Glycogen Storage Disease Type Ia Refractory to Cornstarch: Can Next Generation Sequencing Offer a Solution?

A dietary regimen based on avoidance of fasting and regular ingestion of uncooked cornstarch is the mainstay of treatment of patients with GSD-Ia. We have encountered three unrelated patients with GSD-Ia who despite optimal dietary treatment showed poor glycemic control and resistance to different therapeutic interventions.

Whole Exome Sequencing (WES) was pursued in the three families, in order to both confirm a molecular diagnosis of GSD-Ia, and seek additional variants in genes which may explain the cornstarch intolerance.

Patient I is a 27 year-old male and patient II an 11 year-old girl, each born to non-consanguineous Ashkenazi-Jewish parents. Both show intolerance to cornstarch, with subsequent poor glycemic control and GSD complications, and prove a challenge in their routine care. Patient III is an 18 months-old boy born to a highly consanguineous Arab-Muslim, exhibiting poor glycemic control and diarrhea.

For all three patients, WES confirmed the diagnosis of GSD-Ia, with all three harboring the p.R83C mutation in G6PC. While no other significant variants were identified for patients I and II, patient III was found to be homozygous also for a p.G276V mutation in the SI gene, thus establishing a second diagnosis of Sucrase-Isomaltase Deficiency. Interestingly, two additional family members (his sibling and cousin), who exhibit failure to thrive and chronic diarrhea at infancy, are also being evaluated for the SI mutation.

We suggest that in selected GSD-Ia patients who show persistent symptoms despite optimal dietary control, WES should be considered to search for additional putative diagnoses, and especially in consanguineous kindreds.