Limb-girdle Muscular Dystrophy Type 2I/R9: Future Gene Therapy Options of an Extremely Rare Fukutin Protein-related Dystroglycanopathy

Abstract

Limb-girdle muscular dystrophy type 2I, now designated R9 (LGMD2I/R9), is an autosomal recessive dystroglycanopathy caused by biallelic pathogenic variants in the fukutin-related protein (FKRP) gene. Loss of FKRP glycosyltransferase activity disrupts the ribitol-phosphate-mediated glycosylation of alpha-dystroglycan, reducing matriglycan formation and weakening the link between the sarcolemma and the extracellular matrix. The resulting phenotype ranges from mild, adult-onset limb-girdle weakness to a severe congenital muscular dystrophy, and frequently includes dilated cardiomyopathy and restrictive respiratory failure. No disease-modifying treatment is currently licensed, and management remains supportive. Over the past decade, three broad experimental strategies have moved toward clinical evaluation: adeno-associated virus (AAV)-mediated gene replacement, small-molecule substrate supplementation with ribitol, and combinatorial approaches that pair gene replacement with muscle-anabolic transgenes such as follistatin. Registered early-phase AAV-FKRP programmes and the placebo-controlled FORTIFY trial of oral ribitol provide important translational context, but peer-reviewed clinical efficacy and long-term safety data remain limited; interim registry, conference and sponsor-reported findings should therefore be interpreted cautiously. This narrative review synthesises the molecular pathophysiology of FKRP-related dystroglycanopathy, appraises the natural history and outcome measures relevant to trial design, and critically evaluates the preclinical and early clinical evidence for gene-based and substrate-based therapies. It concludes with a discussion of unresolved translational barriers and a forward-looking assessment of the therapeutic pipeline for this ultra-rare neuromuscular disorder.