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Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

ABSTRACT: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH).We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype.A genetic diagnosis was possible for 59/220 (27%) patients. K(ATP) channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years.In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once K(ATP) channel mutations have been excluded.

SUBMITTER: Flanagan SE

PROVIDER: S-EPMC2857991 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

Flanagan S E SE Kapoor R R RR Mali G G Cody D D Murphy N N Schwahn B B Siahanidou T T Banerjee I I Akcay T T Rubio-Cabezas O O Shield J P H JP Hussain K K Ellard S S

European journal of endocrinology 20100217 5

<h4>Objective</h4>The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH).<h4>Subjects and met ...[more]

PMID: 20164212

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Project description:BackgroundHyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively.ResultsAll patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3.ConclusionsWe demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Project description:BackgroundIn addition to inborn metabolic disorders, altered metabolic profiles were reported to be associated with the risk and prognosis of some non-metabolic diseases, while as a rare metabolic disease, the overall secondary metabolic spectrum in congenital hyperinsulinemic hypoglycemia (HH) is largely undetermined. Therefore, we investigated metabolic profiles in HH patients and used ketotic hypoglycemia (KH) patients as a control cohort to unveil their distinct metabolic features.MethodsA total of 97 hypoglycemia children, including 74 with hyperinsulinemic hypoglycemia and 23 with ketotic hypoglycemia, and 170 euglycemia control subjects were studied retrospectively. Clinical and biochemical data were collected. The normoglycemic spectra of amino acids and acylcarnitines were determined by liquid chromatography tandem mass spectrometry. The serum insulin and fatty acid concentrations during standardized fasting tests in hypoglycemia patients were also collected. Receiver operating characteristic curve analysis was performed to screen potential biomarkers.ResultsAmong the normoglycemic spectra of amino acids, blood valine (p < 0.001), arginine (p < 0.001), threonine (p = 0.001), glutamate (p = 0.002), methionine (p = 0.005), ornithine (p = 0.008), leucine (p = 0.014), alanine (p = 0.017), proline (p = 0.031), citrulline (p = 0.042), aspartate (p = 0.046), and glycine (p = 0.048) levels differed significantly among the three groups. Significantly decreased levels of long- (C14:1, p < 0.001; C18, p < 0.001), medium- (C8, p < 0.001; C10, p < 0.001; C10:1, p < 0.001), and short-chain (C4-OH, p < 0.001; C5OH, p < 0.001) acylcarnitines were found in the hyperinsulinemic hypoglycemia group. Hyperinsulinemic hypoglycemia children with focal lesions and diffuse lesions had similar amino acid and acylcarnitine spectra. C10:1 < 0.09 μmol/L, threonine > 35 μmol/L, and threonine/C10:1 > 440 showed sensitivities of 81.1, 66.2, and 81.1% and specificities of 72.7, 78.3, and 81.8%, respectively, in distinguishing HH from KH.ConclusionsWe found significantly different altered serum amino acid and acylcarnitine profiles at normoglycemia, especially decreased C10:1 and increased threonine levels, between HH and KH children, which may reflect the insulin ketogenesis inhibition effect in HH patients; however, the detailed mechanisms and physiological roles remain to be studied in the future.

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Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

Publications

Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

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