DOI: 10.5061/dryad.116n37m
title: Data from: Adult MTM1-related myopathy carriers: classification based on deep phenotyping

description: Objective To better characterize adult MTM1-related myopathy carriers and
 recommend a phenotypic classification. Methods This cohort study was
 performed at the National Institutes of Health Clinical Center.
 Participants were required to carry a confirmed MTM1 mutation and were
 recruited via the Congenital Muscle Disease International Registry (n=8),
 a traveling local clinic of the Neuromuscular and Neurogenetic Disorders
 of Childhood Section, NINDS, NIH and Cure CMD (n=1) and direct physician
 referral (n=1). Neuromuscular examinations, muscle MRI, dynamic breathing
 MRI, cardiac MRI, pulmonary function tests (PFTs) and physical therapy
 assessments including the Motor Function Measure 32 (MFM-32) scale were
 performed. Results Phenotypic categories were proposed based on ambulatory
 status and muscle weakness. Carriers were categorized as severe
 (non-ambulatory; n=1); moderate (minimal independent ambulation/assisted
 ambulation; n=3); mild (independent ambulation but with evidence of muscle
 weakness; n=4) and non-manifesting (no evidence of muscle weakness; n=2).
 Weaker carriers exhibited a greater severity of respiratory insufficiency
 and abnormal signal on muscle imaging. Skeletal asymmetries were evident
 in both maninfesting and non-manifesting carriers. Skewed X chromosome
 inactivation did not explain phenotypic severity. Conclusion This work
 illustrates the phenotypic range of MTM1-related myopathy carriers in
 adulthood and recommends a phenotypic classification. This classification,
 defined by ambulatory status and muscle weakness, is supported by muscle
 MRI, PFT, and MFM-32 scale composite score findings, which may serve as
 markers of disease progression and outcome measures in future gene therapy
 or other clinical trials.
description: Table
 e-1Table e-1: Review of the
 MTM1-related Myopathy Carrier Literature. Includes clinical phenotypic
 features, genotype and X-inactivation ratios for all reported manifesting
 and non-manifesting MTM1-related myopathy carriers reported so
 far.cocanougher-et-al-table-e-1.xlsxFigure e-1Figure e-1: Motor Function Measure 32 results correlate with symptom severity. The motor function measure 32 (MFM32) scale reveals weakness more severe in standing position and transfers (D1) and axial and proximal motor function (D2), with sparing of distal motor function (D3). The composite score captures the clinical severity for most patients in the cohort.cocanougher-et-al-figure-e-1.tifFigure e-2Figure e-2: The first reported case of a carrier of “X-linked centronuclear myopathy,” diagnosed based on muscle biopsy findings in her son (Heckmatt et al., 1985). Facial weakness was reported as demonstrated by the inability to bury eyelashes completely. There appears to be evidence of mild facial asymmetry, which was not reported. Reproduced with permission (Oxford University Press).cocanougher-et-al-figure-e-2.tifFigure e-3Figure e-3: Pedigree for patients M6 and M7 reveals an extensive X-linked family history. The maternal grandmother (generation I) had six of nine male newborns pass away within hours or days following birth (generation II). The mother of M6 and M7 had six children with two of four male children having passed away in infancy, likely due to MTM1-related myopathy (genetic testing not performed). One of these two male children was the twin brother of M7, who had severe congenial weakness and passed away a few days after birth. Patient M6 had one male child, who was diagnosed as an infant. The first cousin of patients M6 and M7 had two male children who passed away from MTM1-related myopathy (generation IV).cocanougher-et-al-figure-e-3.tif