Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Société de Neurologie Infantile

We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.     

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.     

Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype

Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker–Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.     

Walker-Warburg syndrome in a Japanese patient

We report the first Japanese female patient with Walker-Warburg syndrome. She had generalized muscle hypotonia with hydrocephalus due to Dandy-Walker malformation and bilateral microphthalmia with opaque corneas. She had severe motor and mental retardation. Muscle histology reflected advanced changes of muscular dystrophy. We discuss the relationship between Fukuyama congenital muscular dystrophy and Walker-Warburg syndrome, both of which fall within a spectrum of developmental abnormalities with a common cause. In Fukuyama congenital muscular dystrophy, ocular abnormalities are less severe.     

Congenital muscular dystrophy with secondary merosin deficiency and normal brain MRI: a novel entity?

We describe two Scottish siblings affected by a form of congenital muscular dystrophy characterised by a severe clinical phenotype, similar to that observed in the 6q-linked merosin-deficient CMD but in whom brain MRI and cognitive development were normal. The maximal function achieved in the 2 siblings was sitting independently. Serum CK were grossly elevated and the skin and muscle biopsies showed a severe reduction of merosin in both. The normal brain MRI and normal cognitive development distinguish this form from Fukuyama congenital muscular dystrophy, muscle-eye-brain disease or other forms of CMD with secondary partial merosin deficiency and abnormal brain MRI and/or mental retardation. Linkage analysis excluded all the known loci for CMD. We propose that this may represent a novel variant 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.     

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.     

Two sibling patients with non-Fukuyama type congenital muscular dystrophy with low serum selenium levels--therapeutic effects of oral selenium administration

We report a pair of siblings with non-Fukuyama type, merosin-positive congenital muscular dystrophy, born to unrelated parents. Patient 1 was a 16-year-old girl with myopathy, cardiomyopathy, severe mental retardation and epilepsy. Patient 2 was a younger brother of patient 1, a 10-year-old boy with myopathy, severe mental retardation and epilepsy. Their serum selenium levels were decreased to 25 micrograms/l and 55 micrograms/l, respectively (normal 97-147 micrograms/l). Their muscle biopsy findings were similar to those seen in selenium deficient myopathy, showing abnormal mitochondrial distribution and giant mitochondria. After oral administration of selenium for 3 months, their gait disturbance apparently improved, which was confirmed by a gait analysis system. Why their gait improved remain unclear, but a defect in selenium metabolism may play a role in the development of congenital muscular dystrophy and 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.     

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.     

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.     

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.     

Muscle-eye-brain disease (MEB)

Clinical features of a rare congenital myopathy, muscle-eye-brain (MEB) disease, are described in 19 patients. The pedigree data suggest an autosomal recessive inheritance. The patients presented with congenital hypotonia and muscle weakness. Serum CK was elevated, EMG was myopathic and muscle biopsy showed slight or moderate changes compatible with muscular dystrophy. Ophthalmological findings included severe visual failure and uncontrolled eye movements associated with severe myopia. The flash VEPs were exceptionally high, whereas non-corneal ERG was unrecordable. The EEG showed progressive abnormalities after the age of 6 months. Psychomotor development was slow during the first years of life, and mental retardation was severe. Most patients began to deteriorate around age 5 years. This change included spasticity and joint contractures. CT scans showed ventricular dilatations and abnormally low white matter density in several patients. Spasticity, high VEPs and ocular manifestations differentiate MEB from the Fukuyama type congenital muscular dystrophy.     

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 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.     

Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy

OBJECTIVE: Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy. METHODS: The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of alpha-dystroglycan in skeletal muscle. RESULTS: We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness. INTERPRETATION: Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.     

