Spectrum of Clinical Features in X-Linked Myotubular Myopathy Carriers

Reumers, Stacha F. I.; Braun, Frederik; Spillane, Jennifer; Böhm, Johann; Pennings, Maartje; Schouten, Meyke; Kooi, Anneke J. van der; Foley, A. Reghan; Bönnemann, Carsten G.; Kamsteeg, Erik‐Jan; Erasmus, Corrie E.; Schara‐Schmidt, Ulrike; Jungbluth, Heinz; Voermans, Nicol C.

doi:10.1212/wnl.0000000000012236

Cited by 11 publications

(22 citation statements)

References 48 publications

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“…In addition to limb girdle and axial weakness, we also observed a wide range of other signs suggestive of a myopathic phenotype, such as fatigue, exercise intolerance, myalgia and muscle cramps, and mild (asymmetric) facial weakness including ptosis. In line with our previous study, 16 these signs were also reported, albeit to a lesser extent, in carriers classified as nonmanifesting. Our main finding is that 52% of XL-MTM carriers within our cohort are symptomatic based on physical examination.…”

Section: Discussionsupporting

confidence: 92%

“…The previous analysis of a cohort of 76 carriers also showed the correlation between age and clinical severity. 16 Altogether, this might suggest a slowly progressive disease course with presentation only in later life, but underlying factors need to be further elucidated. 10 Seven manifesting carriers had not been diagnosed with manifesting carriership and had not related their symptoms to their MTM1 carriership before, confirming our hypothesis of a possible ascertainment bias in previous case series.…”

Section: Discussionmentioning

confidence: 99%

“…Participants who were previously recruited to the international questionnaire study by Reumers et al 16 were also invited for participation in this study. Furthermore, carriers were recruited from neuromuscular centers in the Netherlands and through the Dutch and European patient associations (Spierziekten Nederland; ZNM—Zusammen Stark!…”

Section: Methodsmentioning

confidence: 99%

“…Two women could not be contacted after 3 attempts, and 2 others could not participate due to intercurrent illness unrelated to the XL-MTM carriership. Following abovementioned exclusions, we included 21 XL-MTM carriers (84% participation rate) of whom 18 had participated already in the questionnaire study of Reumers et al, 16 and 1 (M2) had already been included in the previously published series of Biancalana et al 12 Of the 21 carriers included, 20 (95%) had genetic confirmation of an MTM1 mutation and 1 was an obligate carrier (5%). 19 More specifically, we included 11 (52%) mothers, 1 (5%) grandmother, 2 (10%) sisters, 2 (10%) daughters, 1 (5%) cousin, and 1 (5%) aunt of male XL-MTM patients (Figure 1).…”

Section: Participantsmentioning

confidence: 99%

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Neuromuscular Features in XL-MTM Carriers

Franken¹,

Bouman²,

Reumers³

et al. 2022

Neurology

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Participantsmentioning

confidence: 99%

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Neuromuscular Features in XL-MTM Carriers

Franken¹,

Bouman²,

Reumers³

et al. 2022

Neurology

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“…Most female XLMTM carriers were first assumed to be asymptomatic, but recent studies have shown they can have symptoms with a wide spectrum of clinical involvement from severe neonatal and generalized weakness with respiratory dysfunction to more commonly observed milder forms in adulthood [ 26 , 27 ]. Prevalence of manifesting XLMTM carriers may be higher than currently assumed as demonstrated with a new cohort of 76 female carriers published in 2021 with 51% manifesting carriers [ 28 ]. It is characteristic to observe asymmetric weakness and growth, facial involvement, ptosis, and skeletal and joint abnormalities [ 26 , 27 ].…”

Section: Mtm1 and Myotubular Myopathymentioning

confidence: 99%

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Gómez-Oca

Cowling²,

Laporte

2021

IJMS

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Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

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