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.     

Four siblings with becker muscular dystrophy (BMD) manifesting severe mental retardation]

A 33-year-old man with BMD manifesting severe mental retardation is reported. This patient has mild pseudohypertrophy in his calf muscles and showed an elevation of creatine kinase (CK) level in the serum (2215 IU/L). He was diagnosed as autistic at the age of three. His intellectual level was estimated to be two years old in social intelligence and four months old in speech ability at the age of 33. However his muscle strength remains within the normal range. All of his three siblings have similar symptoms, such as severe mental retardation and elevated CK level in the serum (1735-3641 IU/L) and lack apparent muscular weakness. Gene analyses by multiplex PCR and Southern blotting showed all of the siblings had the deletion of exon 4 in the dystrophin gene. Pathological findings of a muscle biopsy specimen showed a mild irregular dystrophin stain of the muscle surface membrane. This is a rare familial case of Becker muscular dystrophy manifesting severe mental retardation with scarce muscular weakness.     

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     

Facioscapulohumeral muscular dystrophy with severe mental retardation and epilepsy

We report here a case of a 20-year-old woman with facioscapulohumeral muscular dystrophy (FSHD). In this patient, the involvement of facial muscle had been present since early childhood, but obscured due to the complication of profound mental retardation. Epilepsy emerged at eight years of age. Symmetrical limb muscle weakness appeared at 15 years of age, which progressed such that she was wheelchair-bound at 18 years of age. An elevated serum creatine kinase, predominant involvement of hamstrings, scapular and abdominal muscles, as well as an impaired stapedial reflex at high tune, were compatible with the clinical features of FSHD. The diagnosis of 4q35-FSHD was confirmed by detection of a 10kb EcoRI fragment with a p13E-11 probe on a Southern blot. The intellectual disability in this patient was the most severe of all FSHD patients reported to date and has hindered a correct diagnosis. This entity should be included in the differential diagnoses for patients with muscular symptoms and accompanying mental retardation.     

Multifocal glial nodules in a case of Duchenne muscular dystrophy with severe mental retardation

A case of Duchenne muscular dystrophy with multifocal hamartomatous glial nodules in the cerebral cortex is reported. The patient had suffered severe mental retardation since boyhood, dying of aspiration pneumonia at the age of 23 years. Post-mortem examination revealed an atrophic brain with normal gyri. Microscopically, multifocal small nodules composed of bizzare astrocytic cells, multinucleated cells, neuron-like cells, small astrocytes and glial fibers were found in the first, fifth and sixth layers of the prefrontal cortex. Some of the bizarre cells showed intense immunoreactivity for glial fibrillary acidic protein and moderate to very weak reactivity for ubiquitin, tau protein and αB crystallin but no immunoreactivity for neurofilament and synaptophysin, suggesting that these cells were of astrocytic origin. The nodules were considered to be due to hamartomatous changes that had occurred in the early stage of brain development, and that might have been partly responsible for the pathogenetic mechanisms of mental retardation.     

Merosin-positive congenital muscular dystrophy with mental retardation, microcephaly and central nervous system abnormalities unlinked to the Fukuyama muscular dystrophy and muscular-eye-brain loci: report of three siblings