A case of congenital myotonic dystrophy with infantile autism

An 11-year-old girl with congenital myotonic dystrophy and infantile autism was reported. Her mother also suffered from typical myotonic dystrophy. Since her birth, the patient had been floppy, and showed bilateral talipes equinus at 1 year of age. Her subsequent psychomotor and speech development has been retarded. She showed autistic behavior and persistence to the sameness before 2 years old. She was admitted to Sawarabien at the age of 10 years. She could not talk anything but could understand simple, oral messages. Although she had severe degree of mental retardation, her ability for matching figures was relatively well reserved. Her autism was so manifest that it could not be explained by the degree of mental retardation. Neurological examinations revealed that she had facial diplegia, inverted V-shaped mouth, high-arched palate, talipes equinus, percussion myotonia of the tongue, generalized muscular atrophy and weakness, lordosis, areflexia, and congenital cataracta. The serum CPK was slightly elevated. EMG showed a myopathic pattern but did not show any myotonic discharge yet. The brachioradial muscle was biopsied and examined by light- and electron-microscopy. It mainly showed mild varieties of muscle fiber diameter and internal nuclei. Ultrastructurally, irregularly indented central nuclei and perinuclear degeneration of myofibrils associated with secondary lysosomes, lipid droplets and glycogen granules were revealed. Ventricular dilatation and some dysfunction of the brain were also revealed by CT scan and EEG respectively. The present case suggests that congenital myotonic dystrophy can be added into the disease group associated with infantile autism.     

Congenital inflammatory myopathy: a demonstrative case and proposed diagnostic classification

There have been few reports of congenital inflammatory myopathy in the literature, and most of these have been associated with congenital muscular dystrophy. We review the literature and present a case with electromyographic and muscle biopsy evidence of congenital inflammatory myopathy with onset in the perinatal period and no evidence of a congenital muscular dystrophy. There was evidence of subjective improvement following corticosteroid administration (approximately 1 mg/kg per day) with a concomitant normalization of the serum creatine kinase activity. Of particular interest in the case was the history of maternal infection, suggesting a possible postinfectious molecular mimicry as the etiology of the muscle inflammation. This case suggests that a rare form of congenital inflammatory myopathy does exist that is not associated with a congenital muscular dystrophy. A preliminary classification scheme is proposed to separate true congenital cases from those acquired after birth and those cases associated with congenital dystrophy.     

Muscle pathology in Marinesco-Sj?gren syndrome

Three of 4 adult patients with Marinesco-Sj?gren syndrome (MSS; 2 males and 2 females, aged 26-31 years) in 2 families became non-ambulant because of slowly progressive muscular weakness rather than cerebellar ataxia. Other clinical features in these 4 patients were typical for MSS: bilateral cataracts from infancy, mental retardation, severe cerebellar atrophy, multiple skeletal abnormalities and hypergonadotropic hypogonadism. EMG demonstrated a myopathic pattern and serum CK was mildly elevated. Muscle biopsies from these 3 patients showed myopathic changes including a marked variation in fiber size, an increased number of fibers with centralized nuclei, and scattered necrotic and regenerating fibers. Fiber type analysis with myosin ATPase staining showed type 1 fiber predominance, type 2B fiber deficiency and mild increase in type 2C fibers. Muscle biopsy changes and the clinical course indicate that our MSS patients suffered from a chronic dystrophic process similar to that in congenital muscular dystrophy.     

Severe progressive form of congenital muscular dystrophy with calf pseudohypertrophy,macroglossia and respiratory insufficiency

A novel form of congenital muscular dystrophy in four unrelated patients is proposed. Congenital hypotonia, markedly increased CK, calf pseudohypertrophy and proximal weakness were common early findings. Two cases were severely affected since infancy and never walked. The phenotypical homogeneity was not very evident until advanced stages of the disease. All the patients showed catastrophic progression of the weakness, severe restrictive respiratory insufficiency, macroglossia, peculiar extreme amyotrophy of hands and feet, and a round and 'puffy' face. All patients became tetraplegic and required mechanical ventilation. Two cases had signs of mild cardiac involvement. The only non-tracheotomised patient died of respiratory complications. No mental retardation or specific brain abnormalities were observed. All patients showed secondary deficit of laminin 2 and up-regulation of laminin 5 in muscle. Expression of -dystroglycan was severely reduced in two available muscle samples. The known loci for congenital muscular dystrophies were excluded in the only consanguineous case by linkage analysis. Clinical, immunohistochemical and genetic findings strongly suggest a distinct entity.