Glucose dynamics in glycogen storage disease type IXa with novel PHKA2 variants: insights from our experience and a comprehensive review of the disease spectrum

Background Glycogen storage disease type IXa (GSD IXa), caused by phosphorylase kinase mutations, primarily PHKA2, presents variably from mild hepatomegaly to severe liver dysfunction or isolated ketotic hypoglycemia. Its phenotypic overlap with other metabolic disorders complicates diagnosis, requiring genetic confirmation. Methods We retrospectively analyzed clinical, biochemical, genetic, and radiological data from patients affected by GSD IXa diagnosed at our regional metabolic disease center in Bologna (Emilia-Romagna, Italy) over recent decades and we reviewed the relevant scientific literature on the pathology. Results We report three patients with recurrent symptomatic ketotic hypoglycemia affected by PHKA2 variants of uncertain significance (VUS) and review the literature concerning GSD IXa. Conclusion GSD IXa should be considered in the differential diagnosis even when persistent ketotic hypoglycemia is the sole presenting feature, underscoring the critical importance of clinical suspicion in such cases. Improved genetic testing has refined diagnosis, even in milder cases without hepatomegaly, while dietary management with uncooked cornstarch (CS) and extended-release cornstarch (ER-CS) effectively prevents complications and maintains good glycemic control.