Phenotypic and muscle biopsy features of patients with FKRP c.1387A>G founder mutation (P5.454)

Objective: To further characterize the phenotype of patients with the FKRP mutation c.1387A>G. Background: Fukutin-related protein (FKRP) plays a role in glycosylation of α-dystroglycan (α-DG) with mutations leading to hypoglycosylation and decreased binding of α-DG to the extracellular matrix. When homozygous, the most common FKRP mutation (c.826C>A; p.L276I) causes LGMD2I with onset during adolescence and ambulation preserved into adulthood. LGMD2I muscle biopsies show mild-moderate dystrophic pathology. A novel FKRP mutation (c.1387A>G; p.N463D) was described in two girls from central Mexico in 2007; both had a severe CMD phenotype. Design/Methods: We collected clinical data from all patients with the c.1387A>G mutation known to the authors. When available, muscle biopsies were reviewed. Results: We identified 5 patients with the c.1387A>G mutation. Four are homozygous, of Hispanic origin, and are currently 4–19 years old. The average age at onset of weakness was 9 months. Three of the 4 never stood or walked. Vison is normal. Cognition is normal to mildly impaired. Brain MRIs are normal. Biopsies were available for 2 patients, done at ages 2 and 4 years. Both showed end-stage dystrophic pathology, near absence of glycosylated α-DG by immunofluorescence, and reduced molecular weight α-DG compared to normal controls and homozygous c.826C>A patients. The 5th patient, with FKRP mutations c.1387A>G and c.826C>A, presented in childhood ( A patients. Conclusions: The clinical phenotype and muscle pathology in the 4 patients homozygous for FKRP c.1387A>G support the previous suggestion that this mutation causes CMD. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared to that seen with the c.826C>A mutation. The Hispanic origin of these patients supports the interpretation that c.1387A>G may be a founder mutation. Study Supported by: This research was funded by the Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers (NIH U54 NS053672) Disclosure: Dr. Lee has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Mathews has nothing to disclose. Dr. Moore has nothing to disclose. Dr. Butterfield has nothing to disclose. Dr. Johnson has received personal compensation for consulting, serving on a scientific advisory board, speakering, or other activities with AMO Pharma, AveXis and Strongbridge Pharma. Dr. Johnson has received compensation in an editorial capacity for Neurology Genetics. Dr. Johnson has received research support from Biogen Idec, Cytokinetics, AMO Pharma, AveXis and Ionis Pharmaceuticals. Dr. Konersman has nothing to disclose. Dr. Abdenur has nothing to disclose. Dr. Beson has nothing to disclose.