Intermittent
hypoglycemia has been described in association with
Alpers' syndrome, a disorder caused by mutations in the
mitochondrial DNA polymerase gamma gene. In some patients
hypoglycemia may define the initial disease presentation well before the onset of the classical Alpers' triad of psychomotor retardation, intractable
seizures, and
liver failure. Correlating with the genotype, POLG pathogenicity is a result of increased
mitochondrial DNA mutability, and
mitochondrial DNA depletion resulting in energy deficient states.
Hypoglycemia therefore could be secondary to any metabolic pathway affected by
ATP deficiency. Although it has been speculated that
hypoglycemia is due to secondary
fatty acid oxidation defects or abnormal gluconeogenesis, the exact underlying etiology is still unclear. Here we present detailed studies on carbohydrate metabolism in an Alpers' patient who presented initially exclusively with intermittent episodes of
hypoglycemia and
ketosis. Our results do not support a defect in gluconeogenesis or
fatty acid oxidation as the cause of
hypoglycemia. In contrast, studies performed on liver biopsy suggested abnormal glycogenolysis. This is shown via decreased activities of
glycogen brancher and debrancher
enzymes with normal
glycogen structure and increased
glycogen on histology of the liver specimen. To our knowledge, this is the first report documenting abnormalities in
glycogen metabolism in a patient with
Alpers' syndrome.