Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Merosin (also called as Laminin-2) is an isoform of laminin comprised of the alpha2, beta1 and gamma1 chains. In European populations, half of the patients with classical congenital muscular dystrophy have mutations of the LAMA2 gene (6q22-23) and present reduced or absence of laminin alpha2 chain. This form is generally referred to as merosin-deficient CMD. Merosin-deficient CMD is characterized by involvement of not only skeletal muscle but also central and peripheral nervous systems: Extensive brain white matter abnormalities are found by magnetic resonance imaging (MRI). However, most patients show no mental retardation. Recent case studies reported that some patients have several structural abnormalities such as abnormal cerebral cortical gyration, hypoplasia of cerebellum and pons, and dilation of ventricles. At present, functions of merosin related to muscle degeneration have not been fully elucidated. In addition, the mechanisms responsible for pathogenesis of diffuse brain white matter abnormalities remain to be determined. As mouse models for merosin-deficient CMD, three spontaneous mutants(dy, dy(2J), dy(PAS1)) and two mutants named dy(W) and dy(3K) by targeted gene disruption have been reported. These mice will help to elucidate the pathogenesis of merosin-deficient CMD and serve to develop therapy.
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PMID:Merosin and congenital muscular dystrophy. 1067 65

We present four subjects from one family and one subject (with an affected sibling who had died) from a second, unrelated family, with early onset, Duchenne-like, muscular dystrophy who presented with proximal girdle weakness, calf and generalized muscle hypertrophy, selective wasting of the sternomastoid muscles, rigidity of the spine and contractures of the tendo Achilles. Intellect was normal. Serum creatine kinase was grossly elevated and the muscle biopsies showed a dystrophic picture. All five subjects have developed early respiratory failure due to severe diaphragmatic involvement; two have already died aged 4 and 7 years of age and the remaining three are dependent on night time ventilation. There has been very little deterioration over time in the skeletal muscle function, and the survivors remain ambulant, the oldest being 11 years. Immunocytochemical studies of the muscle biopsy showed a normal pattern for dystrophin and the dystrophin-associated glycoproteins, but a reduction of the laminin alpha2 chain of merosin. Magnetic resonance imaging of the brain was normal. The disease did not link to the LAMA2 locus for laminin alpha2 on chromosome 6q, so that these families seem to represent a new form of autosomal recessive muscular dystrophy with a secondary merosin deficiency. The primary protein deficiency has not yet been identified.
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PMID:An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22. 1072 42

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.
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PMID: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. 1152 87

Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.
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PMID:An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. 1156 31

Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.
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PMID:The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review. 1158 42

The authors report a case of congenital muscular dystrophy with mild nonprogressive muscle weakness, white matter hypodensity, and absence of the laminin alpha2 chain in muscle fibers with two antibodies, but not with four others. They identified mutations in LAMA2, which explain the partial laminin alpha2 deficiency. Analysis of this case and two others allows us to refine the epitopes of two of the commercial antibodies, and illustrate the importance of using antibodies directed against different domains of the protein.
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PMID:Congenital muscular dystrophy with primary partial laminin alpha2 chain deficiency: molecular study. 1159 58

Motor and sensory nerve conduction velocities (NCVs) and needle electromyography (EMG) results were reviewed in 26 children with different types of congenital muscular dystrophy (CMD), including patients with mutations in the genes LAMA2, FKRP, and COL6A2. In every patient, at least one EMG examination detected myopathic changes that were predominant in proximal muscles, although EMG performed at birth was normal in two patients. Brief bursts of high-frequency repetitive discharges were electrically elicited in four patients. Uniformly slowed motor NCVs without signs of denervation were observed in seven patients: five merosin-deficient, one merosin-positive, and one with unavailable merosin status. The merosin-deficient neuropathy also involved sensory nerves in three patients and worsened with age in two. In conclusion, myopathic EMG changes were typical and early findings in all types of CMD. An associated neuropathy was detected in most patients with merosin-deficient CMD, and also in a child with normal merosin expression.
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PMID:EMG and nerve conduction studies in children with congenital muscular dystrophy. 1475 96

The congenital muscular dystrophies (CMD, MDC) represent a heterogeneous group of autosomal recessive disorders manifesting in infancy by muscle weakness and hypotonia. Approximately 40% of patients with CMD have a primary deficiency of the laminin alpha 3. chain of merosin (laminin-2) due to mutations in LAMA2 gene. Laminin-2 bound to alpha-dystroglycan forms a link between actin--associated cytoskeletal proteins and the components of extracellular matrix. Disruption of this axis is responsible for several forms of muscular dystrophy. A unique case of congenital muscular dystrophy simulating a juvenile polymyositis in a muscle biopsy is presented. A profound reduction of alpha-dystroglycan and less pronounced secondary deficiency of alpha 2-laminin were found. All known forms of CMD were excluded, and the disorder was diagnosed as so far undescribed form of CMD. The mutation in a gene encoding the protein, that seems to play a role in a glycosylation of alpha-dystroglycan, is presumed.
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PMID:[A unique case of congenital muscular dystrophy]. 1523 18

The authors report a girl with autosomal recessive congenital muscular dystrophy linked to chromosome 6 (MDC1A) who carries a homozygous out-of-frame deletion in exon 56 of the LAMA2 gene but has a mild phenotype. She is still ambulant at age 13 years, shows white matter abnormalities on MRI, and traces of laminin alpha2 in her muscle biopsy with one of three antibodies used. This patient suggests that modulating factors can be associated with a less severe clinical phenotype in MDC1A.
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PMID:LAMA2 loss-of-function mutation in a girl with a mild congenital muscular dystrophy. 1545 15

Laminin alpha2-deficient congenital muscular dystrophy is a debilitating disease affecting both muscle and neural tissue as a result of mutations in the LAMA2 gene. It presents at or soon after birth with muscle weakness and is further characterised by clinical central nervous system involvement. Laminin alpha2 is part of the extracellular matrix, linked to the cellular cystoskeleton via dystroglycan which is an integral part of the dystrophin-glycoprotein complex (DGC). We examined both short- and long-term synaptic plasticity in the C57BL6J/dy(2J) mouse, an animal model of laminin alpha2 deficient congenital muscular dystrophy. Using a cerebellar slice preparation, we show that the pre-synaptically mediated paired-pulse facilitation (PPF) was no different between dy(2J) and littermate controls. Approximately half (7/12) the dy(2J) Purkinje cells displayed a blunted LTD compared to littermate controls, and one third (4/12) of dy(2J) Purkinje cells displayed LTP. This study demonstrates that a defective laminin alpha2 causes a disruption in long-term synaptic plasticity at the Purkinje cell-parallel fibre synapse.
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PMID:Synaptic plasticity in the dy2J mouse model of laminin alpha2-deficient congenital muscular dystrophy. 1582 49


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