Retrospective Case Series of Fulminant Metabolic Crisis in <scp>GSDIA</scp> : Persistent Lactic Acidosis Despite Correction of Hypoglycemia May Reflect Secondary Mitochondrial Dysfunction

Although several advances in glycogen storage disorder (GSD) management have been made over the years, there is still increased morbidity and mortality in these patients, particularly among those with GSD type I (GSDI). Here, we describe a case series of five patients with GSDIa who presented with severe lactic acidosis and passed away without a clearly identified etiology, despite some having adequate metabolic control at baseline. Based on these presentations and emerging literature, we posit that progressive, secondary mitochondrial dysfunction plays an important role in placing GSDIa patients at increased risk for GSDI-related complications, including fulminant metabolic crisis. Both <i>G6PC1</i> knockout mice and human GSDIa plasma and urinary samples exhibit markers of mitochondrial dysfunction. Our observations of refractory lactic acidosis despite hyper- or eu-glycemia potentially suggest mitochondrial dysfunction as a unique feature of the metabolic decompensation experienced by the patients of this report. Thus, underlying mitochondrial dysfunction may set up certain GSDIa patients for multiorgan failure that is unresponsive to conventional therapies. Further research into the mitochondrial function of GSDIa patients across the lifespan is warranted. By introducing surveillance strategies for mitochondrial dysfunction in GSDI, existing antioxidant therapies could be harnessed to maintain or improve mitochondrial function in this patient population. In turn, the integration of mitochondrial therapies into GSD care may improve quality of life and avoid the development of fulminant metabolic crisis.