P.254 - Severe X-linked myotubular myopathy with unexpected inheritance from the grandfather and identification of necklace fibers in an asymptomatic male

Abstract

X-linked recessive myotubular myopathy (XLMTM) usually affects boys and is associated with mutations in the myotubularin gene (MTM1). In this study we describe a family with a severely affected infant boy with a centronuclear myopathy due to unexpected grand paternal transmission of a novel mutation in MTM1 (c.646_648dupGTT; p.Val216dup). The mother of the affected boy was heterozygous carrier of the variant whereas the maternal grandmother was homozygous for the wild-type allele. The maternal grandfather, who was reported to be healthy, was identified with both the mutated MTM1 gene together with wild-type MTM1. A muscle biopsy showed occasional necklace fibers, a hallmark of MTM1-associated myopathies, especially in manifesting heterozygous carriers. The grandfather, who had a normal karyotype (46,XY), demonstrated equal amounts of DNA with the wild-type sequence and DNA with the c.646_648dupGTT variant in five different tissues that were analyzed. These results were interpreted as postzygotic mosaicism and the mutation had probably occurred at the first mitosis of the zygote. This family demonstrate an unusual pattern of inheritance for a severe X-linked disorder, where the grandfather was transmitting the mutation. Muscle biopsy in the grandfather with presence of necklace fibers was important to further establish the pathogenicity of the novel MTM1 mutation. The results also have important implications for genetic counseling in this family.