Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother

X-linked recessive myotubular myopathy (XLMTM) is a muscle disorder usually affecting newborn males. In the majority of cases, muscle weakness and hypotonia lead to a rapid demise at neonatal age. The responsible MTM1 gene is located in proximal Xq28. Heterozygous carriers are described as being asymptomatic but, in a few cases, mild facial weakness has been reported. We report a family in which a 39-year old female showed severe progressive muscle weakness. XLMTM was initially diagnosed in the male offspring of one of the patient's sisters. The patient, one of her sisters, and their mother were heterozygous carriers for a common MTM1 gene mutation. We found an extremely skewed X-inactivation pattern in the patient and, in the opposite direction, in her non-manifesting carrier mother, thus explaining her normal phenotype and indicating a possible inheritance of skewed X-inactivation. Linkage analysis excluded a possible involvement of the XIST locus at Xq13.