Abstract
Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.
Highlights
Glycogen storage diseases (GSD) are a collection of inherited metabolic disorders caused by pathogenic variants in the genes that encode proteins involved in glycogen synthesis, glycogenolysis and/or gluconeogenesis
Maintaining good glycaemic and metabolic control is crucial as it correlates with long-term outcomes; the lack of precision resulting in fluctuating glucose levels and potential for overtreatment and undertreatment within individual patients means this is difficult to achieve with uncooked cornstarch (UCCS) therapy and may contribute to the risk of metabolic syndrome [70]
The development of new therapeutic opportunities for Glycogen storage disease type Ia (GSDIa), such as gene therapy using AAV8 delivery vectors that are being tested in ongoing clinical trials (NCT03517085 and NCT03970278) [87], might offer the potential to relieve the burden associated with strict dietary treatment, improve glycaemic control and prevent long-term complications that arise due to recurrent hypoglycaemia and related biochemical abnormalities, improving quality of life (QoL) of those affected
Summary
Glycogen storage diseases (GSD) are a collection of inherited metabolic disorders caused by pathogenic variants in the genes that encode proteins involved in glycogen synthesis, glycogenolysis and/or gluconeogenesis. Individuals who are homozygous for the c.648G>T pathogenic splicing variant (common in those of Japanese ancestry) may be at increased risk of developing HCC Those with this nonhelical G6PC variant that only partially inactivates G6Pase [37] exhibit a milder phenotype with respect to onset and severity of hypoglycaemic events, which may explain why they are not diagnosed until adulthood [38,39]. Individuals who are homozygous for the c379_380dupTA G6PC pathogenic variant have a milder phenotype ( less so than observed in patients of Japanese ancestry) with increased residual G6Pase activity leading to longer fasting times These patients display a higher rate of chronic liver complications, such as HCC, compared with patients who are compound heterozygous (unpublished clinical observations by Dr David Rodriguez-Buritica). Dietary treatment and drug therapy for symptoms and secondary complications has improved survival and decreased some of the disease-associated morbidities; current disease management strategies are not without risk of failure and long-term prognosis remains uncertain given the number and variety of disease complications [19,20,41]
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