Hypoglycaemia related to inherited metabolic diseases in adults

Abstract

In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM) should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults) or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family) are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family). Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD) type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD), ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency)].

Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice

“…The mechanism whereby Khk-dependent hypoglycemia occurs in HFI is likely multifaceted and complex. Based on published data, the mechanism would involve a series of molecular events that include impaired glycogenolysis and glycogen accumulation disorders, increased glucokinase-mediated glucose uptake, and reduced de novo glucose production (10,29,30). In this regard, the observation that deletion of Khk prevents the hypoglycemic response to fructose suggests a critical role for Fru1-P in the mechanism.…”

Solving Glycosylation Disorders: Fundamental Approaches Reveal Complicated Pathways

“…More than a dozen glycogen-storage disorders, which impair synthesis or degradation of glycogen, have been described. 46,47 The quantitative contributions of glucose, other dietary oligosaccharides, de novo synthesis, and salvage pathways to each component sugar are not well known 47 but most likely vary among different cells and tissues. However, clues about glycosylation pathways and glucose metabolism emerged recently with the discovery of N-and O-glycosylation abnormalities in glycogen-storage disease Ib (MIM 232220), caused by mutations in the genes that encode glucose-6-phosphate translocase 48 (SLC37A4 [MIM 602671]) and glucose-6-phosphatase 3 (G6PC3 [MIM 611045]).…”

Inborn Errors of Fructose Metabolism. What Can We Learn from Them?

“…Its frequency is much lower than HFI and estimated to be around 1–9/100,000 [35]. Less than 100 patients are described and very few affected adults have been reported.…”