PHKB – Glycogen Storage Disease Type IXb

Glycogen storage disease type IXb is an autosomal recessive hepatic disorder caused by biallelic loss-of-function variants in the PHKB gene, encoding the beta regulatory subunit of phosphorylase kinase. Affected individuals present in infancy with hepatomegaly, hypoglycemia, elevated liver enzymes and growth delay, reflecting impaired glycogen breakdown in liver cells. The gene–disease relationship is supported by multiple unrelated probands with severe PHKB variants and concordant biochemical deficits in enzyme activity.

A recent case report described a 16-month-old male born to consanguineous parents who exhibited motor delay, hypotonia, doll-like facies, hepatosplenomegaly, fasting hypoglycemia, ketonuria and elevated transaminases; whole-exome sequencing revealed a homozygous deletion spanning exons 2–10 of PHKB, confirming GSD IXb ([PMID:39188489]).

In an earlier cohort of five unrelated patients, direct sequencing identified five independent nonsense mutations (including c.2700T>A (p.Tyr900Ter)), a single-base insertion, a splice-site change and a large exon 8 deletion, all predicted to abolish PHKB function ([PMID:9215682]). Together with the recent deletion case, at least six probands with biallelic PHKB loss-of-function variants have been reported.

Inheritance is autosomal recessive, with affected individuals carrying homozygous or compound heterozygous PHKB variants; carriers are asymptomatic. No multi-generation segregation data are available, but the consanguineous pedigree and absence of disease in heterozygotes support recessive transmission.

Functional studies demonstrate that these truncating and deletion alleles reduce phosphorylase kinase activity to ~10% of normal in liver tissue, correlating with hepatic glycogen accumulation and clinical phenotype. The mechanism is haploinsufficiency/loss of function of the beta subunit, leading to impaired regulation of glycogenolysis.

A 2003 study of muscle glycogenoses identified two heterozygous PHKB missense variants of uncertain significance (p.Gln657Lys, p.Tyr770Cys) in non-hepatic phenotypes, but these did not fulfill criteria for GSD IXb and likely represent incidental findings ([PMID:12825073]).

PHKB is thus firmly established as the causative gene for GSD IXb. Genetic testing for PHKB should be prioritized in infants with unexplained hepatomegaly, hypoglycemia and elevated liver enzymes. Key take-home: identification of biallelic PHKB loss-of-function variants enables definitive diagnosis and guides management of GSD IXb.

References

• Cureus • 2024 • Glycogen Storage Disorder Type IXb: Exploring Clinical Patterns and Genetic Insights Into a Rare Phosphorylase Kinase B (PHKB)-Associated Case. PMID:39188489
• Human molecular genetics • 1997 • Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB). PMID:9215682
• European journal of human genetics : EJHG • 2003 • Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. PMID:12825073

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