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.