Classical merosin (2 laminin)-positive congenital muscular dystrophy is a heterogeneous subgroup of disorders; a few cases characterized by severe mental retardation, brain involvement and no ocular abnormalities were called Fukuyama-like congenital muscular dystrophy. We report a family of healthy non-consanguineous parents, with four affected siblings, of which one died at the age of 7 months due to an intercurrent illness, who presented congenital hypotonia, severe mental retardation, microcephaly, delayed psychomotor development, generalized muscular wasting and weakness with mild facial involvement, calf pseudohypertrophy, joint contractures and areflexia. Muscle biopsy disclosed severe muscular dystrophy. Immunostaining for laminin 2 80 kDa and clone Mer3/22B2 monoclonal antibodies, 1 and 1 chain was preserved. Magnetic resonance imaging findings were consistent with pontocerebellar hypoplasia, bilateral opercular abnormalities and focal cortical dysplasia as well as minute periventricular white matter changes. Clusters of small T2-weighted focal hyperintensities in both cerebellar hemispheres consistent with cysts were observed in two of the three siblings studied with magnetic resonance imaging. Ophthalmologic and cardiologic examination was normal. Haplotype analysis using microsatellite markers excluded the Fukuyama congenital muscular dystrophy, LAMA2 and muscle-eye-brain disease loci. Thus, a wider spectrum of phenotypes, gene defects and protein deficiencies might be involved in congenital muscular dystrophy with brain abnormalities.     

Familial lethal cardiomyopathy with mental retardation and scapuloperoneal muscular dystrophy.

A family is described with a neuromuscular disorder characterised by possible X-linked recessive inheritance, a benign, slowly progressive muscular dystrophy with predominant humeroperoneal distribution and lack of contractures or pseudohypertrophy, central nervous system involvement, myopia and lethal cardiomyopathy. The possibility of cardiac transplant as life-saving therapy is suggested.     

Congenital muscular dystrophy with severe infantile scoliosis

A girl with congenital muscular dystrophy with severe scoliosis from birth was presented. No positive family history was obtainable. She developed muscle hypotonia and weakness, and feeding difficulty during the neonatal period. Her developmental milestones were delayed; she learned to walk at the age of 2 years when she walked with a "waddling gait" and stood up with Gowers' maneuver. On physical examination at 2 years old, she had mild proximal dominant muscle weakness and atrophy, and severe scoliosis with a Cobb's angle of 74 degrees but no joint contractures in the extremities. Creatine kinase was slightly elevated. Biopsied muscle showed myopathic changes, including variation in fiber size, moderate fibrous tissue proliferation, some necrotic and regenerating fibers and type 1 fiber predominance, consistent with those seen in chronic progressive muscular dystrophy.     

CNS in congenital muscular dystrophy without mental retardation.

We have evaluated the CNS findings of 30 patients with congenital muscular dystrophy and normal mental development. The intelligence was estimated by psychological testing or school performance. There were more children of above average intelligence than expected. Neuroradiological examination was done to 15/17 patients still alive. White matter changes were seen in five and cerebral atrophy in four patients. Three patients had epilepsy, two mild, one drug resistant. The EEG did not reveal any common pattern, though there were various abnormalities in several children.     

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.     

Association of schizophrenia and mental retardation with facio-scapulohumeral muscular dystrophy

Three members of an Indian family with facio scapulohumeral dystrophy (FSHD linked to chromosome 4q35 with short EcoR1 segment of 23 Kb are reported where two male adults had schizophrenia. One family member developed isolated facial weakness with mild mental retardation. This genetically proven FSHD family is reported because of its uncommon associations.     

Severe fascioscapulohumeral muscular dystrophy presenting with Coats' disease and mental retardation

We describe two Norwegian children with fascioscapulohumeral muscular dystrophy in whom Coats' disease, deafness, mental retardation and possible epilepsy were the presenting features. The children have a 4q35 deletion giving a small residual repeat fragment that they have inherited from their father who is a mosaic. Fundal changes consistent with bilateral Coats' disease were found in both children. The rapid development of neovascular glaucoma necessitated removal of an eye from one child that on pathological examination showed the classical features of Coats' disease. Cryotherapy was successful in maintaining sight in the other affected eyes.     

