Adult MTM1-related myopathy carriers: classification based on deep phenotyping

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.