiologic examination. Only the sibling of case 1 had a diagnosis of myopathy and arthrogryposis, in another service. A second degree cousin of patient 6 has been reported to have similar symptoms, but he could not be evaluated by us. At birth and during the first months of life all patients presented with hypotonia and diffuse moderate weakness (Fig. 1, left). Only one child (case 1) presented also with joint contractures at birth. There were no reports of feeding difficulties, except in one baby (case 4), but 4 patients had one or more infectious respiratory diseases during the first years of life. Motor development was greatly delayed in all children and none was

Fig. 2. Case 4 at 6 years of age. Left: moderate muscle atrophy and joint contractures. Right: MRI findingds - focal hypersignal on T2-weighted image in frontal and temporal white matter.

U.C. Reed et al. /Brain & Development 1996; 18:53-8

56

Fig. 3. Case 1 at 7 years of age. Left: severe dystrophic aspect, diffuse joint contractures, kyphoscoliosis and facial involvement. Right: MRI findings diffuse white matter signal alteration.

Mental status was evaluated by means o f formal psychometric testing in 8 children and by clinical examination in one (case 8). In relation to the s o c i a l / c u l t u r a l / e c o n o m i c a l pattern o f patients that attend our public institution, 8 patients were considered o f normal intelligence and one (case 5) was considered slightly retarded. Follow-up examination (from 9 months to 10 years and 9 months) s h o w e d that the course o f the illness was apparently nonprogressive in 3 and slowly progressive in another 4. In the last 2 patients the time o f follow-up (9 and 10 months, respectively) is not enough to render an adequate evaluation o f the course o f the illness. Follow-up o f patient 3 was discontinued after a period o f 40 months. Cardiac and ophthalmologic evaluations showed no abnormal-

able to stand or walk without support. All s h o w e d normal speech development. In most patients the legs were more impaired than the arms and the proximal muscles more than the distal. All patients had areflexia and all but one (case 9 ) developed multiple joint contractures (cases 1, 2 and 3 in the 4 limbs; cases 4, 5, 6, 7 and 8 only in knees and ankles) (Fig. 2, left). Case 1, the oldest o f our patients and the only child with foot deformities visible at birth, developed severe kyphoscoliosis o f the thoracolumbar spine (Fig. 3, left). Bilateral facial muscle involvement was evident in 6 patients and one o f them (case 4) s h o w e d dysfunction o f muscles innervated by the eleventh cranial nerve. Two patients (cases 1 and 3) had seizures (partial c o m p l e x and generalized tonic-clonic seizures) at 9 years o f age and during the first year o f life, respectively.

Table 2 Muscle biopsy findings in 9 patients with CMD-HWM Case

1

2

3

4

5

6

7

8

9

Fat increase Increased fibrosis endomysial perimysial Variation in fiber size Degenerating/necrotic fibers (%) a Type I fibers (%) a Merosin immunostaining

+ +

+

+ + +

+ + +

+ +

+ + +

+ + +

+ + +

+ + +

+ + + + + + + + 32.7 85 -

+ + + + + + 9.3 90 -

+ + + + + + + + + 7 90 nd

+ + + + + + + + + 12.7 90 -

+ + + + + + 5.5 77 nd

+ + + + + + + + + 18 80 -

+ + + + + + + + + 10 85 -

+ + + + + + + + + 16 90 nd

+ + + + + + + + + 43.7 80 -

Score: - : none; + : slight; + + : moderate; + + + : severe. a Percent of acid phosphatase positive fibers and type I fibers based on myosin ATPase, pH 9.4 staining, counted on 400 X field; nd: not done; - : negative.

57

U.C. Reed et aL / Brain & Development 1996; 18:53-8

Table 3 MRI findings

Case

1

2

4

5

6

7

8

9

Age at examination TR/TE FrontalWM ParietalWM TemporalWM Occipital WM Internal capsule Basal ganglia Corpus callosum Atrophy

7y 2500/90 +++

5y 2100/90 +

6y 2100/90 +

19too 2900/120 +++

22mo 2900/120 +++

2y 2900/120 ++

6mo 2500/90 ++

15mo 2100/90 +++

+++

+

-

+++

+++

++

++

+++

+++ PV . . . .

PV

+ PV

+++ + + + . . . .

