Nemaline Myopathy

This single-arm pilot study aims to investigate the effects of a whole-body electrical muscle stimulation (WB-EMS) exercise program on neuromuscular and physical function in adults with neuromuscular disease (NMD). The background rationale is that individuals with NMD often experience significant barriers to traditional exercise due to impaired voluntary motor unit activation, leading to sedentary behavior, physical deconditioning, and worsened long-term health outcomes. WB-EMS may offer a therapeutic alternative by bypassing voluntary activation limits and directly stimulating muscle contractions through externally applied electrical currents. The intervention utilizes the Katalyst system, an FDA-cleared device being used off-label in this population, which delivers targeted stimulation to major muscle groups during synchronized exercise movements. Up to 50 adults diagnosed with various NMDs, including amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis, and Charcot-Marie-Tooth disease, will be enrolled. Eligible participants must be at least 18 years old, able to stand continuously for 15 minutes with or without assistance, and have at least anti-gravity strength in major muscle groups. Key exclusion criteria include implanted electrical devices, unstable medical conditions, pregnancy, and conditions affecting muscle fiber structural integrity. The intervention consists of 20-minute supervised exercise sessions performed 1-2 times per week over 4-8 weeks, with real-time monitoring of pain, perceived exertion, and tolerability. Outcome measures include neural excitability assessed via transcranial magnetic stimulation, voluntary motor unit characteristics via decomposition electromyography, stimulated motor unit characteristics via compound muscle action potential nerve conduction study, functional performance tests (10-meter walk, timed up and go, five-time sit-to-stand, stair ascent/descent, broad jump, multidirectional lunge), and patient-reported outcomes evaluating fatigue, pain, and quality of life. This pilot study will generate critical preliminary data on the feasibility, safety, and efficacy of WB-EMS as a novel exercise modality for adults with NMD, with the goal of informing future large-scale clinical trials.

The Congenital Myopathy Research Program consists of a group of scientists and healthcare providers all working to better understand the congenital myopathies. We are taking two approaches to reach our research goals. The first involves identifying and describing new genes and proteins involved in the skeletal muscles that allow our bodies to move. Simultaneously, studies are underway to identify genetic changes (mutations) that cause human neuromuscular disease. Thus, our second approach is to identify mutations, learn how they are inherited in families, and understand how they lead to weakness in individuals with neuromuscular disease. These approaches allow correlation of our basic muscle biology findings with our studies on muscle tissue of affected individuals. Our research would not be possible without the generous participation of individuals and families with congenital myopathies. Participation in our studies is free of charge. Travel to Boston is not required, and we welcome the participation of individuals from around the world. We appreciate the participation of all individuals with a congenital myopathy, as well as their first-degree relatives. Participants with a congenital myopathy are asked to donate medical records, a blood or saliva sample, and a muscle tissue sample (if available). Participating relatives are asked to donate a blood sample. The blood/saliva sample is used to acquire DNA (genetic material) which can be used to identify genetic changes and to study how a disease is inherited in a family. The medical records are employed to understand a participant's symptoms. The muscle tissue is used to better understand the disease at the muscular level by studying the gene expression and protein levels in individuals with congenital myopathies. For more information, visit the Laboratory Website at www.childrenshospital.org/research/beggs.

The aims of the study are: * Identify the specific genes and mutations responsible for NM in Spain. * Define the in-depth phenotyping of NM and the phenotype-genotype relationship. * Characterize the natural history of NM through the systematic collection of clinical (retrospective and prospective data), functional, and respiratory data in diagnosed patients in order to: * Describe the progression of the disease without disease-modifying therapies. * Identify reliable biomarkers and outcome measures for future clinical trials. * Align the national protocol with international efforts to generate comparable data.

The Neurogenetics Branch (NGB) within the National Institute of Neurological Disorders and Stroke (NINDS) is conducting a study to evaluate and provide genetic diagnosis to participants with various diagnosed and undiagnosed neurological conditions. OBJECTIVES: The primary objective of this protocol is to provide a resource of participants for enrollment into new research protocols throughout the NGB and other NIH laboratories. Evaluating and diagnosing participants will allow the NGB specialists to maintain their expertise and gain additional knowledge of the course of various neurological disorders. The information obtained will allow for the evaluation and diagnosis of the studied neurological diseases. This understanding may lead to ideas for future protocols. In some cases, blood or other biologic samples (including urine, saliva, or a cheek (buccal) swab) will be obtained for future laboratory studies. STUDY POPULATION The number of participants to be enrolled will be set to 3,500 participants with neurological diseases and their unaffected relatives. DESIGN: This is an observational diagnostic study of multiple neurological diseases and their pathophysiology. OUTCOME MEASURES: No formal outcomes will be measured; however the clinical assessments of enrolled participants can be used to characterize the disease manifestations. In addition, DNA samples obtained may be used to identify and verify causative mutations as well as identify novel genes, which may help establish pathogenic mechanisms and genotype-phenotype correlations.

Rationale: Patients with CCD/MmD, NEM and CNM report symptoms of weakness in the arms and legs. Other symptoms include weakness of the respiratory, facial and swallowing muscles. No treatments are available for congenital myopathies (CM) to slow down or cure the disease. A few type I-II trials have taken place and more are expected. Therefore it is important to reach trial readiness. To create trial readiness, there is a need for natural history study to create a detailed report of the disease course and a selection of the most sensitive clinical and functional outcome measures and biomarkers. Besides muscle weakness, several patients report muscle fatigability. This has not been investigated systematically in CM. The lack of evidence calls for a cross-sectional study assessing muscle fatigability and neuromuscular transmission in CM. Objectives: i) To assess the natural disease course of CCD/MmD, NEM and CNM during 24 months. ii) To select relevant and sensitive clinical and functional outcome measures and biomarkers. iii) To assess the severity of muscle fatigability in CCD/MmD, NEM and CNM. Study design: Patients with a genetically confirmed CCD/MmD, NEM or CNM will be able to participate in this study. The study consist of 2 parts. Part 1: a prospective cohort study with 5 visits every 6 months, for a total of 2 years. 45 patients will be included for this part. Part 2: an observational study with 2 visits. For this part 75 patients will be included. There will be an overlap in patients for the two parts. So a total of approximately 100 patients will be included. A large set of tests will be performed to assess the full capabilities of the patient, e.g. muscle strength/endurance, muscle imaging (MRI/ultrasound), activities, walking ability, quality of life, muscle fatigability and the feeling of fatigue.

WiTNNess is an observational study that includes prospective and cross-sectional arms, both of which include people diagnosed with autosomal recessive TNNT1-associated muscle disease, commonly described as a form of infantile-onset (NEM5A) or childhood-onset (NEM5B) nemaline rod myopathy. The study's primary objective is to establish the nature and time course of disease outcomes under current treatment, so that these can later be compared to outcomes achieved with novel disease-modifying therapies (i.e., interventional trials). Participants from all over the world are welcome to enroll in either arm of the WiTNNess study. Following appropriate consent, those in the prospective arm are followed long-term. Recurring assessments are performed at the participant's home, the Clinic for Special Children, or a partnering clinical site, depending on the individual's particular circumstances. Basic assessments include vital signs, a physical exam, documentation of motor milestones, growth measurements, and blood chemistry values. Participant's may also undergo non-invasive ultrasound of the heart (echocardiogram) and one or more chest radiographs. Participants in the cross-sectional arm are contacted once after consent. Members of the WiTNNess study team partner with healthcare providers and family members to capture pertinent medical history, physical exam findings, growth metrics, and motor milestones at the time of contact.