Abnormalities in Glycogen Metabolism in a Patient with Alpers’ Syndrome Presenting with Hypoglycemia

Abstract

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.

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

“…Of interest, two infants had normal muscle findings in the presence of severe liver abnormalities . Similar to in liver, nonspecific microscopic changes and mitochondrial abnormalities were observed (n = 28) (Table ). Among these patients, abnormalities in both muscle and liver were detected in seven …”

“…A total of 11 liver biopsies and 2 postmortem liver samples were identified. Tissue source for 17 patients was not specified . Of the patients reviewed, there were 28 infants/children (range 0–8.5 years), one 12‐year‐old adolescent, and a 39‐year‐old adult …”

“…The RC activity was highly variable among different tissues. Normal RC activity and a number of RC defects (isolated and multicomplex deficiencies) were detected. Complex V defects were rarely reported in muscle and liver samples (Table ).…”

“…41 Microvesicular fatty changes, microvesicular steatosis, fibrosis, and cirrhosis were prominent features. 9,13,30,38,40,42 Other changes have been reported, although uncommonly detected 9,13,39,40 It is intriguing that one pediatric patient who had AHS clinically had histologically normal liver on postmortem. 13 A number of mitochondrial abnormalities were observed (Table 4).…”

“…Tissue source for 17 patients was not specified. 9,13,30,31,36,[38][39][40][41][42][43] Of the patients reviewed, there were 28 infants/children (range 0-8.5 years), one 12-year-old adolescent, and a 39-year-old adult. 41 Microvesicular fatty changes, microvesicular steatosis, fibrosis, and cirrhosis were prominent features.…”