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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 79299
Hyperinsulism due to glucokinase deficiency (HIGCK) is a form of diazoxide- sensitive diffuse hyperinsulinism (see this term), caused by a lowered threshold for insulin release, characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia) and recurrent episodes of profound hypoglycemia induced by fasting and protein rich meals, requiring rapid and intensive treatment to prevent neurological sequelae.
Prevalence for congenital isolated hyperinsulinism (CHI, see this term) is estimated at 1/50,000 live births. GCK alterations are noted in 1.2% of patients with non-syndromic CHI.
Clinical picture is similar to that described in CHI with mild manifestations leading to a delay in diagnosis until adulthood. A notable clinical feature is the remarkable stability of their hypoglycemia consistent with a resetting of the threshold for insulin release. The clinical spectrum can range from mild and intermediate cases that respond well to dietary modifications and medical management with diazoxide to severe cases that are unresponsive to diazoxide necessitating near-total pancreatectomy. The potential development of type 2 diabetes with age is another notable feature Neurological sequelae due to rapidly falling glucose levels are rare.
Activating mutations of GCK (7p15.3-p15.1) that encodes glucokinase have been identified to cause HIGCK. Glucokinase has been described as the glucose sensor of pancreatic beta-cells. These mutations localize to an allosteric activator site and increase the protein's affinity to glucose and its efficacy in ATP-dependent phosphorylation of glucose, causing resetting of the threshold for insulin release at a value lower than normal. Recently, a somatic activating mutation in GCK has been proposed as a cause of a novel form of diazoxide-responsive focal CHI. Inactivating mutations GCK have been identified in cases of maturity onset diabetes of the young 2 (MODY 2, see this term).
Most activating mutations of genes GCK identified to date are dominant. De novo mutations have also been reported.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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