Merosin-positive congenital muscular dystrophy in two siblings with cataract and slight mental retardation.

We report on two siblings that have been followed for 14 years, with merosin-positive congenital muscular dystrophy (CMD), cataract, retinitis pigmentosa, dysversion of the optic disc, but no cerebral anomalies, except for microcephaly and slight mental retardation (MR). The younger child had three generalized seizures easily controlled by anticonvulsant therapy. Both children presented hypotonia from birth, delayed psychomotor development, generalized muscular weakness, and atrophy and joint contractures of knees and ankles. The course of the disease, apparently static during the first 10 years of life, became progressive during the second decade with loss of deambulation by the age of 13. Creatine kinase was increased in both children. Bilateral cataract was diagnosed at 6-months of age. In spite of the occurrence of microcephaly, MR was slight and the siblings acquired reading and writing skills after the aged 10. Head magnetic resonance imaging showed normal results in both siblings. The classification of these cases within the broad spectrum of CMD is difficult since most of the known muscle-eye-brain syndromes generally show severe MR and brain anomalies. We consider these cases as corresponding to the rarer syndromes of merosin-positive CMD with associated features such as cataract and MR that were particularly emphasized during the 50th ENMC International Workshop on CMD [Dubowitz V. Workshop report: 50th ENMC International workshop on congenital muscular dystrophy. Neuromusc Disord 1997;7:539-547]. Further genetic, pathological, neuroradiological, and immunocytochemical studies will be necessary for better elucidation of the classification and pathogenesis of CMD.     

Merosin-positive congenital muscular dystrophy with transient brain dysmyelination, pontocerebellar hypoplasia and mental retardation

The congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders. Among these, the laminin alpha 2 chain 'merosin' deficient CMD is caused by mutations of the LAMA2 gene on chr 6q2 and Fukuyama CMD is linked to chr 9q31. We report a 7-year-old boy who was born to consanguineous healthy parents. His motor and mental development were slow. Creatine kinase (CK) was elevated (2.100 U/l), and the muscle biopsy was dystrophic. He sat unsupported at 12 months and took his first steps at 3 years of age. At 6 years of age he could walk up to 500 m. He was mentally retarded and spoke single words only. At 1 year, MR imaging of the brain showed abnormal increased periventricular T2-signal, consistent with dysmyelination as well as pontocerebellar hypoplasia and several cerebellar cysts. The pattern of gyration was normal. Follow-up at 4 years showed normalization of the previously abnormal periventricular T2-signal. Immunohistochemical analysis of the skeletal muscle showed normal expression of laminin alpha 2 for a C-terminal antibody and antibodies to the 300 and 150 kDa fragments, as well as of laminins alpha 5, beta 1, beta 2 and gamma 1. The boy has two healthy younger brothers. Linkage analysis excluded the candidate loci on chromosomes 6q2 and 9q31. As such, the patient's data are suggestive of a new form of laminin alpha 2 positive CMD characterized by transient brain dysmyelination, pontocerebellar hypoplasia and mental retardation.     

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci

We report a case of congenital muscular dystrophy with secondary merosin deficiency, structural involvement of the central nervous system and mental retardation in an 8-year-old girl from a consanguineous family. She had early-onset hypotonia, generalized muscle wasting, with weakness especially of the neck muscles, joint contractures, mental retardation and high creatine kinase. Muscle biopsy showed dystrophic changes with partial deficiency of the laminin ₂ chain. Cranial magnetic resonance imaging revealed multiple small cysts in the cerebellum, without cerebral cortical dysplasia or white matter changes. The laminin ₂ chain (6q2), Fukuyama type congenital muscular dystrophy (9q31–q33) and muscle–eye–brain disease (1p32–p34) loci were all excluded by linkage analysis. We suggest that this case represents a new entity in the nosology of congenital muscular dystrophy.     

