Rare hereditary paediatric onset neuromuscular diseases : from genes to gene-targeted therapies

Abstract

Hereditary Neuromuscular Diseases (HNMDs) encompass a diverse group of rare disorders affecting various components of the neuromuscular system. They present a wide spectrum of clinical manifestations, varying severity and age of onset, and diverse genetic causes. Healthcare provision for HNMD patients often lacks consistency due to inadequate knowledge among healthcare providers, leading to disparities in care across hospitals and regions. This work aims to provide a comprehensive overview of HNMDs, detailing their subcategories, causative genes, and prevalence worldwide. It also discusses the role of diagnostic modalities and deep phenotyping in genetic diagnosis, both before and during the Next Generation Sequencing (NGS) era, highlighting the importance of NGS as a first-tier diagnostic tool for HNMDs. The text delves into the complexities of dystrophinopathy, the most common pediatric-onset muscular dystrophy, and explains the development of disease-modifying treatments, clinical trials, and stem cell-based therapies. The author's research on induced pluripotent stem cell-derived cardiomyocytes as a disease model for studying disease mechanisms, drug screening, and genetic regulation is also presented. In addition, the work explores Spinal Muscular Atrophy (SMA), discussing its clinical presentation, genetic causes, and pathogenetic mechanisms. While established multidisciplinary care is available, the development of three new disease-modifying drugs has significantly improved patient outcomes. However, challenges remain in defining emerging clinical phenotypes and new standards of care. The findings on healthcare burden, clinical outcome, and health-related quality of life changes in SMA patients receiving disease-modifying treatments, are shared. Furthermore, the upcoming Hong Kong SMA newborn screening program and ongoing global research for cost-effective treatments and an SMA cure are discussed. Finally, the text illustrates how diagnostic modalities combined with deep phenotyping aid genetic diagnosis of rare HNMDs through selected local and overseas collaborative studies. The absence of local facioscapulohumeral muscular dystrophy (FSHD) diagnostic service in Hong Kong and the incorporation of NGS diagnostics into healthcare systems to improve patient care and management are also addressed.