Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies.

Glycogen storage disease XV is caused by variants in the glycogenin-1 gene, GYG1, and presents as a predominant skeletal myopathy or cardiomyopathy. We describe two patients with late-onset myopathy and biallelic GYG1 variants. In patient 1, the novel c.144-2A>G splice acceptor variant and the novel frameshift variant c.631delG (p.Val211Cysfs*30) were identified, and in patient 2, the previously described c.304G>C (p.Asp102His) and c.487delG (p.Asp163Thrfs*5) variants were found. Protein analysis showed total absence of glycogenin-1 expression in patient 1, whereas in patient 2 there was reduced expression of glycogenin-1, with the residual protein being non-functional. Both patients showed glycogen and polyglucosan storage in their muscle fibers, as revealed by PAS staining and electron microscopy. Age at onset of the myopathy phenotype was 53 years and 70 years respectively, with the selective pattern of muscle involvement on MRI corroborating the pattern of weakness. Cardiac evaluation of patient 1 and 2 did not show any specific abnormalities linked to the glycogenin-1 deficiency. In patient 2, who was shown to express the p.Asp102His mutated glycogenin-1, cardiac evaluation was still normal at age 77 years. This contrasts with the association of the p.Asp102His variant in homozygosity with a severe cardiomyopathy in several cases with an onset age between 30 and 50 years. This finding might indicate that the level of p.Asp102His mutated glycogenin-1 determines if a patient will develop a cardiomyopathy.

Glycogenin is considered essential for glycogen synthesis, as it acts as a primer for the initiation of the polysaccharide chain. Against expectations, glycogenin-deficient mice (Gyg KO) accumulate high amounts of glycogen in striated muscle. Furthermore, this glycogen contains no covalently bound protein, thereby demonstrating that a protein primer is not strictly necessary for the synthesis of the polysaccharide in vivo. Strikingly, in spite of the higher glycogen content, Gyg KO mice showed lower resting energy expenditure and less resistance than control animals when subjected to endurance exercise. These observations can be attributed to a switch of oxidative myofibers toward glycolytic metabolism. Mice overexpressing glycogen synthase in the muscle showed similar alterations, thus indicating that this switch is caused by the excess of glycogen. These results may explain the muscular defects of GSD XV patients, who lack glycogenin-1 and show high glycogen accumulation in muscle.