The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism

Banerjee, Indraneel; Skae, Mars; Flanagan, Sarah E.; Rigby, Lindsey; Patel, Leena; Didi, Mohammed; Blair, Jo; Ehtisham, Sarah; Ellard, Sian; Cosgrove, Karen E.; Dunne, Mark J.; Clayton, Peter E.

doi:10.1530/eje-10-1136

Cited by 67 publications

(106 citation statements)

References 25 publications

(46 reference statements)

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“…In three patients with ABCC8 heterozygous mutations who were responsive to diazoxide treatment, the hyperinsulinism resolved after several months. The transient nature of CHI in these patients agrees with previous reports (10,17,21). Of these patients, one (patient 20) had transient hypoglycemia that progressed to diabetes later in childhood.…”

Section: Discussionsupporting

confidence: 90%

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Clinical and genetic characterization of congenital hyperinsulinism in Spain

Martı́nez

Fernández-Ramos

Vela

et al. 2016

European Journal of Endocrinology

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Context: Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. Objective: To characterize clinically and genetically CHI patients in Spain. Design and methods: We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. Results: We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in K ATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the K ATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. Conclusions: Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the K ATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.

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Section: Discussionsupporting

confidence: 90%

“…It has been described that hypoglycemia may resolve in as many as a half of newly diagnosed children with CHI (21). A lack of known mutations seems to make remission more likely, ranging from 44% in an Italian cohort (17) to 88% in the study by Banerjee et al (21), and to date 41% have remitted in our series.…”

Section: Discussionsupporting

confidence: 40%

Clinical and genetic characterization of congenital hyperinsulinism in Spain

Martı́nez

Fernández-Ramos

Vela

et al. 2016

European Journal of Endocrinology

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“…Biallelic ABCC8/KCNJ11 mutations result in diffuse CHI, whereas monoallelic mutations can either be asymptomatic (38). In our cohort of 53 CHI patients associated with paternally inherited monoallelic ABCC8/KCNJ11 mutations, 18 (33%) patients either responded to diazoxide or resolved spontaneously and are likely to have dominant acting CHI.…”

Section: Discussionmentioning

confidence: 78%

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Arya

Güemes

Nessa

et al. 2014

European Journal of Endocrinology

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Context: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. Objective: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. Design: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. Results: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography ( 18 F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (nZ8) or 18

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“…w50% of patients (Banerjee et al 2011, Senniappan et al 2012. In our studies, computational biology of disease-causing genes has recently been used to seed an interaction network model.…”

Section: Congenital Hyperinsulinism In Infancymentioning

confidence: 99%

Network analysis: a new approach to study endocrine disorders

Stevens¹,

Leonibus²,

Hanson³

et al. 2013

Journal of Molecular Endocrinology

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Systems biology is the study of the interactions that occur between the components of individual cells -including genes, proteins, transcription factors, small molecules, and metabolites, and their relationships to complex physiological and pathological processes. The application of systems biology to medicine promises rapid advances in both our understanding of disease and the development of novel treatment options. Network biology has emerged as the primary tool for studying systems biology as it utilises the mathematical analysis of the relationships between connected objects in a biological system and allows the integration of varied 'omic' datasets (including genomics, metabolomics, proteomics, etc.). Analysis of network biology generates interactome models to infer and assess function; to understand mechanisms, and to prioritise candidates for further investigation. This review provides an overview of network methods used to support this research and an insight into current applications of network analysis applied to endocrinology. A wide spectrum of endocrine disorders are included ranging from congenital hyperinsulinism in infancy, through childhood developmental and growth disorders, to the development of metabolic diseases in early and late adulthood, such as obesity and obesity-related pathologies. In addition to providing a deeper understanding of diseases processes, network biology is also central to the development of personalised treatment strategies which will integrate pharmacogenomics with systems biology of the individual.

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The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism

Cited by 67 publications

References 25 publications

Clinical and genetic characterization of congenital hyperinsulinism in Spain

Clinical and genetic characterization of congenital hyperinsulinism in Spain

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Network analysis: a new approach to study endocrine disorders

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