Neuromuscular Features in XL-MTM Carriers: A Cross-Sectional Study in an Unselected Cohort

Abstract

BackgroundX-linked myotubular myopathy (XL-MTM) is an early onset congenital myopathy characterized by mild to severe muscle weakness in males.ObjectiveTo characterize the clinical spectrum of neuromuscular features in X-linked myotubular myopathy (XL-MTM) carriers.MethodsWe performed a nationwide cross-sectional study focusing on neuromuscular features in an unselected cohort of Dutch XL-MTM carriers. Participants were recruited from neuromuscular centres in the Netherlands and through the Dutch and European patient associations. Genetic results were collected. Carriers were classified based on ambulatory status and muscle weakness. We used a questionnaire focussing on medical and family history and neuromuscular symptoms. Additionally, we performed a neurological examination including Manual Muscle Testing (MMT), Timed Up and Go test (TUG), and 6 Minutes Walking Test (6MWT).ResultsWe included 21 carriers (20 genetically confirmed and one obligate), of whom eleven (52%) carriers were classified as manifesting, with severe (non-ambulatory; n=2), moderate (minimal independent ambulation/assisted ambulation; n=2), mild (independent ambulation but with limb or axial muscle weakness; n=3) and minimal (only facial muscle weakness, n=4) phenotypes. Three of the manifesting carriers (two severe, one moderate) were from families without genetically confirmed male XL-MTM patients. Furthermore, seven manifesting carriers (one moderate; two mild; four minimal) were not classified as manifesting carriers before participation in our study. Three carriers reported a history of pneumothorax. The obstetric history revealed frequent polyhydramnios (50%) and reduced fetal movements (36%) in pregnancies of affected sons. Muscle weakness was most pronounced in proximal and limb girdle muscles. Other frequently reported sign included (asymmetric) facial weakness (73%), reduced or absent deep tendon reflexes (45%), scoliosis (40%), and ptosis (45%). Ten participants (48%) were classified as non-manifesting. Manifesting carriers had lower functional testing scores on 6MWT and TUG compared to non-manifesting carriers.DiscussionThis study showed that 52% of an unselected group of XL-MTM carriers has muscle weakness (three of whom previously unclassified as manifesting). This corresponds to findings of our recent questionnaire study on self-reported symptoms in XLMTM carriers. These observations should raise awareness of the neuromuscular manifestations of the XL-MTM carrier state, and provide important epidemiological information required for future clinical trials.