+++ + +

+ PV

++ PV

+++ + + +

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

TR: repetition time; TE: echo time; PV: periventricular white matter involvement; + + + : severe; + + : moderate; + : slight white matter involvement. Case 3: MRI not done. ities in all children. The CK level was slightly increased in 2 patients, moderately increased in 3 and markedly elevated in 3 patients. EMG studies showed a myopathic diffuse disorder with abnormal myogenic potentials and normal nerve conduction velocities in all patients. Seven children had head CT scan and MRI examination. Case 3 had only CT scan and case 8 only MRI. CT scans were repeated once in 2 children (cases 1 and 2) with an interval of 3 years. All 9 patients had diffuse changes in the white matter of the CNS (Figs. 1-3, right), that remained unchanged in cases 1 and 2. The leukodystrophic pattern of case 8 could be attributed to incomplete myelination and sequential exams will be necessary to confirm the real nature of this finding. We did not observe any developmental changes, atrophic alterations, or ventricular dilatation in neuroimaging studies on all children. Findings of muscle biopsy in 9 patients and head MRI in 8 are summarized in Tables 2 and 3, respectively.

4. D I S C U S S I O N The 9 patients from the present report belong to the subtype of CMD with normal or subnormal intelligence and hypodensity of cerebral white matter on CT scan (CMD-HWM), which some authors refer to as the ' western' form of cerebromuscular dystrophy [7-9] to differentiate it from the FCMD subtype, originally described in Japan [2]. It is questionable whether the designation 'western' form should be kept because this subtype was also described in non-western countries like Japan [10,11], China [16], Saudi Arabia [14] and Turkey [8,9]. Yoshioka [17] and Echenne [18] consider it preferable not to utilize the designation 'western' form of CMD, as there are not sufficient pathological and follow-up studies to clarify the nature of the brain white matter attenuation. To us the purely descriptive designation of CMDHWM seems more adequate, as there are already so many reports of patients with these characteristics [5,7-16,19-22] to allow the identification of a clinically more severe subgroup of CMD that includes a high rate of fibrotendinous retractions and facial involvement, normal intelligence or slight mental deficiency, nonprogressive or gradually progressive course in spite of evident invalidity, and cerebral white matter hypodensity on CT scan or MRI examination [5,7-9,14]. Even authors who reported isolated cases [7,10,11] consider that CMD-HWM should be regarded as a homogeneous subgroup that is more common in western countries. Besides the more frequent clinical findings described above, it is possible occasionally to find dysmorphism such as an

elongated face and ogive palate [7,8,18]. The former aspect was evident in 2 of our patients. An increased CK serum level was verified in all of our patients examined, in accordance with most of the reports [8,9,12-14,20]. The exact nature of the CNS involvement in CMD-HWM and in other subtypes of CMD has not yet been elucidated. Some authors consider the existence of a 'continuum' of disorders of brain organogenesis associated with CMD, which when severe would correspond to FCMD or COD-MD and when more discrete to CMD-HWM [5,13,14]. Others disagree, emphasizing that FCMD and COD-MD have different neuropathological findings, and should be recognized as different disease entities [23,24]. However, cases have been described with clinical and radiological aspects that could be considered intermediate between FCMD, COD-MD and CMD-HWM [25-27]. As observed by Pihko et al. [12], we cannot find any explanation for the variable incidence of the CMD-HWM form among the total number of CMD patients. In different series the reported incidences varied from 0 to 58% [3,8,9,12-15,19,21,28]. In Brazil, our 9 patients corresponded to 37% of our CMD cases, which together with the 58% of CMD patients described by Oliveira et al. [19] allows us to conclude that the CMD-HWM form is relatively common in our country. The high rate of consanguinity and familial cases verified by different authors [8,9,12-14,18,22] and also in our series gives support to autosomal recessive inheritance that occurs in most of CMD cases [1,3,4]. The occurrence of families with members affected by different forms of CMD [12,13,23,29] may suggest the possibility of allelic syndromes [3,14,29]. The recent discovery of the localization of a gene for FCMD to chromosome 9q31-33 [30] and some studies about the possible occurrence of abnormal expression of dystrophin associated proteins in FCMD [31] or laminin subunits in FCMD [32] and in other forms of CMD [33] probably will soon allow a definition about the pathogenesis of this myopathy. Some authors [33,34] found that one of the laminin subunits, protein merosin, may be absent from the muscle biopsies of patients affected by the classical non-Japanese form of CMD. As the laminin gene had been previously localized on chromosome 6q2 [35], Hillaire et al. [34] suggest that the merosin-negative type of CMD could be mapped to the same locus. Our finding of an absence of merosin in 6 patients with CMD-HWM is in accordance to this report [34]. Up to the present time, the pathogenesis of the white matter alteration in CMD-HWM remains obscure. It is known, however, that this alteration differs from that observed in FCMD, as in the

