Biallelic Pathogenic Variants in PYGM Impair Retinal Glycogenolysis Causing a Range of Phenotypes

Purpose: Biallelic pathogenic variants in PYGM (glycogen myophosphorylase) cause glycogen storage disease V (GSDV), a skeletal muscle disorder with reported association with hereditary macular dystrophy (HMD). This study investigated the role of PYGM in HMD and broader retinal disease through clinical and functional analyses. Methods: An autosomal recessive HMD family underwent phenotyping and genome sequencing. Separately, data from 65 patients with GSDV (mean age = 51.7 years) were analyzed for retinal involvement. Immunohistochemistry, RT-qPCR and translating ribosome affinity purification assays assessed retinal expression of glycogen phosphorylase (GP) isoenzymes. Glycogenolysis was studied in retinal pigment epithelial (RPE-1) cells. Retinal sections from PygmR50*/R50* mice were also examined. Results: Genome sequencing identified a homozygous pathogenic stop-gain variant in PYGM (NM_005609.4:c.148C > T; p.[Arg50*]) in the proband and affected sibling, and re-phenotyping revealed features of GSDV. Retinal involvement was identified in 30 of 65 GSDV cases (23 bilateral), with higher prevalence in participants >60 years (approximately 2.6-fold) and men (approximately 2-fold). PYGM expression was localized to Müller glia and photoreceptors. Cell-type-specific GP isoenzyme expression was found in mouse retina and RPE-1 cells. RPE-1 cells demonstrated glycogenolysis. PygmR50*/R50* mice lacked glycogen accumulation but exhibited photoreceptor outer segment thinning consistent with Pygm being the predominant isoform expressed in mouse photoreceptors. Conclusions: GSDV is moderately associated with retinopathy, and may present as non-syndromic HMD, warranting retinal monitoring for patients, and the inclusion of PYGM in retinal dystrophy gene panels. Redundancy in retinal glycogenolysis may account for lower penetrance and higher age-related prevalence in patients. Photoreceptor thinning observed in PygmR50*/R50* mice strengthens the association between HMD and GSDV in humans.