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts,unlinked to the LAMA2, FCMD,MEB and CMD1B loci,in three Tunisian patients

We report three Tunisian patients affected by congenital muscular dystrophy with mental retardation and cerebellar cysts on cranial magnetic resonance imaging. The clinical features were characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absence of speech, inability to walk in three patients, but calf hypertrophy was noted only in two patients. Brain magnetic resonance imaging showed several cerebellar cysts and vermis hypoplasia in all of the patients. Abnormality of the white matter was present in two patients. The pattern of gyration was normal in all cases. Serum creatine kinase was elevated in all three cases and their muscle biopsy showed dystrophic changes compatible with congenital muscular dystrophy. The immunohistochemical analysis of the skeletal muscle revealed partial merosin deficiency, more pronounced for the N-terminal antibody. Linkage analysis excluded congenital muscular dystrophy loci on chromosomes 6q22, 9q31, 1p32 and 1q42. These patients constituted a particular form of congenital muscular dystrophy with a combination of severe motor delay, mental retardation, partial merosin deficiency and cerebellar cysts. Two patients showed white matter abnormalities on magnetic resonance imaging and hypertrophy of the calves. These cases, in addition to those reported previously, confirmed the large phenotypic variability in the group of secondary merosin deficiency congenital muscular dystrophy.     

Two Dutch siblings with congenital muscular dystrophy (Fukuyama type)

Two Dutch siblings are described suffering from muscular weakness, hypotonia, severe joint contractures, mental retardation and epileptic fits. E.M.G. showed a characteristic myopathic pattern. Muscle biopsy revealed changes consistent with congenital muscular dystrophy. On CT marked hypodensities of the cerebral white matter were noticed. These findings are consistent with congenital muscular dystrophy of the Fukuyama type, a peculiar form of congenital muscular dystrophy, extremely rare outside Japan.     

Pial-glial barrier abnormalities in fetuses with Fukuyama congenital muscular dystrophy

This report concerns light and electron microscopic studies on the central nervous system of a 20-week and an 18-week fetus with Fukuyama congenital muscular dystrophy (FCMD). The diagnosis of FCMD was established by prenatal molecular genetic analysis. Cerebral lesions containing neurites, subpial granular cells and glias, accompanied by cortical dysplasia were found in both cases. Small irregular defects, readily detectable by periodic acid-methenamine-silver staining or by immunohistochemical staining for S-100 protein, were observed in the cerebral surface. More severe dysplasia was evident at the areas with the larger defects. Surface defects were also observed in the cerebellum and brain stem, with brain tissue extruding into the leptomeninges. The pyramidal tract was aberrant in the pons and medulla oblongata. The spinal cord appeared normal by light microscopy. Electron microscopic examination revealed an abnormal configuration of the basement membrane and glial cytoplasmic membrane of the brain and spinal cord surfaces, including areas with no detectable defects by light microscopy. These findings suggest that abnormalities of the pial-glial barrier, especially the basement membrane and/or basement membrane-related structures, are involved in the genesis of cortical dysplasia.     

Localization of laminin subunits in the central nervous system in Fukuyama congenital muscular dystrophy: an immunohistochemical investigation

We have undertaken an immunohistochemical study of laminin subunits in the central nervous system (CNS) of fetuses and patients with Fukuyama congenital muscular dystrophy (FCMD) and of controls including five fetuses. Immunoreaction product deposits with antibodies to laminin α1, α2, β1 and γ1, and β-dystroglycan were detected on the surface and vessels of the CNS of controls. No staining with anti-α-sarcoglycan antibody was detected in the CNS. Neurons and glia did not react with any of the antibodies used. In utero expression of laminin subunits and β-dystroglycan seemed to be lower in the cerebrum than in the spinal cord. Moreover, immunostaining for laminin α2 and β1 tended to be weak on the fetal spinal cord surface. Expression of laminin subunits and dystrophin-associated proteins in the CNS may be modulated during development, as in the skeletal muscle. The distribution of immunoreaction product deposits was basically the same in FCMD and controls, although laminin α2 and β-dystroglycan expression appeared to be decreased in the CNS of the FCMD cases. Defects of the pial-glial barrier of the fetal brain surface have been considered the main cause of micropolygyria in FCMD, and these observations suggest that the co-localization and secondary loss of these proteins in association with the unknown product(s) of the FCMD gene might be involved in the CNS lesions of this disorder. Received: 15 July 1996 / Revised, accepted: 13 January 1997     

New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families

The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of -dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.     

