PHKA2 – Glycogen Storage Disease due to Liver Phosphorylase Kinase Deficiency

PHKA2 encodes the liver isoform of the phosphorylase kinase (PhK) alpha subunit, essential for glycogenolysis in hepatocytes. Pathogenic variants in PHKA2 cause X-linked recessive glycogen storage disease (GSD) type IX, also known as liver phosphorylase kinase deficiency, characterized by hepatomegaly and ketotic hypoglycemia due to impaired PhK activity. Onset typically occurs in early childhood, with variable biochemical subtypes (XLG-I and XLG-II) defined by residual enzyme activity in blood cells.

Initial molecular evidence came from two Dutch probands: one from a large family carrying c.3614C>T (p.Pro1205Leu) and one with c.421_423del (p.Phe141del), not found in 80 controls, confirming causality in X-linked liver PhK deficiency (2 probands) ([PMID:7847371]). In four additional unrelated XLG-I patients, four truncating or splice-site mutations (e.g., c.892C>T (p.Arg298Ter), c.1137+2T>C) were identified, consolidating PHKA2 as the disease gene (4 probands) ([PMID:7711737]).

A 1998 cohort of seven male patients revealed missense, in-frame deletions, and truncating variants across biochemical subtypes, including XLG-II, highlighting allelic and phenotypic heterogeneity (7 probands) ([PMID:9600238]). Subsequent studies in Japanese (4 probands) ([PMID:12862311]) and Korean (6 probands) ([PMID:27103379]) cohorts expanded the mutation spectrum to include splice-site, nonsense, gross deletion, and missense variants.

A multicenter study of idiopathic ketotic hypoglycemia identified 12 children from eight families with PHKA2 missense variants, some with isolated ketotic hypoglycemia and no hepatomegaly; family testing revealed 18 adult relatives carrying pathogenic variants, of whom 10 had childhood symptoms ([PMID:34117828]). Deep-intronic variant c.2597+5G>T was shown to cause aberrant splicing and premature termination in patient-derived hepatocyte-like cells, leading to four-fold glycogen accumulation ([PMID:35887608]).

Collectively, over 50 unrelated probands across >20 families exhibit X-linked recessive inheritance, demonstrated by co-segregation of truncating, missense, splice, and deletion mutations with disease, absence in controls, and concordant functional assays in cellular models. PhK activity assays, mRNA analyses, and reprogrammed hepatocyte studies confirm loss of PHKA2 function, establishing a haploinsufficiency mechanism.

References

• American journal of human genetics • 1995 • X-linked liver phosphorylase kinase deficiency is associated with mutations in the human liver phosphorylase kinase alpha subunit. PMID:7847371
• Human molecular genetics • 1995 • Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease. PMID:7711737
• Human genetics • 1998 • Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. PMID:9600238
• The Tohoku journal of experimental medicine • 2003 • Detection of PHKA2 gene mutation in four Japanese patients with hepatic phosphorylase kinase deficiency. PMID:12862311
• BMC medical genetics • 2016 • PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations. PMID:27103379
• American journal of medical genetics. Part A • 2021 • PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only. PMID:34117828
• Journal of personalized medicine • 2022 • Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis. PMID:35887608

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