Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation

Vieira, Teresa C.; Bergamin, Carla Sanchez; Gurgel, Lucimary Cavalcante; Moisés, Regina S.

doi:10.1111/j.1399-5448.2009.00626.x

Cited by 28 publications

(29 citation statements)

References 19 publications

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“…Variations in the severity of HH and clinical course have also been reported in a mother and her daughter with an heterozygous E1506K mutation in ABCC8. In this report the child had severe symptoms and hypoglycaemic convulsion at 3 months while the mother had subtle symptoms of hypoglycaemia followed by gestational diabetes which persisted after delivery (20). Similarly, a marked clinical heterogenity was also observed in our family.…”

Section: Treatment and Follow Upsupporting

confidence: 77%

“…Patients with dominant mutations of K ATP channel genes, ABCC8 and KCNJ11, may cause variable phenotype ranges from asymptomatic macrosomia, mild diazoxide responsive CHI to severe persistent HH as well as diabetes mellitus in later life (7,8,9,11). CHI within the neonatal period and evolution to diabetes later in life has been reported in individuals with heterozygous inactivating mutations in the Hepatocyte nuclear factor 4A and 1A (HNF4A & HNF1A) (12,13,14) and dominant mutations in ABCC8 genes in very limited number of cases (1,7,11,13,15,16,17,18,19,20,21). To the best of our knowledge, CHI due to homozygous ABCC8 mutations and evolution to complete insulin deficient-diabetes later in life has not been reported.…”

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confidence: 99%

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Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Isik¹,

Demirbilek²,

Houghton³

et al. 2018

Jcrpe

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What is already known on this topic?Homozygous ABCC8 mutations cause severe persistent diffuse hyperinsulinemic hypoglycaemia (HH) which is usually diazoxide unresponsive and requires surgical therapy. In medically managed patients with congenital hyperinsulinism (CHI), disease symptoms become milder overtime. Hyperinsulinemic hypoglycemia at neonatal period and later diabetes have been reported in heterozygous mutation of HNF4A and HNF1A as well as heterozygous ABCC8 mutations What this study adds? We describe the first homozygous ABCC8 mutation with HH at neonatal period and evolution to complete insulin deficient, sulphonylurea responsive diabetes mellitus. Findings from present work which show a broad range of clinical spectrum from asymptomatic, mild symptomatic hypoglycemia, severe hypoglycemia as well as insulin deficient diabetes mellitus in family members with identical mutation confirms the phenotypical variations in ABCC8 mutations Present case report emphasizes the need for long-term follow up of patients with HH at neonatal period due to ABCC8 mutations, particularly those managed with medical therapy for risk of developing diabetes in later life. Abstract:Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. Recessive inactivating mutations in the ABCC8 and KCNJ11 genes account for approximately 50 % of all CHI cases. Hyperinsulinaemic hypoglycaemia (HH) in infancy and diabetes in later life have been reported in subjects with HNF1A, HNF4A and ABCC8 mutations. Case report: Herein, we present a child who was diagnosed with CHI at birth, then developed diabetes mellitus at the age of 9 years due to a novel homozygous missense, p.L171F (c.511C>T) mutation in the exon 4 of ABCC8. The parents and one sibling were heterozygous carriers, whilst a younger sibling who had transient neonatal hypoglycemia was homozygous for the mutation. The mother and (maternal) uncle, who was also heterozygous for the mutation, developed diabetes within their third decade of life. The preliminary results of sulphonylurea (SU) treatment was suggestive for SU responsiveness. Patients with homozygous ABCC8 mutations can present with CHI in the newborn period, the hyperinsulinism can show variability in terms of clinical severity and age at presentation and can cause diabetes later in life. Patients with homozygous ABCC8 mutations who are managed medically should be followed as they may be at increased risk of developing diabetes.

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Section: Treatment and Follow Upsupporting

confidence: 77%

mentioning

confidence: 99%

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Isik¹,

Demirbilek²,

Houghton³

et al. 2018

Jcrpe

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“…The first dominant heterozygous inactivating ABCC8 mutation reported, causing a mild form of CHI, was p.Glu1506Lys (p.Glu1507Lys according to reference sequence NM_001287174.1); the authors also reported a loss of insulin secretory capacity in early adulthood and an increased risk of diabetes in middle age in adult carriers (8). This mutation has also been reported in a Brazilian family with CHI in childhood, which developed gestational diabetes, glucose intolerance, and diabetes in adulthood (28). Kapoor et al (10) have shown a progression from hypoglycemia to diabetes later in life in two individuals with ABCC8 dominant mutations, p.Gly1479Arg and p.Ala1508Pro, but also gestational diabetes or diabetes in ABCC8 mutation carriers (p.Ala1537Val, p.Gln1459Glu, p.Leu1431Phe, and p.Ala1508Pro).…”

Section: Discussionmentioning

confidence: 79%

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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“…Other groups have reported that individuals with congenital hyperinsulinemia due to inactivating ABCC8 mutations eventually developed early-and adult-onset diabetes [124,125]. Identification of a loss-of-function variant in ABCC8 with a carrier frequency of 3.3% suggested that homozygous carriers of this mutation are not uncommon in this American Indian population.…”

Section: A Loss-of-function Mutation In Abcc8 Increases the Risk For mentioning

confidence: 99%

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Nair

Baier

2015

Rev Diabet Stud

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■ AbstractGenetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking. Studies in isolated populations offer several advantages over outbred populations despite being, on average, much smaller in sample size. For example, reduced genetic variability, enrichment of rare variants, and a more uniform environment and lifestyle, which are hallmarks of isolated populations, can reduce the complexity of identifying disease-associated genes. To date, studies in isolated populations have provided valuable insight into the genetic basis of T2D by providing both a deeper understanding of previously identified T2D-associated variants (e.g. demonstrating that variants in KCNQ1 have a strong parent-of-origin effect) or providing novel variants (e.g. ABCC8 in Pima Indians, TBC1D4 in the Greenlandic population, HNF1A in Canadian Oji-Cree). This review summarizes advancements in genetic studies of T2D in outbred and isolated populations, and provides information on whether the difference in the prevalence of T2D in different populations (Pima Indians vs. non-Hispanic Whites and non-Hispanic Whites vs. non-Hispanic Blacks) can be explained by the difference in risk allele frequencies of established T2D variants.

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Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation

Cited by 28 publications

References 19 publications

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Clinical and genetic characterization of congenital hyperinsulinism in Spain

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

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