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The Myotubular and Centronuclear Myopathy Registry is an international research database containing key longitudinal data on a diverse and growing cohort of individuals affected by this group of rare and ultra-rare neuromuscular conditions. It can inform and support all areas of translational research including epidemiological and natural history studies, clinical trial feasibility planning, recruitment for clinical trials or other research studies, stand-alone clinical studies, standards of care development, and provision of real-world evidence data. For ten years, it has also served as a valuable communications tool and provided a link between the scientific and patient communities. With the anticipated advent of disease-modifying therapies for these conditions, the registry is a key resource for the generation of post-authorisation data for regulatory decision-making, real world evidence, and patient-reported outcome measures. In this paper we present some key data from the current 444 registered individuals with the following genotype split: MTM1 n=270, DNM2 n=42, BIN1 n=4, TTN n=4, RYR1 n=12, other n=4, unknown n=108. The data presented are consistent with the current literature and the common understanding of a strong genotype/phenotype correlations in CNM, most notably the data supports the current knowledge that XLMTM is typically the most severe form of CNM. Additionally, we outline the ways in which the registry supports research, and, more generally, the importance of continuous investment and development to maintain the relevance of registries for all stakeholders. Further information on the registry and contact details are available on the registry website at www.mtmcnmregistry.org., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background and Objective: X-linked myotubular myopathy (XL-MTM) is an early-onset congenital myopathy characterized by mild to severe muscle weakness in male individuals. The objective was to characterize the clinical spectrum of neuromuscular features in X-linked myotubular myopathy (XL-MTM) carriers., Methods: We performed a nationwide cross-sectional study focusing on neuromuscular features in an unselected cohort of Dutch XL-MTM carriers. Participants were recruited from neuromuscular centers 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 focusing on medical and family history and neuromuscular symptoms. In addition, we performed a neurologic examination including manual muscle testing (MMT), timed up and go (TUG) test, and 6-minute walking test (6MWT)., Results: We included 21 carriers (20 genetically confirmed and 1 obligate), of whom 11 (52%) carriers were classified as manifesting, with severe (nonambulatory; 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 (2 severe and 1 moderate) were from families without genetically confirmed male XL-MTM patients. Furthermore, 7 manifesting carriers (1 moderate; 2 mild; and 4 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 signs included (asymmetric) facial weakness (73%), reduced or absent deep tendon reflexes (45%), scoliosis (40%), and ptosis (45%). Ten participants (48%) were classified as nonmanifesting. Manifesting carriers had lower functional testing scores on 6MWT and TUG compared with nonmanifesting carriers., Discussion: This study showed that 52% of an unselected group of XL-MTM carriers has muscle weakness (3 of whom were previously unclassified as manifesting). This corresponds to findings of our recent questionnaire study on self-reported symptoms in XL-MTM carriers. These observations should raise awareness of the neuromuscular manifestations of the XL-MTM carrier state and provide important epidemiologic information required for future clinical trials., (© 2022 American Academy of Neurology.)

Objective: To characterize the spectrum of clinical features in a cohort of X-linked myotubular myopathy (XL-MTM) carriers, including prevalence, genetic features, clinical symptoms, and signs, as well as associated disease burden., Methods: We performed a cross-sectional online questionnaire study among XL-MTM carriers. Participants were recruited from patient associations, medical centers, and registries in the United Kingdom, Germany, and the Netherlands. We used a custom-made questionnaire, the Checklist Individual Strength (CIS), the Frenchay Activities Index (FAI), the Short Form 12 (SF-12) health survey, and the McGill Pain Questionnaire. Carriers were classified as manifesting or nonmanifesting on the basis of self-reported ambulation and muscle weakness., Results: The prevalence of manifesting carriers in this study population (n = 76) was 51%, subdivided into mild (independent ambulation, 39%), moderate (assisted ambulation, 9%), and severe (wheelchair dependent, 3%) phenotypes. In addition to muscle weakness, manifesting carriers frequently reported fatigue (70%) and exercise intolerance (49%). Manifesting carriers scored higher on the overall CIS ( p = 0.001), the fatigue subscale ( p < 0.001), and least severe pain subscale ( p = 0.005) than nonmanifesting carriers. They scored lower on the FAI ( p = 0.005) and the physical component of the SF-12 health survey ( p < 0.001)., Conclusions: The prevalence of manifesting XL-MTM carriers may be higher than currently assumed, most having a mild phenotype and a wide variety of symptoms. Manifesting carriers are particularly affected by fatigue, limitations of daily activities, pain, and reduced quality of life. Our findings should increase awareness and provide useful information for health care providers and future clinical trials., (© 2021 American Academy of Neurology.)

X-linked myotubular myopathy (XLMTM) is a life-threatening rare neuromuscular disease, which is caused by pathogenic variants in the MTM1 gene. It has a large phenotypic heterogeneity, ranging from patients, who are able to walk independently to immobile patients who are only able to bring hand to mouth and depend on a respirator 24 hours a day every day. This suggests that ventilator requirements may not illustrate the full clinical picture of patients with XLMTM. At present, there is no curative therapy available, despite first promising results from ongoing gene therapy studies.In this study, we evaluated in detail the data from 13 German XLMTM patients, which was collected over a period of up to 20 years in our university hospital. We compared it to the international prospective longitudinal natural history study (NHS) data from 45 patients (containing 11 German patients). To highlight the broad phenotypic spectrum of the disease, we additionally focused on the clinical presentation of three cases at a glance.Comparing our data with the above mentioned natural history study, it appears the patients of the present German cohort seem to be more often severely affected, with higher frequency of non-ambulatory patients and patients on ventilation (and for longer time) and a higher proportion of patients needing a percutaneous endoscopic gastrostomy. Another key finding is a potential gap in time between first clinical presentation and final diagnosis, showing a need for patients to be treated in a specialized center for neuromuscular diseases.