Expression of laminin chains in skin in merosin-deficient congenital muscular dystrophy

Laminin-2 (merosin) is a heterotrimer composed of alpha 2, beta 1 and gamma 1 chains. Approximately half of the cases with the classical form of congenital muscular dystrophy (CMD) have a deficiency of the laminin alpha 2 chain, encoded by the LAMA2 gene on chromosome 6q22. This disorder is often termed merosin-deficient CMD. Skeletal and cardiac muscle, and the peripheral and central nervous systems, all express laminin alpha 2 and can be affected in merosin-deficient CMD. Normal skin also expresses all three chains of laminin-2 at the epidermal/dermal junction, around hair follicles and in the sensory nerves. Skin biopsies can therefore be used to assess merosin status in patients. We show here an absence of laminin alpha 2 in skin from four cases of CMD with a severe phenotype and abnormal magnetic resonance image (MRI) of the brain, in contrast to normal expression in one case of mild CMD with normal MRI, and in five controls. An additional case of CMD had a partial deficiency of laminin alpha 2 in the skin and severe motor disability, but a normal MRI. Sensory nerves in this case showed normal expression of laminin alpha 2, in contrast to its absence in the severe cases. The expression of laminin beta 1 was also reduced in skin from cases of merosin-deficient CMD. In contrast to human fetal muscle, the laminin alpha 2 protein was not detected in fetal skin up to 23 weeks of gestation. The laminin beta 1 and gamma 1 chains, and the mRNA for laminin alpha 2, however, were present. Studies of mRNA of cultured skin cells suggest that fibroblasts are the major source of laminin alpha 2, not keratinocytes. Our data show that skin is useful for the assessment of merosin status in patients with CMD and that skin fibroblasts may be a useful source of tissue-specific RNA. In addition, we show that there is a tissue-specific difference in the developmental expression of the laminin alpha 2 protein

Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation

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Mutations in the nebulin gene can cause severe congenital nemaline myopathy.

Item does not contain fulltextPreviously, we reported results indicating that nebulin was the gene causing the typical form of autosomal recessive nemaline (rod) myopathy. Here we describe the identification of mutations in the nebulin gene in seven offspring of five families affected by the severe congenital form of nemaline myopathy. One pregnancy was terminated on the grounds of foetal abnormality, while six affected infants died at ages ranging from the first day of life to 19 months. Only three of the six neonates were able to establish spontaneous respiration. Three had arthrogryposis. In three of the five families, the mutations were located in exon 184. These mutations are predicted to cause absence of the C-terminal part of nebulin

Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom

The congenital myopathies are a group of inherited neuromuscular disorders mainly defined on the basis of characteristic histopathological features. We analysed 66 patients assessed at a single centre over a 5 year period. Of the 54 patients where muscle biopsy was available, 29 (54%) had a core myopathy (central core disease, multi-minicore disease), 9 (17%) had nemaline myopathy, 7 (13%) had myotubular/centronuclear myopathy, 2 (4%) had congenital fibre type disproportion, 6 (11%) had isolated type 1 predominance and 1 (2%) had a mixed core-rod myopathy. Of the 44 patients with a genetic diagnosis, RYR1 was mutated in 26 (59%), ACTA1 in 7 (16%), SEPN1 in 7 (16%), MTM1 in 2 (5%), NEB in 1 (2%) and TPM3 in 1 (2%). Clinically, 77% of patients older than 18 months could walk independently. 35% of all patients required ventilatory support and/or enteral feeding. Clinical course was stable or improved in 57/66 (86%) patients, whilst 4 (6%) got worse and 5 (8%) died. These findings indicate that core myopathies are the most common form of congenital myopathies and that more than half can be attributed to RYR1 mutations. The underlying genetic defect remains to be identified in 1/3 of congenital myopathies cases