Inherited metabolic disorders associated with hypoglycaemia in adulthood: a narrative review

Abstract

: In health, blood glucose homeostasis is maintained by the action of pancreatic hormones on the metabolic pathways of glycogenolysis and gluconeogenesis. Inherited metabolic disorders (IMD) are caused by mutations in genes encoding enzymes or transporter proteins directly involved in these pathways or indirectly via the fatty acid oxidation pathway. The clue to an IMD diagnosis comes from determining whether hypoglycaemia occurs in the fasting or post-prandial state and whether ketones are absent or present. In adults, hypoglycaemia is milder than in children and other clinical features usually predominate providing additional clues to the diagnosis. Confirmatory tests include acylcarnitine profile, free carnitine, urine organic acid profile and mutation analysis. Non-ketotic hypoglycaemia is indicative of either a fatty acid oxidation disorder or glycogen storage disorder Type 1 (GSD I). The differential diagnosis of fasting ketotic hypoglycaemia is broader and includes endocrine causes which must be excluded first. IMDs in this category include other GSDs and the gluconeogenesis disorder, fructose 1,6 bisphosphatase deficiency. Postprandial hypoglycaemia also more commonly has a non-IMD aetiology, but is a feature of hereditary fructose intolerance (HFI) and three of the congenital disorders of glycosylation (CDG). In the last two decades, better lifelong holistic care and advances in gene sequencing technology have improved our understanding of how IMDs affect adults. Consequently, attenuated IMD phenotypes are increasingly being recognised. 13