PHKA2 – Glycogen Storage Disease IXa1

Phosphorylase kinase alpha 2 (PHKA2) encodes the liver isoform of the phosphorylase kinase (PhK) holoenzyme. X‐linked recessive loss‐of‐function variants in PHKA2 abolish PhK activity, leading to hepatic glycogen accumulation and the clinical spectrum of glycogen storage disease type IXa (GSD IXa) (PMID:7711737).

Numerous hemizygous missense and truncating variants have been reported in male probands presenting with hepatomegaly, elevated transaminases, growth retardation and ketotic hypoglycemia. A recurrent c.133C>T (p.Arg45Trp) variant was identified in an 11-year-old boy with persistent hepatomegaly and high aminotransferase levels (PMID:31725618).

In a cohort of 17 unrelated Chinese male patients with clinically suspected GSD IXa, 14 distinct PHKA2 variants were identified. All patients exhibited hepatomegaly, growth delay and biochemically confirmed liver dysfunction, with spontaneous improvement over time in most cases (17 probands; PMID:28627441).

Familial segregation was demonstrated in a pedigree of two adult brothers sharing a hemizygous c.1561A>G (p.Thr521Ala) variant who developed neonatal hepatosplenomegaly and later-onset neurological features including hearing and cognitive impairment (2 affected relatives; PMID:31987065).

Functional assays of PHKA2 variants demonstrate that premature stop codons and splice‐site mutations lead to absent or truncated protein and severely reduced PhK enzyme activity in vitro (PMID:7711737). A patient‐derived hepatocyte model of the intronic c.2597+5G>T variant confirmed aberrant splicing and complete loss of substrate phosphorylation with consequent glycogen overload (PMID:35887608).

Dietary management with cornstarch supplementation prevents hypoglycemia, and adjunctive glycyrrhizin may improve hepatic injury, as shown in a treated 18-month-old patient with a PHKA2 partial deletion (PMID:40046366).

Collectively, over 50 male probands across multiple ethnicities harbor pathogenic PHKA2 variants with consistent genotype–phenotype correlation, robust segregation and concordant functional data. Genetic confirmation of GSD IXa informs early dietary intervention and long-term monitoring.

Key Take-home: PHKA2 variant analysis is essential for definitive diagnosis of X-linked GSD IXa1 and guides effective cornstarch-based therapy.

References

• Human molecular genetics | 1995 | Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease. PMID:7711737
• Gene | 2017 | Clinical and genetic characteristics of 17 Chinese patients with glycogen storage disease type IXa. PMID:28627441
• The Canadian journal of neurological sciences | 2020 | Neurological Involvement in Glycogen Storage Disease Type IXa due to PHKA2 Mutation. PMID:31987065
• 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
• Cureus | 2025 | Oral Cornstarch and Glycyrrhizin Improve Severe Liver Injury Caused by Glycogen Storage Disease Type IXa. PMID:40046366

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