PGK1 – Glycogen Storage Disease due to Phosphoglycerate Kinase 1 Deficiency

Phosphoglycerate kinase 1 (PGK1) deficiency (MONDO:0010392) is an X-linked recessive metabolic disorder caused by pathogenic variants in the PGK1 gene (HGNC:8896). Clinically, it presents with chronic nonspherocytic hemolytic anemia, skeletal muscle myopathy, and variable central nervous system dysfunction, including developmental delay and intellectual disability. Diagnosis relies on low erythrocyte PGK enzyme activity and molecular confirmation of PGK1 variants.

Genetic evidence supports an X-linked recessive inheritance pattern, with hemizygous males affected and heterozygous females typically asymptomatic carriers. Nearly 40 reported cases, including 27 characterized at the DNA or protein level, involve over 20 distinct missense and splicing mutations across unrelated families ([PMID:22705348]). A nationwide French retrospective study identified 3 unrelated patients harboring hemizygous PGK1 mutations, further substantiating the gene-disease link ([PMID:30887539]).

The variant spectrum is dominated by missense changes that impair enzyme stability and catalytic function. A recurrent founder variant c.491A>T (p.Asp164Val) has been reported in American, French, and Chinese-Australian kindreds, indicating either recurrence or shared ancestry ([PMID:16740138], [PMID:30887539]). For example, c.1060G>C (p.Ala354Pro) was identified in a Japanese patient with hemolytic anemia, developmental delay, and rhabdomyolysis ([PMID:12956773]). Other notable variants include c.1112T>A (p.Ile371Lys) and c.1180A>G (p.Thr394Ala), each correlating with multi-tissue involvement ([PMID:22705348], [PMID:24934115]).

Segregation data are limited but include affected sibling pairs. In one White American family, two hemizygous brothers presented with hemolysis, seizures, and developmental delay, both harboring the c.491A>T mutation ([PMID:16740138]). No significant segregation beyond sib pairs has been reported, and heterozygous females remain largely unaffected.

Functional studies demonstrate markedly reduced PGK activity (<5%–36% of normal) in patient erythrocytes and recombinant assays of 16 mutant enzymes show decreased thermal stability and catalytic efficiency, consistent with clinical severity ([PMID:22348148], [PMID:22705348]). In vitro rescue models are lacking, but biochemical concordance across variants underpins pathogenicity.

Mechanistically, destabilizing missense and splicing mutations lead to enzyme misfolding and accelerated denaturation, resulting in insufficient ATP generation in red blood cells and muscle fibers. This energy deficit underlies hemolytic anemia, rhabdomyolysis, and neurodevelopmental impairment. The genotype–phenotype correlation is modulated by residual enzyme activity and potential compensatory factors.

Taken together, PGK1 deficiency has a Strong gene-disease validity classification based on over 40 probands, multiple unrelated cases, and concordant biochemical/functional data. Genetic evidence attains a Strong level with numerous hemizygous variants characterized across families, and functional evidence is Moderate due to robust in vitro enzymology studies. Clinical genetic testing for PGK1 should be pursued in males with unexplained hemolytic anemia and neuromuscular symptoms; early diagnosis guides supportive care and genetic counseling.

Key Take-home: X-linked PGK1 variants cause a triad of hemolytic anemia, myopathy, and neurodevelopmental deficits via enzyme instability; molecular diagnosis informs management and family screening.

References

• British journal of haematology • 2003 • A novel missense mutation (1060G --> C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhabdomyolysis. PMID:12956773
• Molecular genetics and metabolism • 2012 • A new variant of phosphoglycerate kinase deficiency (p.I371K) with multiple tissue involvement: molecular and functional characterization. PMID:22705348
• Journal of inherited metabolic disease • 2019 • Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study. PMID:30887539
• British journal of haematology • 2006 • The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA. PMID:16740138
• PLoS One • 2012 • Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency. PMID:22348148
• International journal of hematology • 2014 • Phosphoglycerate kinase deficiency due to a novel mutation (c. 1180A>G) manifesting as chronic hemolytic anemia in a Japanese boy. PMID:24934115

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