RESUMO
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1.
Assuntos
Proteínas Cromossômicas não Histona/genética , Distrofia Muscular Facioescapuloumeral/genética , Adolescente , Adulto , Idoso , Alelos , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/metabolismo , Mutação , Linhagem , Adulto JovemRESUMO
By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.
Assuntos
Doenças Neuromusculares/urina , Consenso , França , Pessoal de Saúde , Humanos , Qualidade de Vida , TelemedicinaRESUMO
BACKGROUND: Facioscapulohumeral muscular dystrophy is a rare inherited neuromuscular disease with an estimated prevalence of 1/20,000 and France therefore harbors about 3000 FSHD patients. With research progress and the development of targeted therapies, patients' identification through registries can facilitate and improve recruitment in clinical trials and studies. RESULTS: The French National Registry of FSHD patients was designed as a mixed model registry involving both patients and physicians, through self-report and clinical evaluation questionnaires respectively, to collect molecular and clinical data. Because of the limited number of patients, data quality is a major goal of the registry and various automatic data control features have been implemented in the bioinformatics system. In parallel, data are manually validated by molecular and clinical curators. Since its creation in 2013, data from 638 FSHD patients have been collected, representing about 21% of the French FSHD population. The mixed model strategy allowed to collect 59.1% of data from both patients and clinicians; 26 and 14.9% from respectively patients and clinicians only. With the identification of the FSHD1 and FSHD2 forms, specific questionnaires have been designed. Though FSHD2 patients are progressively included, FSHD1 patients still account for the majority (94.9%). The registry is compatible with the FAIR principles as data are Findable, Accessible and Interoperable. We thus used molecular standards and standardized clinical terms used by the FILNEMUS French network of reference centers for the diagnosis and follow-up of patients suffering from a rare neuromuscular disease. The implemented clinical terms mostly map to dictionaries and terminology systems such as SNOMED-CT (75% of terms), CTV3 (61.7%) and NCIt (53.3%). Because of the sensitive nature of data, they are not directly reusable and can only be accessed as aggregated data after evaluation and approval by the registry oversight committee. CONCLUSIONS: The French National Registry of FSHD patients belongs to a national effort to develop databases, which should now interact with other initiatives to build a European and/or an international FSHD virtual registry for the benefits of patients. It is accessible at www.fshd.fr and various useful information, links, and documents, including a video, are available for patients and professionals.
Assuntos
Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/epidemiologia , Sistema de Registros , Bases de Dados Factuais , França , Humanos , Doenças Raras , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: The aim of this study was to investigate the effects on motor function, muscle strength, and endurance of short-term neuromuscular electrical stimulation training of the tibialis anterior muscles in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1) in comparison with healthy controls. DESIGN: This prospective study included 10 patients with FSHD1 and 10 healthy participants. Maximal voluntary isometric contraction of ankle dorsiflexion and a 2-min sustained dorsiflexion maximal voluntary contraction with surface electromyography recordings of the tibialis anterior and the soleus muscles were measured and motor function clinical tests were performed before and after the training period. RESULTS: No significant short term training effect was found in any of the investigated variables for either group, although a tendency towards an increase was noted for the manual muscle testing of the FSHD1. Patients with FSHD1 showed lower maximal voluntary contraction force and lower maximal tibialis anterior surface electromyography amplitude than healthy participants. During the 2-min sustained maximal voluntary contraction, the percentage of force loss was lower for the FSHD1 patients, suggesting that they were experiencing a lower amount of muscle fatigue compared to the healthy participant group. CONCLUSION: The present neuromuscular electrical stimulation protocol was not strenuous enough and/or the parameters of stimulation were not adequate to improve dorsiflexion strength, muscle endurance, and motor function in FSHD1 patients and healthy participants.