Compound heterozygous mutations of the TNXB gene cause primary myopathy.

Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions.

Axon cytoskeleton ultrastructure in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: To detail the extent and pattern of axon cytoskeleton alterations in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Nerve biopsies from 7 cases of CIDP, including 4 cases with severe fiber loss, were compared with 5 controls by morphometric transmission electron microscopy (TEM). RESULTS: Despite demyelination of single fibers, myelin ultrastructure was otherwise normal. Contrary to immunolabeling, TEM revealed a decrease in neurofilament (NF) density in every case, although there were pronounced variations among fibers even in the same sample. The NF decrease reached the same extent in large- and small-diameter fibers. It was observed in normally myelinated fibers, suggesting they were demyelinated at a distance from the section. Minimal inter-NF distance increased roughly inversely to NF density. Microtubules increased in 3 cases previously characterized by increased growth-associated protein (GAP-43) immunolabeling. CONCLUSION: These data demonstrate the severity and constancy of axonal lesions, and especially of NF, in residual fibers in our cases of CIDP.

Diagnosis of myotubular myopathy in the oldest known manifesting female carrier: a clinical and genetic study.

X-linked myotubular myopathy is a congenital myopathy due to mutation in the MTM1 gene, encoding myotubularin. Most of the affected male neonates die early of respiratory failure. The female carriers are usually asymptomatic. The authors report a novel MTM1 mutation in a 77-year-old woman. She presented with progressive ptosis since childhood, proximal limb weakness, and a severe restrictive respiratory dysfunction with a hemidiaphragmatic paresis, leading to death at 84 years of age. The muscle biopsy showed centrally nucleated fibers and mitochondrial abnormalities. A stop mutation Leu498X in MTM1 gene was identified in the proband and in her two healthy daughters. The X-inactivation pattern was random in the proband's blood and muscle DNA, and in blood DNA from her two unaffected MTM1 mutation carrier daughters. Two large heteroplasmic deletions were also detected in the muscle mitochondrial DNA of the propositus, raising the question of their putative impact on the phenotype.

Myotilinopathy in a family with late onset myopathy.

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.