title: "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.
authors.affiliation: INSERM, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bevilacqua
authors.forename: Marc
authors.initials: M
authors.lastname: Bitoun
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.forename: Gisela
authors.initials: G
authors.lastname: Stoltenburg
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lacène
authors.forename: Guy
authors.initials: G
authors.lastname: Brochier
authors.forename: Linda
authors.initials: L
authors.lastname: Manéré
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforêt
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Norma Beatriz
authors.initials: NB
authors.lastname: Romero
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D009210:Myofibrils / Q000648:ultrastructure; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin