PFKM – Glycogen Storage Disease Type VII (Tarui Disease)

Muscle phosphofructokinase (PFKM) deficiency, also known as Tarui disease, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the PFKM gene, leading to impaired glycolysis in muscle and red blood cells. Patients present with exercise intolerance, muscle cramps, myoglobinuria, compensated hemolytic anemia, and hyperuricemia. PFKM variants have been conclusively linked to glycogen storage disease VII (Tarui disease).

Genetic evidence for the PFKM–GSDVII association includes over 25 unrelated probands across multiple ethnicities. In a cohort of nine Ashkenazi Jewish families, three recurrent mutations (including a delta 5 splicing defect) accounted for 17 of 18 disease alleles, with a 0.4% carrier frequency for the most common allele in 250 controls (PMID:8037209). Compound heterozygous and homozygous PFKM variants have been documented in Swedish, Spanish, Chinese, and Japanese families, demonstrating autosomal recessive segregation in at least four additional pedigrees (PMID:8659544; PMID:39156960).

The PFKM variant spectrum encompasses splice-site mutations (e.g., c.1341+1G>C), small deletions causing frameshifts, nonsense changes (e.g., c.283C>T (p.Arg95Ter)), missense substitutions (e.g., c.116G>A (p.Arg39Gln)), and intron retentions leading to premature termination. The c.116G>A (p.Arg39Gln) variant is noted as a founder allele in Ashkenazi patients and also observed in non-Ashkenazi siblings with juvenile onset (PMID:27066546).

Functional assays demonstrate severely reduced PFK activity (1–5% residual) in muscle and erythrocytes, consistent with the biochemical hallmark of GSDVII (PMID:22133655). Muscle biopsies reveal extralysosomal glycogen accumulation, while murine PFK1 knockout recapitulates exercise intolerance and metabolic deficits. High-resolution crystal structures of PFK isoforms further substantiate the impact of pathogenic mutations on enzyme tetramerization and allosteric regulation, supporting a loss-of-function mechanism (PMID:25985179).

Although classic histochemical stains may occasionally yield false-negative results, biochemical activity assays and molecular genetic testing reliably establish the diagnosis. No studies have refuted the PFKM–GSDVII association, and genotype–phenotype correlations remain consistent across populations.

PFKM deficiency meets ClinGen criteria for a Definitive gene–disease relationship, with strong genetic and moderate functional evidence. Early genetic diagnosis enables carrier screening in high-risk populations, informs prognosis, and guides management such as exercise restriction and supportive care.

Key Take-home: Biallelic PFKM variants cause autosomal recessive Tarui disease, presenting with exertional myopathy and hemolysis; definitive genetic testing is essential for accurate diagnosis and family counseling.

References

• American Journal of Human Genetics • 1994 • Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis VII--and their population frequency PMID:8037209
• American Journal of Human Genetics • 1996 • Glycogenosis type VII (Tarui disease) in a Swedish family: two novel mutations in muscle phosphofructokinase gene (PFK-M) resulting in intron retentions PMID:8659544
• Neurology: Genetics • 2015 • PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry PMID:27066546
• Frontiers in Genetics • 2024 • Case report: Comprehensive exploration of a novel PFKM mutation in glycogen storage disease Type VII PMID:39156960
• Nature • 2015 • Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations PMID:25985179
• Neuromuscular Disorders • 2012 • Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII) PMID:22133655

Evidence Based Scoring (AI generated)