PHKA2 – Disorder of Glycogen Metabolism

PHKA2, encoding the liver isoform of the phosphorylase kinase (PhK) α-subunit, is associated with X-linked glycogen storage disease type IXα (GSD IXa), a subset of Disorder of Glycogen Metabolism (MONDO_0002412). This X-linked recessive condition manifests predominantly with hepatomegaly, transaminitis, and ketotic hypoglycemia, typically in childhood (PMID:32387637). Studies have identified both truncating and missense variants throughout PHKA2’s 33 exons, implicating haploinsufficiency as the primary pathogenic mechanism. The spectrum includes nonsense (e.g., c.1489C>T (p.Gln516Ter)), splicing (c.2226+2T>C), frameshift (c.3308_3312dup (p.Leu1105MetfsTer11)), and missense changes (c.3614C>T (p.Pro1205Leu)) with recurrent and population-specific alleles (PMID:21646031). A comprehensive Korean cohort confirmed that gross deletions (exons 18–33) and single-nucleotide variants contribute equally to disease prevalence (PMID:27103379). Female carriers can express disease when skewed X-chromosome inactivation leads to preferential mutant allele expression (PMID:24055370).

Genotypic studies of 45 unrelated pediatric patients with suspected liver PhK deficiency revealed PHKA2 mutations in 26 individuals, supporting a strong gene–disease link (PMID:21646031). Variants cluster in functional domains: the glucoamylase-like N-terminal region and the calcineurin B-like C-terminal domain, consistent with disrupted subunit assembly and loss of enzymatic activation (PMID:18950708). Segregation analysis in a family of two affected brothers harboring c.1561A>G (p.Thr521Ala) further confirms X-linked inheritance (affected_relatives: 2). Case series have expanded the phenotype to include late-onset hearing loss and cognitive impairment in adults, underlining phenotypic heterogeneity (PMID:31987065).

Functional assays demonstrate that PHKA2 truncating and splice-site mutations result in absent or unstable α-subunit, abolishing PhK activity in hepatocytes and erythrocytes (PMID:7711737). In vitro splicing assays of novel intronic changes (c.2597+5G>T) confirm exon skipping and premature termination, leading to ~80% reduction in enzyme function and four-fold glycogen accumulation in patient-derived hepatocyte-like cells (PMID:35887608). Thermal stability studies also support loss-of-function via conformational instability of mutant proteins. Rescue experiments, including allele-specific expression analyses, reinforce haploinsufficiency rather than dominant-negative effects.

No major conflicting evidence has been reported, though variability in erythrocyte versus hepatic PhK activity suggests sub-phenotypes (XLG I vs. XLG II). Missense mutations clustering in the regulatory domains may yield milder or tissue-restricted phenotypes that escape blood-cell assays, warranting careful molecular and enzymatic evaluation. Skewed XCI in symptomatic female carriers underlines the necessity of X-inactivation testing when clinical presentation is atypical for X-linked recessive inheritance (PMID:24055370).

Integration of genetic and functional data yields a Strong ClinGen clinical validity classification: over 26 probands with PHKA2 mutations, multi-family segregation, and concordant biochemical and cellular models (gene_disease_association value: "Strong"). Genetic evidence meets Strong level, with 26 unrelated cases and segregation in pedigrees (genetic_evidence value: "Strong"). Functional assays provide Moderate support for a loss-of-function mechanism (functional_evidence value: "Moderate").

Key take-home: Molecular diagnosis of PHKA2-related GSD IXa is critical for accurate subtype classification, prognostication, and tailored management, including dietary therapy and genetic counseling.

References

• Molecular Genetics and Metabolism • 2011 • Liver glycogen storage diseases due to phosphorylase system deficiencies... PMID:21646031
• Clinica Chimica Acta • 2020 • A novel frameshift PHKA2 mutation in a family with glycogen storage disease type IXa... PMID:32387637
• Clinical Chimica Acta • 2013 • X-linked glycogen storage disease IXa manifested in a female carrier due to skewed X chromosome inactivation. PMID:24055370
• BMC Medical Genetics • 2016 • PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX... PMID:27103379
• Human Molecular Genetics • 1995 • Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease. PMID:7711737
• Journal of Personalized Medicine • 2022 • Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System... PMID:35887608

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