The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

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Abstract
Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease’s progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders.
Funding Information
  • Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund
  • HM Toupin Neurological Science Research Fund
  • Canadian Institutes of Health Research (CIHR)
  • Canada Foundation for Innovation
  • Alberta Advanced Education and Technology
  • Alberta Innovates: Health Solutions (AIHS)
  • Women and Children’s Health Research Institute (WCHRI)
  • the Rare Disease Foundation
  • BC Children’s Hospital Foundation
  • Maternal and Child Health (MatCH) Program
  • Alberta Innovates
  • Women and Children’s Health Research Institute (WCHRI)
  • Andrew Stewart Memorial Graduate Prizes
  • Alberta Graduate Excellence Scholarships (AGES)

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