“Necklace” fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy

Abstract

Mutations in the gene encoding the phosphoinositide phosphatase myotubularin 1 protein (MTM1) are usually associated with severe neonatal X-linked myotubular myopathy (XLMTM). However, mutations in MTM1 have also been recognized as the underlying cause of “atypical” forms of XLMTM in newborn boys, female infants, female manifesting carriers and adult men. We reviewed systematically the biopsies of a cohort of patients with an unclassiWed form of centronuclear myopathy (CNM) and identiWed four patients presenting a peculiar histological alteration in some muscle Wbers that resembled a necklace (“necklace Wbers”). We analyzed further the clinical and morphological features and performed a screening of the genes involved in CNM. Muscle biopsies in all four patients demonstrated 4–20% of Wbers with internalized nuclei aligned in a basophilic ring (necklace) at 3 m beneath the sarcolemma. Ultrastructurally, such necklaces consisted of myoWbrils of smaller diameter, in oblique orientation, surrounded by mitochondria, sarcoplasmic reticulum and glycogen granules. In the four patients (three women and one man), myopathy developed in early childhood but was slowly progressive. All had mutations in the MTM1 gene. Two mutations have previously been reported (p.E404K and p.R241Q), while two are novel; a c.205_206delinsAACT frameshift change in exon 4 and a c.1234A>G mutation in exon 11 leading to an abnormal splicing and the deletion of nine amino acids in the catalytic domain of MTM1. Necklace Wbers were seen neither in DNM2- or BIN1-related CNM nor in males with classical XLMTM. The presence of necklace Wbers is useful as a marker to direct genetic analysis to MTM1 in CNM.