Qualitative or quantitative defects of FKRP

Qualitative or quantitative defects of FKRP (fukutin-related protein) encompass a spectrum of rare genetic disorders caused by mutations in the FKRP gene, which plays a critical role in the glycosylation of alpha-dystroglycan, a protein essential for maintaining the structural integrity of muscle cells and their connection to the extracellular matrix. These conditions are classified among the dystroglycanopathies and range in severity from the severe Walker-Warburg syndrome and muscle-eye-brain disease phenotypes to milder forms such as limb-girdle muscular dystrophy type R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophy type 1C (MDC1C). The body systems primarily affected include skeletal muscle, the central nervous system, and the eyes, though the extent of involvement varies considerably depending on the specific mutation and its impact on residual FKRP function. Patients with severe forms may present at birth or in infancy with profound muscle weakness (hypotonia), structural brain abnormalities such as cobblestone lissencephaly, cerebellar malformations, hydrocephalus, and eye anomalies including retinal dysplasia and microphthalmia. Milder forms, particularly LGMDR9, typically present in childhood or adulthood with progressive proximal limb-girdle muscle weakness, elevated serum creatine kinase levels, respiratory insufficiency, and dilated cardiomyopathy. Cardiac involvement is a significant concern across the spectrum and requires regular monitoring. Cognitive impairment may be present in more severe phenotypes but is generally absent in milder forms. There is currently no cure for FKRP-related dystroglycanopathies. Management is supportive and multidisciplinary, including physical therapy, respiratory support, cardiac monitoring and treatment, orthopedic interventions, and seizure management when needed. Gene therapy and ribitol supplementation strategies are under active investigation in preclinical and early clinical studies, offering hope for future disease-modifying treatments.

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