Congenital muscular dystrophy with adducted thumbs,ptosis, external ophthalmoplegia,mental retardation and cerebellar hypoplasia: a novel form of CMD

At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal eyes, and congenital muscular dystrophy with severe mental retardation and cerebellar cysts are nosologically distinct and have been excluded from the known congenital muscular dystrophy loci with structural changes of the central nervous system. Here, we describe a novel congenital muscular dystrophy syndrome which is phenotypically distinct from the recognized forms of congenital muscular dystrophy with brain involvement. Two siblings, a boy and a girl, were born to consanguineous parents from Sicily. Both children were born with adducted thumbs and toe contractures. They were floppy from birth, walked late, showed profound generalized muscle weakness including facial muscles, elevated creatine kinase levels of 200-700U/l, and histological changes compatible with muscular dystrophy. In addition, both showed ptosis, external ophthalmoplegia, mild mental retardation, and mild cerebellar hypoplasia on MRI. Immunocytochemistry showed normal expression of muscle membrane proteins including laminin alpha 2, laminin beta 2, and alpha-dystroglycan. Linkage analysis excluded the candidate loci on chromosomes 6q2, 9q31, and 1q32. The gene locus for congenital muscular dystrophy 1B, MDC 1B, on chromosome 1q42 was also excluded. Adducted thumbs are a distinct clinical sign that has not been reported in congenital muscular dystrophy before and should facilitate recognition of further patients with this disorder.     

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.     

Fukuyama congenital muscular dystrophy in two Australian female siblings

The clinical course of two female siblings with congenital muscular dystrophy is briefly described, and includes congenital cerebral malformations consisting of pachygyria, polymicrogyria and white matter abnormalities. The first sibling died in infancy; the second is now 18 years of age. The changes found at autopsy in the first sibling are identical to MRI changes in the surviving sibling.     

Congenital progressive muscular dystrophy of Fukuyama type: report of a case

The authors report the first Fukuyama type congenital progressive muscular dystrophy case described in Brazil, and confirmed through clinical findings and complementary tests. Emphasis is given to the presence of early fibrotendinous retractions and impairment of the central nervous system, which constitute the fundamental characteristics of this affection. This disease is very common in Japan but very seldom described in other countries. Its etiopathogeny has not yet been defined.     

Congenital muscular dystrophy with leukoencephalopathy

Two patients with 'benign' congenital muscular dystrophy (CMD) have been observed for several years. Symptoms and signs of central nervous system (CNS) disease occurred at the age of 7 and 16 years, respectively. CNS involvement in CMD may be more common than generally recognized, slowly progressive and delayed in onset. The combination of congenital hypotonia, contractures, 'dystrophic' muscle biopsy changes and diffuse subcortical hypodensity on computed-tomographic scans seems unique and specific for CMD and of differential diagnostic significance.     

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.     

Congenital muscular dystrophy: case reports and reappraisal.

We report four cases of congenital muscular dystrophy; all demonstrated hypotonia and multiple contractures at birth. Strength remained stationary or improved, but the tendency for contracture formation persisted. Brief small amplitude polyphasic potentials were recorded on electromyography, and muscle biopsy revealed extensive fat and/or collagen replacement, which was out of proportion to fiber necrosis or patient strength. The consistent clinical and pathologic features of these patients and others described in the literature justify considering this disorder to be a specific nosologic entity.     

Cerebro-ocular dysplasia and muscular dystrophy: report of two cases

The authors report two cases with severe cerebro-ocular malformations and muscular dystrophy who died at 14 and 8 months of age. In both, muscular dystrophy was confirmed by EMG and high muscle enzyme values. In one case, autopsy showed severe cerebral malformation consisting of lissencephaly, hydrocephalus, agenesis of corpus callosum, chiasma and olfactory bulb and lobe, absence of pyramides and cerebellar vermis. In sections of cerebral cortex a clear absence of structural cellular organization and spongiosis of the white matter were evident. Similar disorganization was found in the cerebellum where numerous calcifications were present. The muscle showed signs of primitive muscular dystrophy. The clinical autonomy of the cerebro-ocular-dysplasia-muscular-dystrophy syndrome is discussed. The clinical and pathological data are compared with the two other similar syndromes (i.e. Fukuyama's and Warburg's diseases).