Case report: Comprehensive exploration of a novel PFKM mutation in glycogen storage disease Type VII

Abstract

Glycogen Storage Disease Type VII (GSD VII) is a rare glycogen metabolism disorder resulting from mutations in the PFKM gene, inherited in an autosomal recessive manner. It is characterized by exercise intolerance, muscle cramps, myoglobinuria, compensatory hemolysis, and later onset de novo myasthenia and mild myopathy, contributing to its clinical heterogeneity and diagnostic challenges. Here, we report a rare case of a 17-year-old Chinese woman exhibiting substantial muscle weakness and compensated hemolysis. Muscle biopsies showed glycogen deposition, and blood tests showed hyperuricemia and significantly elevated creatine kinase. Whole genome sequencing (WGS) and whole exome sequencing (WES) identified two compound heterozygous mutations in the PFKM (NM_000289.6) gene: c.626G>A and c.1376G>A in exons 7 and 15, respectively. According to the clinical presentation, diagnostic examination, and WES results, the patient was finally diagnosed with GSDVII. The discovery of these two new PFKM mutations expands the genetic spectrum, and understanding the clinical manifestations of these mutations is critical to preventing diagnostic delays and timely intervention and treatment.

Keywords: PFKM; case report; compound heterozygous mutations; glycogen storage disease Type VII; hemolysis.

FIGURE 1

Histopathologic manifestations of the patient muscle. (A) Hematoxylin-eosin (HE) staining revealing vacuole formation beneath the myoplasmic membrane. (B) Glycogen deposition in muscle fibers, identified as PAS-positive in glycogen staining. (C) NADH staining indicating an absence of evident positive areas. (D) No abnormalities observed in COX + SDH double staining. PAS, Schiff periodic acid shiff; NADH, Nicotinamide adenine dinucleotide; COX, cytochrome c oxidase; SDH, Succinate dehydrogenase.

FIGURE 2

Whole genome sequencing (WGS) and whole exome sequencing (WES) were performed on the proband and her parents. (A, D) The results indicated that the proband had compound heterozygous mutations in the PFKM gene: (C)1376 (exon15) G>A variant in exon 15 and (C)626 (exon7) G>A variant in exon 7. (B, C and E, F) Sanger traces for PCR of her parents. The (C)1376 (exon15) G>A on exon15 and (C)626 (exon7) G>A on exon 7 come from the mother and father, respectively. The arrows in the figure indicate exonic regions.