58

U.C. Reed et aL /Brain & Development 1996; 18:53-8

latter it is of a transitory nature suggesting only a delay in myelination [36,37], whereas in C M D - H W M it remains unaltered [12,14,18,22] or increases with time [10], which is corroborated by the finding of unchanged white matter alteration on sequential CT scans of 2 of our patients. In conclusion, correlation studies between molecular and clinical findings will be very important to enhance our comprehension of the underlying pathological mechanism leading to this condition.

[16]

[17]

[18] [19]

Acknowledgements The authors are particularly grateful to Beatriz Lef~vre, psychologist of the Divis~o de Psicologia da Cllnica Neurol6gica, Hospital das Cllnicas da Faculdade de Medicina da Universidade de Silo Paulo, who revised the data from the psychological evaluation of the patients.

[20]

[21]

[22]

References [1] Fenichel GM. Congenital muscular dystrophies. Neurol Clin 1988; 6: 519-28. [2] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type. Clinical, genetic and pathological considerations. Brain Dev (Tokyo) 1981; 3: 1-29. [3] Leyten QH, Gabre~ls FJM, Renier WO, Ter Laak HJ, Sengers RCA, Mullaart RA. Congenital muscular dystrophy. J Pediatr 1989; 115: 214-21. [4] Nonaka I, Chou SM. Congenital muscular dystrophy. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Vol 41. Amsterdam: North Holland, 1979: 27-50. [5] Echenne B, Arthuis M, Billard C, et al. Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Soci6t6 de Neurologie Infantile. J Neurol Sci 1986; 75: 7-22. [6] Dubowitz V. Workshop report: 22 "d ENMC sponsored workshop on congenital muscular dystrophy held in Baarn, The Netherlands, 14-16 May 1993. Neuromusc Disord 1994; 4: 75-81. [7] Castro-Gago M, Pefia-Guiti~n J. Congenital muscular dystrophy of a non-Fukuyama type with characteristic CT images (letter). Brain Dev (Tokyo) 1988; 10: 60. [8] Topaloglu H, Yalaz K, Renda Y, et al. Occidental type cerebromuscular dystrophy: a report of eleven cases. J Neurol Neurosurg Psychiatry 1991; 54: 226-9. [9] Topaloglu H, Kale G, Yalnizoglu D, et al. Analysis of 'pure' congenital muscular dystrophies in thirty-eight cases. How different is the classical type 1 from the occidental type cerebromuscular dystrophy? Neuropediatrics 1994; 25: 94-100. [10] Tanaka J, Mimaki T, Okada S, Fujimura H. Changes in cerebral white matter in a case of congenital muscular dystrophy (nonFukuyama type). Neuropediatries 1989; 21: 183-6. [11] Yoshioka M, Kuroki S, Mizue H. Congenital muscular dystrophy of non-Fukuyama type with characteristic CT images. Brain Dev (Tokyo) 1987; 9: 316-8. [12] Pihko H, Louhimo T, Valanne L, Donner M. CNS in congenital muscular dystrophy without mental retardation. Nearopediatrics 1992; 23: 116-20. [13] Trevisan CP, Carollo C, Segalla P, Angelini C, Drigo P, Giordano R. Congenital muscular dystrophy: brain alterations in an unseleeted series of Western patients. J Neurol Neurosurg Psychiatry 1991; 54: 330-4. [14] Cook JD, Gascon GG, Haider A, et al. Congenital muscular dystrophy with abnormal radiographic myelin pattern. J Child Neurol 1992; 7 (suppl): $51-63. [15] Leyten QH, Ter Laak HJ, Gabrefils FJM, Renier WO, Renkawek K, Sengers RCA. Congenital muscular dystrophy. A study on the

[23]

[24]

[25]

[26]

