“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 unclassified form of centronuclear myopathy (CNM) and identified four patients presenting a peculiar histological alteration in some muscle fibers that resembled a necklace ("necklace fibers"). 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 fibers with internalized nuclei aligned in a basophilic ring (necklace) at 3 microm beneath the sarcolemma. Ultrastructurally, such necklaces consisted of myofibrils 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 fibers were seen neither in DNM2- or BIN1-related CNM nor in males with classical XLMTM. The presence of necklace fibers is useful as a marker to direct genetic analysis to MTM1 in CNM.

Congenital myopathy with “corona” fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

“…We also describe unusual muscle pathology associated with mutations in SCN4A. The muscle biopsy for Sibling 2 has features reminiscent of necklace fibres, previously described only in centronuclear myopathies [8][9][10][11]. However, the muscle pathology we describe differs from the classic necklace fibres reported initially by Bevilacqua et.al.…”

Clinical Phenotype of X‐Linked Myotubular Myopathy in Labrador Retriever Puppies

“…Pathologic changes were diagnostic of myotubular myopathy. Typical pathologic changes included excessive variability in myofiber size, type 1 fiber predominance, centrally placed nuclei in most myofibers, and subsarcolemmal ringed and central dense areas highlighted with mitochondrial specific reactions typical of “necklace fibers” 11. By immunohistochemical and ultrastructural analysis, centrally located muscle nuclei were confirmed, and muscle triads were disorganized and exhibited an abnormal orientation of T tubules.…”

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

“…This might be attributed to the recent identification of additional XLMTM cases with a milder phenotype, often associated with these types of sequence variants. [36][37][38][39] Analysis of the distribution of point mutations reveals a higher incidence in exons Expanding the MTM1 gene mutation spectrum J Oliveira et al 8, 11, 9, 4 and 12 (in decreasing order of frequency), and this should be taken into consideration when conducting MTM1 gene mutation screening. Altogether, mutations in these exons account for almost half of all reported XLMTM cases.…”