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.     

Merosin-deficient congenital muscular dystrophy in an Omani boy

Merosin-deficient congenital muscular dystrophy is an autosomal recessive disease that can manifest differently in different ethnic groups. This often presents as a floppy infant, and normal mental development. The creatine kinase is usually elevated with white matter abnormalities on brain imaging. In this report, we describe an infant with Merosin-deficient congenital muscular dystrophy who presented with delayed motor milestones and hypotonia. The clinical features, biopsy findings, and neuroimaging abnormalities in our patient are described.     

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.     

Dystrophia myotonica (Steinert disease)--a frequently misdiagnosed disease

Dystrophia myotonica (Steinert's disease) is the most common hereditary disease of the neuromuscular system in adults. Its mode of inheritance is autosomal dominant. The gene responsible for its is located on chromosome 19 in the linkage domain of the loci for the apolipoproteins C2, C1 und E and of the creatine kinase of skeletal muscle (CKMM). Myotonic dystrophy is categorized in an adult and in a congenital form. In the adult form, the characteristic findings are muscular atrophy in certain regions of the body (face, neck and distally in the extremities) and myotonia. Cataract, intraocular hypotension, gonadal atrophy, conduction abnormalities in the heart and hearing deficiencies appear quite often in the course of the disease. In the congenital form, general muscle weekness (particularly pronounced in the face) is the leading finding, combined with retarded loco motor and mental development. A decisive criterion for the diagnosis of this form is the occurrence of myotonic dystrophy in the patient's mother. Electromyographic investigation is indicated when a suspicion of myotonic dystrophy cannot be ascertained on the basis of clinical and genetic findings. Myotonic runs in the EMG will then corroborate the suspicion. Recent electrophysiological investigations have indicated that at least three different types of channels for the passage of ions through the membrane of the skeletal muscle cells show abnormal behaviour, i.e. the channel for Cl-, Na+ and K+. These findings corroborate the hypothesis that the abnormality responsible for myotonic dystrophy is situated in the membrane systems. A pharmacological treatment of the muscular dystrophy has not yet been developed.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

The clinical effect of mechanical ventilatory assistance with tracheotomy in terminal phase muscular dystrophy]

The clinical effect of mechanical ventilatory assistance with tracheotomy in respiratory failure of terminal phase muscular dystrophy was studied. The subjects were 6 Duchenne muscular dystrophy cases and 1 Ullrich type congenital muscular dystrophy case. Duration of the longest survival case was 4 years and 5 months. General physical conditions, complications, ADL and muscular atrophy were examined. By ventilatory assistance respiratory failure improved, and the physical condition stabilized and took good progress. Arterial hemorrhage which is lethal complication was observed in 2 cases. Mechanical ventilatory assistance with tracheotomy is an effective symptomatic therapy for the improvement of respiratory failure that can be applied when life prolongation is wished for by the patients or their families.     

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.     

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 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.     

Ten years follow up study of steroid therapy for congenital encephalomyopathy

Two 10-year-old boys with mental retardation and myopathy which were present since birth are described. Both had elevated serum creatine phosphokinase (CK) and one of them had a positive family history. The clinical features were consistent with Fukuyama type congenital muscular dystrophy, but muscle biopsies suggested an inflammatory process. Adrenal cortical steroids were given and they were followed up until 10 years of age. Serum CK showed a significant response to the treatment, and mental retardation in case 1 and motor dysfunction in case 2 improved. It is postulated that an inflammatory process might be a causative factor in some patients with congenital muscular dystrophy.     

Cognitive impairment in neuromuscular disorders

Several studies have suggested the presence of central nervous system involvement manifesting as cognitive impairment in diseases traditionally confined to the peripheral nervous system. The aim of this review is to highlight the character of clinical, genetic, neurofunctional, cognitive, and psychiatric deficits in neuromuscular disorders. A high correlation between cognitive features and cerebral protein expression or function is evident in Duchenne muscular dystrophy, myotonic dystrophy (Steinert disease), and mitochondrial encephalomyopathies; direct correlation between tissue-specific protein expression and cognitive deficits is still elusive in certain neuromuscular disorders presenting with or without a cerebral abnormality, such as congenital muscular dystrophies, congenital myopathies, amyotrophic lateral sclerosis, adult polyglucosan body disease, and limb-girdle muscular dystrophies. No clear cognitive deficits have been found in spinal muscular atrophy and facioscapulohumeral dystrophy.     

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 fiber type disproportion myopathy in Lowe syndrome

Two brothers with the typical clinical features of oculo-cerebro-renal syndrome of Lowe exhibited delays in developmental milestones, muscular weakness and hypotonia, and high serum creatine kinase activity. The biopsied muscle revealed selective type 1 fiber atrophy and mild type 1 fiber predominance, similar to that observed in congenital fiber type disproportion myopathy. The abnormal fiber type distribution may be responsible for the common finding of muscle hypotonia in this syndrome.     