Leigh syndrome with Fukuyama congenital muscular dystrophy: A case report

We report the first case of Leigh syndrome (LS) with Fukuyama congenital muscular dystrophy (FCMD). A neonate suffered from lactic acidosis and subsequently presented with poor feeding, muscle weakness, hypotonia, cardiopulmonary dysfunction, and hydrocephalus. He died at 17 months. The findings of brain magnetic resonance imaging indicated some specific features of both LS and FCMD, and FCMD gene mutation was detected. Decreased mitochondrial respiratory complex I and II activity was noted. Mitochondrial DNA sequencing showed no pathogenic mutation. A case with complex I + II deficiency has rarely been reported, suggesting a nuclear gene mutation.     

Congenital muscular dystrophy with severe retrocollis and mental retardation: a report of two siblings.

Two siblings with a congenital muscular dystrophy and severe mental retardation which was not due to dystrophin, merosin, or adhalin deficiency are described. These cases overlap with congenital muscular dystrophy of the Fukuyama-type but are less severe. Atypical features include limited facial involvement, retained ambulation, and severe retrocollis.     

Congenital muscular dystrophy with central nervous system involvement: case report

A case of a mediterranean boy with congenital muscular dystrophy (CMD) and central nervous system (CNS) involvement with mild intellectual impairment and seizures is reported. Muscular dystrophy involved both skeletal and mimic muscles, and histological findings were consistent with a congenital dystrophy. EEG recordings showed generalized and localized paroxysmal activities. CT scan demonstrated low-density periventricular areas. Ophthalmoplegia was also observed. A literature review disclosed that in some western cases of CMD plus CNS involvement, cranial muscles other than mimic muscles may be involved.     

Muscle histochemistry in congenital muscular dystrophy with central nervous system involvement

Muscles from 13 patients with clinical characteristics of congenital muscular dystrophy and central nervous system involvement (Fukuyama type) (FCMD) were examined using morphometric and fiber type analysis. The muscles from patients aged 5 months to 3 years demonstrated small-calibered fibers with increased variation in fiber size, connective tissue proliferation, and scattered necrotic and regenerating fibers. Groups of atrophic fibers were absent. Both type 1 and type 2 fibers were affected, though type 1 fibers predominated and type 2B fibers decreased as the disease progressed. The muscle changes were apparently progressive, affecting not only the limbs but also the intercostal, diaphragm, and cardiac muscles. Although there was no qualitative difference in the muscle histochemistry between FCMD and Duchenne muscular dystrophy (DMD), there was a greater proportion of type 2C fibers and fibrosis was present at the early infantile stage of FCMD.     

Congenital muscular dystrophy and severe central nervous system atrophy in two siblings

Severe degenerative features of the nervous system of a hitherto unknown kind, associated with a neuromuscular disorder with histopathological features of congenital muscular dystrophy, are reported in two female siblings. The clinical profile was characterized by generalized hypotonia followed by spastic tetraplegia, contractures, polyneuropathy, lack of cognitive development and progressive microcephaly. There was no involvement of the eyes. Neuropathological examination of the brain of one sibling, who died at the age of 30 months, revealed subtotal loss of neurons in the cerebral and cerebellar cortex and in the ventral pons, and secondary loss of myelin in the cerebral and cerebellar subcortical white matter. Sural nerve biopsy in the other sibling, who had a similar neurological affection, showed a lack of large myelinated fibers.This investigation is part of the research program Disorders of the Neuromuscular System of the University of Nijmegen     

Congenital muscular dystrophy with characteristic radiological findings similar to those with Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is the most common congenital muscular dystrophy in Japan and there are isolated reports of non-Japanese patients with FCMD. We report an Indian patient with congenital muscular dystrophy and characteristic radiological findings similar to those with FCMD.     

