Common mutation in the PHKA2 gene with variable phenotype in patients with liver phosphorylase b kinase deficiency

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Hepatic phosphorylase-kinase (PhK) deficiency is a rare genetic disorder affecting glycogen metabolism.
• The PHKA2 gene is a known cause of PhK deficiency, but specific mutations and their prevalence can vary geographically.

Purpose of the Study:

• To investigate the genetic basis of hepatic phosphorylase-kinase deficiency in Dutch patients.
• To characterize the clinical presentation and disease course associated with a specific PHKA2 mutation.

Main Methods:

• Genetic analysis to identify mutations in the PHKA2 gene.
• Clinical data collection including patient history, symptoms, and treatment outcomes.
• Biochemical analysis of tetraglucoside excretion as a disease marker.

Main Results:

• The missense mutation p.Pro1205Leu in the PHKA2 gene was identified as a common cause of PhK deficiency in Dutch patients, suggesting a founder effect.
• Patients often presented with isolated growth delay and diarrhea before hepatomegaly, which delayed diagnosis.
• Tetraglucoside excretion levels correlated with disease severity and were useful for monitoring patient compliance.
• Clinical manifestations and treatment needs varied among individuals carrying the same mutation, with some requiring tube feeding.

Conclusions:

• The p.Pro1205Leu mutation in PHKA2 is a significant cause of hepatic phosphorylase-kinase deficiency in the Dutch population.
• Delayed diagnosis is common due to atypical initial symptoms, highlighting the need for increased awareness.
• Disease presentation and management requirements are variable even within families with the same mutation.