Expanding the clinical phenotype and understanding the biochemical consequences of Muscle Glycogen Synthase...

Glycogen storage disease type 0b (GSD 0b) is an exceptionally rare metabolic disorder caused by biallelic pathogenic variants in the GYS1 gene, leading to deficient glycogen synthase (GS) activity. In 2022, two cases were reported for the first time with a phenotype presenting as adult-onset myopathy.

A 56-year-old woman with a history of progressive limb-girdle and axial weakness was evaluated. Clinical assessments, muscle biopsy, genetic analyses, RNA sequencing from muscle tissue, and western blot analyses were performed. Muscle glycogen levels were quantified using spectrophotometry.

The patient was found to have a biallelic pathogenic variant (c.678 + 1G > A) in the GYS1 gene. Skeletal muscle MRI showed a distinctive pattern with potential diagnostic value. Transcriptome sequencing indicated that the variant caused skipping of exon 4 in half of the transcripts and retention of intron 4 in the remainder. Muscle biopsy revealed marked glycogen depletion. In our study, we have also observed the molecular and biochemical consequences resulting from the presence of pathogenic variants in the GYS1 gene. Glycogen quantification confirmed a significant reduction in muscle glycogen content. Our findings elucidate the molecular consequences of GYS1 deficiency, showing severely reduced GS protein levels, leading to compensatory decreases in glycogen degradation (PHKA1, PHKB, PHKG1 and AGL) and glycolytic (PFKM, PKM1 and the phosphorylated form of pPDHE) enzymes. Additionally, the absence of GS affects STBD1 and prompts a shift towards oxidative metabolism due to reduced glycogen levels.

This case of GSD 0b, caused by a novel GYS1 variant, highlights the disease's clinical and molecular heterogeneity. Understanding the molecular consequences of GS deficiency can aid in developing management strategies for GSD 0b.