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Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy.

ABSTRACT: We aimed to correlate pathologic findings with MTM1 mutation type in a series of molecularly defined XLMTM cases. Clinical data from 15 XLMTM patients and their corresponding 16 muscle biopsies were studied. All patients were infants (range: 6-217 days old) when initially biopsied. The proportion of myofibers with central nuclei did not correlate with clinical outcome, however, morphometric studies showed that survivors had larger myofiber diameters in infancy than those who died (10.4+/-3.9microm versus 8.9+/-3microm; p<0.001). As a corollary, patients with MTM1 missense mutations had larger myofiber diameters (11.1+/-4microm), than those with truncation/deletion mutations (8.6+/-2.7microm) (controls 11.7+/-2.5microm) (p<0.0001). These data indicate that differences in myofiber size correlate with MTM1 mutation type and patient outcome. Failure to attain and/or maintain myofiber size, along with fiber type perturbations and the misplacement of myofiber nuclei and other organelles, are important components of XLMTM muscle pathology.

SUBMITTER: Pierson CR

PROVIDER: S-EPMC2043149 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy.

Pierson Christopher R CR Agrawal Pankaj B PB Blasko Jessica J Beggs Alan H AH

Neuromuscular disorders : NMD 20070529 7

We aimed to correlate pathologic findings with MTM1 mutation type in a series of molecularly defined XLMTM cases. Clinical data from 15 XLMTM patients and their corresponding 16 muscle biopsies were studied. All patients were infants (range: 6-217 days old) when initially biopsied. The proportion of myofibers with central nuclei did not correlate with clinical outcome, however, morphometric studies showed that survivors had larger myofiber diameters in infancy than those who died (10.4+/-3.9micr ...[more]

PMID: 17537630

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Project description:BackgroundCongenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. In fact, canine models of dystrophin deficient muscular dystrophy and X-linked myotubular myopathy are of tremendous value in the translation of new and promising therapies for the treatment of these diseases. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death. X-linked myotubular myopathy was suspected based on the early and severe clinical presentation and histopathological changes within muscle biopsies. The aim of this study was to determine the genetic basis for myopathy in these dogs and compare and contrast the clinical presentation, histopathology, ultrastructure, and mutation in this family of Rottweiler dogs with the previously described myotubular myopathy in Labrador retrievers.ResultsHistopathology, histochemistry, and ultrastructural examination of muscle biopsies from affected Rottweiler puppies were consistent with an X-linked myotubular myopathy. An unusual finding that differed from the previously reported Labradors and similar human cases was the presence of excessive autophagy and prominent autophagic vacuoles. Molecular investigations confirmed a missense mutation in exon 11 of MTM1 that was predicted to result in a non-functional phosphatase activity. Although the clinical presentations and histopathology were similar, the MTM1 p.(Q384P) mutation is different from the p.(N155K) mutation in exon 7 affecting Labrador retrievers with X-linked myotubular myopathy.ConclusionsHere we describe a second pathogenic mutation in MTM1 causing X-linked myotubular myopathy in dogs. Our findings suggest a variety of MTM1 mutations in dogs as seen in human patients. The number of MTM1 mutations resulting in similar severe and progressive clinical myopathy and histopathological changes are likely to increase as canine myopathies are further characterized.

Dataset Information

Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy.

Publications

Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy.

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