Natural History Study for Patients With Nemaline Myopathy in Belgium

A Monocentre, Prospective, Longitudinal and Observational Natural History Study for Patients With Nemaline Myopathy

This is a prospective, longitudinal, observational study designed to characterize the natural history of Nemaline Myopathy (NM), a rare congenital neuromuscular disorder. The study will follow up to 10 participants of any age with genetically confirmed NM over a period of three years. Data will be collected during routine annual hospital visits and include clinical, motor, respiratory, and quality-of-life assessments. The goal is to improve clinical trial readiness by identifying disease-specific outcome measures and potential biomarkers.

Nemaline Myopathies (NM) are a group of rare, genetically and clinically heterogeneous congenital myopathies characterized by the presence of nemaline bodies (rods) on muscle biopsy. The estimated incidence is approximately 1 in 50,000, though this is likely underestimated due to phenotypic variability and underdiagnosis of milder forms. NM typically presents in childhood, but adult-onset cases have been reported, often with retrospectively recognized early symptoms. Clinical manifestations range from severe neonatal presentations requiring mechanical ventilation, to milder forms compatible with ambulation and normal lifespan. Common features include congenital hypotonia, bulbar and respiratory involvement, and proximal muscle weakness, with sparing of extraocular muscles.

NM is associated with mutations in at least 12 genes, including NEB and ACTA1, which account for the majority of genetically confirmed cases. Inheritance patterns can be autosomal dominant or recessive. Despite advances in genetic diagnostics, a subset of patients remains without a confirmed molecular diagnosis.

Currently, treatment is supportive and aligned with general standards of care for congenital myopathies. However, several therapeutic strategies are in preclinical development, targeting gene-specific mechanisms, muscle function, and myogenesis. Clinical translation is challenged by disease rarity, heterogeneity, and the lack of validated outcome measures and biomarkers.

This monocentric study aims to address these gaps by prospectively observing up to 10 patients with NM over three years. Study assessments will coincide with routine annual hospital visits to minimize participant burden. For participants under 18 years of age, additional assessments at 6 and 18 months will be conducted to capture developmental changes.

Data collection will include:

Medical and neurological examinations Age- and ability-adapted motor and respiratory outcome measures Questionnaires assessing swallowing, fatigue, quality of life, and health economics.

Visit durations will vary based on age and ability, including standard care appointments. This study will provide critical longitudinal data to support the development of future clinical trials by identifying relevant outcome measures and potential biomarkers for NM.

Inclusion Criteria:

• Male or Female
• Any age
• Patient and/or parent or legal guardian must be willing and have the ability to provide written informed consent for participation in the study.
• Diagnosis of NM which in most cases includes having a disease-causing variant/s in one of the known NM causative genes and a consistent clinical phenotype.

Exclusion Criteria:

• Any confirmed chronic or acute condition or disease affecting any system(s), which could interfere with the results of the study and/or the compliance with the study procedures. This will be subject to the clinical judgement of the Coordinating Investigator (CI) and/or the Principal Investigator (PI).
• Clinically significant medical finding on the physical examination other than NM that, in the judgment of the Investigator, will make the patient unsuitable for participation in, and/or completion of the study procedures.
• Participants of ongoing (interventional) clinical trials that assess the efficacy of potential treatments will be excluded as assessments need to be done on the basis that represent the natural progression of NM.
• Safety concerns. This includes anything that might put the participant and/or their Parent(s) or Guardian(s) at risk through participating in the study potentially including but not limited to: Safeguarding concerns, Social Issues and Health issues.
• Ongoing pregnancy (for participants becoming pregnant during the trial, some assessments may be cancelled or postponed. This will be subject to the clinical judgement of the Coordinating Investigator and/or the Principal Investigator)