PHKG2 – Glycogen Storage Disease Due to Liver Phosphorylase Kinase Deficiency

PHKG2 encodes the γ subunit of phosphorylase kinase, and biallelic loss-of-function variants cause autosomal recessive liver phosphorylase kinase deficiency (Glycogen Storage Disease Due to Liver Phosphorylase Kinase Deficiency). Affected individuals typically present in early childhood with hepatomegaly, growth restriction, elevated transaminases and hypertriglyceridemia.

Multiple case series and reports have identified at least 36 unrelated probands harboring bi-allelic PHKG2 variants with concordant clinical features. Segregation in a family with two affected siblings confirms recessive transmission, and diverse variant classes include missense, nonsense, splice-site and frameshift changes ([PMID:29360628]; [PMID:32697758]; [PMID:35549678]).

In a Chinese pedigree, a novel truncating mutation c.553C>T (p.Arg185Ter) was discovered and validated by NGS and Sanger sequencing, and a literature review of 25 GSD IXc patients revealed missense (39%) and nonsense (23%) variants clustering in exons 3 and 6 ([PMID:29360628]).

A cohort of ten Pakistani children from seven families showed seven PHKG2 variants—three stop codons (p.Arg76Ter, p.Arg152Ter, p.Arg320Ter), one missense (p.Ser36Phe) and a splice change (c.557-3C>G)—reinforcing autosomal recessive inheritance and a consistent biochemical phenotype ([PMID:32697758]).

Functional assays in a neonatal case demonstrated that p.Phe233Ser (c.698T>C) and p.Arg320AspfsTer5 markedly reduce phosphorylase kinase activity in vitro, supporting a loss-of-function mechanism ([PMID:35549678]).

These data across populations and variant types establish a Strong gene–disease association. PHKG2 sequencing enables definitive diagnosis, informs prognosis and guides dietary management to mitigate liver injury. Key take-home: Genetic testing of PHKG2 is essential for accurate diagnosis and personalized care of liver phosphorylase kinase deficiency.

References

• Journal of pediatric endocrinology & metabolism : JPEM • 2018 • PHKG2 mutation spectrum in glycogen storage disease type IXc: a case report and review of the literature. PMID:29360628
• Journal of pediatric endocrinology & metabolism : JPEM • 2020 • Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene. PMID:32697758
• BMC pediatrics • 2022 • A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants. PMID:35549678

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