Coexisting muscular dystrophies and epilepsy in children

Muscular dystrophies are composed of a variety of genetic muscle disorders linked to different chromosomes and loci and associated with different gene mutations that lead to progressive muscle atrophy and weakness. Fukuyama congenital muscular dystrophy is frequently associated with partial and generalized epilepsy and congenital brain anomalies, including cobblestone complex and other neuronal migration defects. We report generalized convulsive epilepsy in a boy with normal brain magnetic resonance imaging and Duchenne muscular dystrophy with deletion of dystrophin gene, and we report absence epilepsy with normal brain magnetic resonance imaging in another boy with limb girdle muscular dystrophy with partial calpain deficiency. We, therefore, review coexisting muscular dystrophies and epilepsy in children. In addition to Fukuyama congenital muscular dystrophy, partial or generalized epilepsy has also been reported in the following types of muscular dystrophies, including Duchenne/Becker dystrophy, facioscapulohumeral dystrophy, congenital muscular dystrophy with partial and complete deficiency of laminin alpha2 (merosin) chain, and limb girdle muscular dystrophy with partial calpain deficiency.     

Merosin negative congenital muscular dystrophy: a short report

We report a rare case of an infant with congenital muscular dystrophy who presented at birth with marked generalized hypotonia and normal mental development. Creatinine phosphokinase (CPK) level was markedly raised; however no white matter abnormalities were detected by brain imaging techniques. Immunohistochemical staining for merosin (laminin alpha 2) was negative, thereby confirming merosin-deficient congenital muscular dystrophy.     

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.     

Evaluation of cranial CT findings of patients with muscular dystrophy: with a reference to cerebral vascular disease and cardiac complications]

We evaluated cranial CT findings of 160 patients with various type of progressive muscular dystrophy (PMD). Significant brain atrophy was observed in 21 out of 63 cases of Duchenne muscular dystrophy (DMD), 7 out of 15 Becker muscular dystrophy (BMD), no case of 2 female dystrophinopathy (F-dyst), 11 out of 21 limb-girdle muscular dystrophy (LG), all cases of 10 Fukuyama type congenital muscular dystrophy (FCMD), 2 out of 5 fascioscapulohumeral muscular dystrophy (FSH), and 32 out of 44 myotonic dystrophy (MyD). Genetical degenerative process and vascular insufficiency seemed to cause brain atrophy in these disease. The intracranial calcification was observed in one DMD, one LG and seven MyD. One LG patient showed focal atrophy in left temporal lobe, and one MyD demonstrated right temporal meningioma. The trace of cerebral vascular accident was disclosed in eleven patients with PMD (1 DMD, 2 BMD, 1 F-dyst, 2 LG, 5 MyD). In these cases, 2 patients had dilated cardiomyopathy, 6 patients with decreased left ventricular ejection fraction, 3 with atrial fibrillation, 1 with cardiac arrest followed by pacemaker instillation, 1 with Adam-Stokes attack, and 3 with 1 degree AV-block. Diffuse low density in the white matter was seen in a patient with F-dyst, a FCMD patient, and 8 MyD patients. Cardiac emobolism, severe arrythmia, cardiogenic shock and hemodynamic disorder were seemed to cause cerebral vascular disease in PMD.     

Peroneal muscular atrophy with parkinsonism, ptosis, and congenital strabismus

Peroneal muscular atrophy (PMA) may be occasionally associated with other neurodegenerative features including parkinsonism. We report the association of PMA of neuronal type with parkinsonism, ptosis and congenital strabismus in a 62-year-old Sicilian woman. The complete syndrome was present only in the proband, but variously combined features were present in ten other family members over four generations, with likely autosomal dominant inheritance. Although a similar syndrome of PMA, ptosis, parkinsonism and dementia was already reported, this family showed a previously undescribed combination of features in view of the presence of congenital strabismus.     

Ocular findings in Fukuyama type congenital muscular dystrophy

In Fukuyama type congenital muscular dystrophy (FCMD), congenital muscular dystrophy and anomalies of the central nervous system are regarded as the major features, but the existence of ocular lesions has hardly been recognized as being important. In the present study, close ophthalmologic examinations were performed on 11 patients with FCMD, and we found myopia, weakness of the orbicularis oculi, congenital nystagmus, cortical blindness, optic atrophy, chorioretinal degeneration, etc. In particular, the chorioretinal degeneration observed in the ocular fundus was considered to be specific to FCMD. It is thought that these ocular lesions or changes are caused by the same mechanism as that involved in the central nervous system anomalies.