[27] [28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36] [37]

variability of morphological changes and dystrophin distribution in muscle biopsies. Acta Neuropathol (Berl) 1993; 86: 386-92. Kao KP, Lin KP. Congenital muscular dystrophy of a non-Fukuyama type with white matter hyperlucency on CT scan. Brain Del, (Tokyo) 1992; 14: 420-2. Yoshioka M. Congenital muscular dystrophy of a non-Fukuyama type with characteristics CT images (letter reply). Brain Dev (Tokyo) 1988; 10: 60. Echenne B. Congenital muscular dystrophy of a non-Fukuyama type (letter). Brain Dec, (Tokyo) 1988; 10: 397. Oliveira ASB, Gabbai AA, Kiyomoto BH, Schmidt B. Distrofia muscular cong~nita. Apresenta~o de oito casos com evid~ncia de comprometimento do SNC. Rev Paul Med 1990; 108: 139-41. Bernier JP, Brooke MH, Naidich TP, Carroll JE. Myoencephalopathy: cerebral hypomyelination revealed by CT scan of the head in a muscle disease. Trans Am Neurol Assoc 1979; 104: 244-6. Nucci A. Distrofia muscular cong~nita. Variables fenotlpicas em 27 casos. Tese. Faculdade de Ci~ncias M6dicas da Universidade Estadual de Campinas/SP, 1993. Egger J, Kendall BE, Erdohazi M, Lake BD, Wilson J, Brett EM. Involvement of the central nervous system in congenital muscular dystrophies. Dev Med Child Neurol 1983; 25: 32-42. Kimura S, Sasaki Y, Kobayashi T, et al. Fukuyama-type congenital muscular dystrophy and the Walker-Warburg syndrome. Brain Dev (Tokyo) 1993; 15: 182-91. Laverda AM, Battaglia MA, Drigo P, et al. Congenital muscular dystrophy, brain and eye abnormlalities: one or more clinical entities?. Childs Nerv Syst 1993; 9: 84-7. Di Rocco M, Leveratto L, Cama A, et al. Report on a patient with congenital muscular dystrophy, hydrocephalus, Dandy-Walker malformation and leukodystrophy. Genet Couns 1993; 4: 295-8. Okudaira Y, Bandoh K, Wachi A, Sato K, Osawa M. A case of congenital muscular dystrophy associated with hydrocephalus-CSF dynamics and surgical treatment (in Japanese). No To Hattatsu (Tokyo) 1994; 26: 57-62. Olive M, Sirvent J, Ferrer I. Congenital muscular dystrophy with distinct CNS involvement. Neuropediatrics 1994; 25: 48-50. Parano E, Fiumara A, Falsaperla R, Vita G, Trifiletti RR. Congenital muscular dystrophy: correlation of muscle biopsy and clinical features. Pediatr Neurol 1994; 10: 233-6. Yoshioka M, Kuroki S, Nigami H, Kawai T, Nakamura H. Clinical variation within sibships in Fukuyama-type congenital muscular dystrophy. Brain Dev (Tokyo) 1992; 14: 334-7. Toda T, Segawa M, Nomura Y, et al. Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q 31-33. Nature Genet 1993; 5: 283-6. Matsumura K, Nonaka I, Campbell KP. Abnormal expression of dystrophin-associated proteins in Fukuyama-type congenital muscular dystrophy. Lancet 1993; 341 (8844): 521-2. Hayashi YK, Engwall E, Arikawa-Hirasawa E, Goto K, Koga R, Nonaka I. Abnormal localization of laminin subunits in muscular dystrophies. J Neurol Sci 1993; 119: 53-64. Tom~, FMS, Evangelista T, Leclerc A, et al. Congenital muscular dystrophy with merosin deficiency. C R Acad Sci (Paris) 1994; 317: 351-7. Hillaire D, Leclerc A, Faur6 S, et al. Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 1994; 3: 1657-61. Vuolteenaho R, Nissinen M, Sainio K, et al. Human laminin M chain (merosin): complete primary structure, chromosomal assignment and expression of the M and A chain in human fetal tissue. J Cell Biol 1994; 124: 381-94. Aihara M, Tanabe Y, Kato K. Serial MRI in Fukuyama type congenital muscular dystrophy. Neuroradiology 1992; 34: 396-8. Yoshioka M, Saiwai S. Congenital muscular dystrophy (Fukuyama type) - Changes in the white matter low density on CT. Brain Dev (Tokyo) 1988; 10: 41-4.