Adult MTM1 -related myopathy carriers

Abstract

ObjectiveTo better characterize adult myotubularin 1 (MTM1)–related myopathy carriers and recommend a phenotypic classification.MethodsThis cohort study was performed at the NIH 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, National Institute of Neurological Disorders and Stroke, 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), physical therapy assessments including the Motor Function Measure 32 (MFM-32) scale, and X chromosome inactivation (XCI) studies were performed.ResultsPhenotypic categories were proposed based on ambulatory status and muscle weakness. Carriers were categorized as severe (nonambulatory; n = 1), moderate (minimal independent ambulation/assisted ambulation; n = 3), mild (independent ambulation but with evidence of muscle weakness; n = 4), and nonmanifesting (no evidence of muscle weakness; n = 2). Carriers with more severe muscle weakness exhibited greater degrees of respiratory insufficiency and abnormal signal on muscle imaging. Skeletal asymmetries were evident in both manifesting and nonmanifesting carriers. Skewed XCI did not explain phenotypic severity.ConclusionThis 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.

Spectrum of Clinical Features in X-Linked Myotubular Myopathy Carriers

“…Previous observations in male patients with XL-MTM showed that missense mutations were often associated with a mild phenotype, independent ambulation, and longer survival, but most truncating and nonsense mutations cause severe and early lethal phenotypes. 1,18,42 This was not observed in the carriers in our cohort. In the absence of protein data, we could not investigate whether the MTM1 missense mutations we identified result in protein reductions significant enough to cause a severe phenotype.…”

“…However, a systematic study investigating the prevalence of manifesting XL-MTM carriers has not been performed. 18,20 Our study indicates that there may be more manifesting XL-MTM carriers than previously assumed. 15,19 The observed prevalence of manifesting carriers in XL-MTM (51%, based on self-reported muscle weakness) is higher than in other X-linked neuromuscular disorders.…”

“…We used the phenotype classification by Cocanougher et al, 18 which is based on ambulatory status and muscle weakness determined by neurologic examination. We used self-reported data to classify the carriers into groups.…”

“…These studies demonstrated a wide range of phenotypes and suggested a higher number of manifesting carriers than currently assumed. 15,18,19 Furthermore, a literature review of 57 manifesting and nonmanifesting carriers showed a wide spectrum of disease, ranging from severe congenital weakness to limb girdle weakness of later onset. 18 Moreover, observations from clinical practice suggest that XL-MTM carriers with mild muscular symptoms do not necessarily seek medical attention, and the overall prevalence of manifesting XL-MTM carriers may thus still be underestimated.…”

“…15,18,19 Furthermore, a literature review of 57 manifesting and nonmanifesting carriers showed a wide spectrum of disease, ranging from severe congenital weakness to limb girdle weakness of later onset. 18 Moreover, observations from clinical practice suggest that XL-MTM carriers with mild muscular symptoms do not necessarily seek medical attention, and the overall prevalence of manifesting XL-MTM carriers may thus still be underestimated. Attempts have been made to extrapolate both incidence and prevalence for centronuclear myopathy with the limited epidemiologic data available.…”