A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy

X-linked myotubular myopathy (XLMTM) characteristically causes severe or fa tal muscle weakness in male infants. Mutations in the gene MTM1, encoding t he protein myotubularin, can be identified in most families. Prior to this report, XLMTM was thought not to cause symptomatic manifestations in female carriers. We describe an adult female from a large family with typical XLM TM. The patient had progressive disabling muscle weakness of later onset an d lesser severity than that observed in affected males. The distribution of weakness resembled typical XLMTM with facial weakness, marked limb-girdle weakness, respiratory muscle involvement and dysphagia. Analysis of the MTM 1 gene identified a heterozygous missense mutation (G378R) within the highl y conserved tyrosine phosphatase site of myotubularin. We did not identify significantly skewed X-inactivation. We conclude that XLMTM is capable of c ausing significant disability in heterozygotes (C) 2000 Elsevier Science B. V. All rights reserved.