Submission Details

PHKA1was first reported in relation to X-linked recessive Glycogen storage disease type IX d (GSD IXd) in 1994 (Wehner et al., PMID: 7874115). GSD IXd (OMIM:311870) is caused by a defect in the PHKA1 gene, which encodes the alpha subunit of phosphorylase kinase (PhK) in muscle. A defect in this subunit leads to reduced PhK enzyme activity. This enzyme deficiency impairs the breakdown of glycogen, resulting in its accumulation in muscle cells. Symptoms of GSD IXd commonly include muscle weakness, exercise intolerance, cramps, and, in some cases, progressive myopathy.

At least 14 variants (e.g. missense, nonsense, and frameshift) have been reported in humans. Clinical evidence supporting this gene-disease relationship includes case-level data. Variants in this gene have been reported in at least 15 probands in 14 publications (PMID: 7874115, 12825073, 15637709, 22238410, 18401027, 34615823, 9731190, 35957617, 32303402, 28600779, 20080404, 35710611, 33799212, 38586167). There is no more prevalent in any ethnic group with PHKA1 gene mutation

This gene-disease relationship is also supported by experimental evidence, including animal models, expression studies, biochemical function analysis. (PMID: 6020474, 8298647, 13402896, 25613900, 32707033, 33961781, 38548794, 1409665). The I strain of mice is characterized by significantly higher muscle glycogen levels compared to other strains. Studies have shown that these mice maintain elevated muscle glycogen concentrations in both fed and fasted states, regardless of dietary fat content. Notably, the I strain exhibits a deficiency in phosphorylase kinase (PhK) activity. A cross-mating study between I-strain and C57-strain mice demonstrated that the inheritance pattern is X-linked. This PhK deficiency in I-strain mice is caused by frameshift mutations in the PHKA1 gene, which encodes the alpha subunit of PhK. Protein interaction studies suggest that the alpha subunit may bind to calmodulin and the delta subunit of PhK, and also interacts with the beta and gamma subunits, contributing to the enzyme's regulatory functions. Farnesylation of the alpha subunit of phosphorylase kinase is critical for maintaining the enzyme's structural integrity.

In summary, there is definitive evidence supporting the relationship between PHKA1 and X-linked recessive Glycogen storage disease type IX d. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [January 10, 2025] (SOP Version 10).