Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization

Martı́nez, Rosa; Gutiérrez-Nogués, Ángel; Fernández-Ramos, Concepción; Velayos, Teresa; Vela, Amaia; Navas, María-Ángeles; Castaño, Luís

doi:10.1111/cen.13318

Cited by 17 publications

(9 citation statements)

References 32 publications

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“…To date, just 20 cases of naturally occurring GCK‐CHI mutations were reported, including the two variants in the present study (Table ), sorting by amino acid sequences as S64Y, T65I, G68V, K90R (case 2 of this study), V91L, W99R, W99L, W99C, T103S, N180D, M197I, M197T, M197V (case 1 of this study), Y214C, V389L, E442K, V452L, ins454A, V455M and A456V. Of the 20 GCK‐CHI mutations, the missense mutations account for 95% (19/20), and the remaining mutation was an insertional mutation (5%, 1/20).…”

Section: Resultsmentioning

confidence: 79%

Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase‐activating mutations: A report of two cases and a brief overview of the literature

Ping

Wang

Xiao

2019

J of Diabetes Invest

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Aims/IntroductionThe principal aim of this study was to investigate the clinical, genetic and functional characteristics of two cases of congenital hyperinsulinism (CHI) caused by glucokinase (GCK) mutations in young patients.Materials and MethodsNovel mutations were detected by CHI next‐generation sequencing, and the kinetic parameters and thermal stability of recombinant wild‐type and mutant glucokinase were determined in vitro. In addition, 18 naturally occurring GCK‐CHI mutations reported previously were also summarized.ResultsA de novo mutation (M197V) was found in a 17‐year‐old male with an epilepsy history, whereas an autosomal dominant mutation (K90R) was found in a 20‐year‐old female with inherited asymptomatic hypoglycemia. Kinetic analysis showed increased enzyme activity for both mutants (RAI 4.7 for M197V and 1.6 for K90R) and enhanced thermal stability for the M197V mutant. However, of all the GCK‐CHI mutants, the increase in enzyme activity (RAI between 1.6 and 130) did not correlate strongly with the severity of hypoglycemia. The de novo group (7/19) showed distinctive phenotypes from the autosomal dominant group (12/19), such as a higher proportion of diazoxide unresponsiveness (28.6% vs 0%), a higher incidence of macrosomia (85.7% vs 40%) and a rarer incidence of adulthood onset (0% vs 25%).ConclusionsThe clinical phenotypes of GCK‐CHIs were highly heterogeneous. We have identified two novel GCK‐CHI mutations in young patients and investigated their pathogenicity by enzyme kinetic analysis, which expanded the spectrum of this rare disease.

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Section: Resultsmentioning

confidence: 79%

Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase‐activating mutations: A report of two cases and a brief overview of the literature

Ping

Wang

Xiao

2019

J of Diabetes Invest

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“…Patients presenting with GCK-CHI have a wide spectrum of clinical presentations with a varying severity of the symptoms. Children usually have a family history of hypoglycaemia and age at clinical diagnosis ranging from birth to adulthood (98–101). Although most of the reported GCK mutations lead to CHI responsive to diazoxide therapy (98, 99), some patients may need more aggressive treatment to control hypoglycaemia such as octreotide administration or surgery (100, 102).…”

Section: Chi Due To Abnormalities In Metabolic Pathwaysmentioning

confidence: 99%

“…Children usually have a family history of hypoglycaemia and age at clinical diagnosis ranging from birth to adulthood (98–101). Although most of the reported GCK mutations lead to CHI responsive to diazoxide therapy (98, 99), some patients may need more aggressive treatment to control hypoglycaemia such as octreotide administration or surgery (100, 102). For example, the Y214C mutation in the putative allosteric activator site has been found in a patient with medically-unresponsive CHI (103).…”

Section: Chi Due To Abnormalities In Metabolic Pathwaysmentioning

confidence: 99%

The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism

et al. 2019

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Congenital hyperinsulinism (CHI) is a heterogenous and complex disorder in which the unregulated insulin secretion from pancreatic beta-cells leads to hyperinsulinaemic hypoglycaemia. The severity of hypoglycaemia varies depending on the underlying molecular mechanism and genetic defects. The genetic and molecular causes of CHI include defects in pivotal pathways regulating the secretion of insulin from the beta-cell. Broadly these genetic defects leading to unregulated insulin secretion can be grouped into four main categories. The first group consists of defects in the pancreatic K ATP channel genes ( ABCC8 and KCNJ11 ). The second and third categories of conditions are enzymatic defects (such as GDH, GCK, HADH) and defects in transcription factors (for example HNF1α, HNF4α) leading to changes in nutrient flux into metabolic pathways which converge on insulin secretion. Lastly, a large number of genetic syndromes are now linked to hyperinsulinaemic hypoglycaemia. As the molecular and genetic basis of CHI has expanded over the last few years, this review aims to provide an up-to-date knowledge on the genetic causes of CHI.

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“…Patients with GCK mutations can have a wide range of clinical presentations. These vary from severe, neonatal-onset HH which is medically unresponsive and requiring surgery to mild, adult-onset HH which may be asymptomatic ( 3 , 72 , 73 , 74 , 75 ).…”

Section: Introductionmentioning

confidence: 99%

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Demirbilek¹,

Hussain²

2018

Jcrpe

105

112

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Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH.

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Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization

Cited by 17 publications

References 32 publications

Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase‐activating mutations: A report of two cases and a brief overview of the literature

Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase‐activating mutations: A report of two cases and a brief overview of the literature

The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism

Congenital Hyperinsulinism: Diagnosis and Treatment Update

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