Heterogeneity of classic congenital muscular dystrophy with involvement of the central nervous system: report of five atypical cases

A heterogeneous group of patients with congenital muscular dystrophy associated with clinical or radiologic central nervous system involvement other than the severe classic form with merosin deficiency, muscle-eye-brain disease, and Walker-Warburg syndrome is described. A probable hereditary or familial occurrence could be suggested in all patients. One merosin-positive patient presented severe motor incapacity and cerebral atrophy without any clinical manifestation of central nervous system involvement. A second patient, also merosin-positive, had moderate motor and mental handicap, and epilepsy with no changes in neuroimaging. A third patient, found to have partial merosin deficiency by muscle biopsy, manifested severe psychomotor retardation and cerebral atrophy with foci of abnormal white-matter signal on magnetic resonance imaging. Finally, two merosin-positive siblings with microcephaly, mental retardation, and an incapacitating progressive neuromuscular course, exhibited cataracts without defects of neuronal migration or brain malformation. This report emphasizes the broad clinical spectrum and heterogeneity of merosin-positive congenital muscular dystrophy with associated central nervous system involvement, and illustrates the importance of further studies on clinical, immunohistochemical, and genetic grounds for identifying new subsets of congenital muscular dystrophy.     

Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome

We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest in their surroundings. In addition, all patients had a striking enlargement of the calf and quadriceps muscles. Ophthalmologic examination revealed no structural ocular abnormalities in any of the children; one patient had severe myopia. In all cases a magnetic resonance imaging of the brain showed an abnormal posterior cranial fossa with enlargement of the cisterna magna and variable hypoplasia of the vermis of the cerebellum. Abnormality of the white matter was also present in all patients, in the form of patchy signal most evident in the periventricular areas. Serum CK was grossly elevated in all. The muscle biopsy from all cases showed dystrophic changes compatible with congenital muscular dystrophy. Immunofluorescence studies showed mild to moderate partial deficiency of laminin 2 chain. Linkage analysis in the only informative family excluded the known loci for congenital muscular dystrophy, including laminin 2 chain on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3 and the muscle-eye-brain disease on chromosome 1p3. We propose that this represent a novel severe variant of congenital muscular dystrophy, with associated central nervous system involvement.     

Experimental intrauterine infection of akabane virus. Pathological studies of skeletal muscles and central nervous system of newborn hamsters with relevances to the Fukuyama type congenital muscular dystrophy

A vertical infection system in hamsters produced by inoculating with Akabane virus was established as an experimental model of congenital muscular dystrophy (Fukuyama type) (FCMD) and arthrogryposis multiplex congenita (AMC) in humans. Swollen fetuses, mummified fetuses, arthrogryposis and cranial deformities were produced in 13 of 415 newborn hamsters inoculated transplacentally (3.1%). The incidence was significantly higher than that in the control group (p less than 0.05). Eight cases presenting apparent abnormalities were examined histologically and virologically. Pictures of skeletal muscles showing such immature features as chains of internal nuclei and myotubular muscle fibers were demonstrated in all cases. In addition, perivascular infiltration of small round cells and thickening of vascular walls were seen in 5 cases, while myogenic changes such as broken myofibrils, small muscle fibers and changes in fiber size were observed in 6 cases. In the anterior horn of the spinal cord, swelling and loss of nuclei and cell matrices were noticed in 4 cases. In the cerebral cortex, disarrangement of cell layers, edematous changes and loss of nerve cells were revealed in 5 cases. In 4 cases virus particles were found on electron microscopy in the cerebral cortex. The authors considered that this experimental system of intrauterine viral infection would be useful for the etiological study of FCMD and AMC in humans in which not only skeletal muscles but also the central nervous system is affected congenitally.