Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome

Department of Pediatrics, University Children's Hospital, Kiel, Germany.
Human Genetics (Impact Factor: 4.82). 02/2001; 108(1):66-71. DOI: 10.1007/s004390000432
Source: PubMed


The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from 'gain-of-function' mutations of the glutamate dehydrogenase (GlDH) gene, GLUD1. In the original report, all mutations were found in a narrow range of 27 base pairs within exons 11 and 12 which predicted an effect on the presumed allosteric domain of the enzyme and all these mutations were associated by a diminished inhibitory effect of guanosine triphosphate (GTP) on GlDH activity. We have investigated 14 patients from seven European families with mild hyperinsulinism. In four families, more than one member was affected. In eight cases hyperammonemia was documented, and eight cases had signs of significant leucine sensitivity. In one of the families, a novel heterozygous missense mutation in exon 6 [c.833C>T (R221C)] was detected, and in all other cases from six unrelated families the novel heterozygous missense mutation c.978G>A (R269H) was found in exon 7. When GIDH activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. It is the first time that this effect is reported for mutations located in the presumed catalytic site and outside the GTP allosteric domain of the enzyme. The observation of the high prevalence of the exon 7 mutation both in familial and sporadic cases of HHS suggests a mutation hot spot and justifies a mutation screening for this novel mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism.

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    • "These mutations are found in exons 11 and 12 and have been reported to account for more than half of the cases in a cohort of 48 unrelated GDH–CHI patients (Stanley et al. 2000). However, mutations have also been identified in exons 6 and 7 of the catalytic domains, causing normal GDH activity but diminished GTP-sensitivity (Santer et al. 2001). "
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    ABSTRACT: Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin sensitive tissues, such as the muscle, liver and adipose tissue leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in 9 different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2, HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically-unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH and these two genes encode for the key enzymes (glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase) which play a key role in amino acid and fatty acid regulation of insulin secretion, respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.
    Journal of Molecular Endocrinology 03/2015; 54(2). DOI:10.1530/jme-15-0016 · 3.08 Impact Factor
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    • "The mean amount of glucose required in our patients was 9.5±3.5 mg/kg/min. Elevated serum ammonia levels are diagnostic for the hyperinsulinism/hyperammonemia syndrome; therefore, ammonia measurements are recommended for all patients with HIH (12). Clinical manifestations of patients with hyperinsulinism/hyperammonemia syndrome include postprandial hypoglycemia following protein meals, fasting hypoglycemia, diet-independent hyperammonemia, and hypoglycemia-independent seizures (13). "
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    ABSTRACT: Objective: Hyperinsulinemic hypoglycemia (HIH) is a genetically heterogeneous disorder with both familial and sporadic variants. Patients with HIH may present during the neonatal period, infancy, or childhood and may show transient, prolonged, and persistent features. In this study, we aimed to discuss our experience with HIH patients, based on a series of 17 patients. Methods: We retrospectively analyzed the clinical and laboratory characteristics at the time of diagnosis and during treatment and evaluated the neurodevelopmental outcomes during follow-up in 17 HIH patients, who presented or were referred to the Pediatric Endocrinology Clinic of Dr. Sami Ulus Training and Research Children’s Hospital between 1998 and 2011. The patients (7 male, 10 female) were aged between the first day of life and 7 years - 10 were in their first week of life, 6 in their infancy, and 1 in childhood. Results: None of the mothers had gestational diabetes. Hypoglycemic seizure (76.5%) was the most common presenting symptom. Medical treatment failed in two patients, and was stopped in eight patients. Of two diazoxide-unresponsive patients, one underwent near-total pancreatectomy, but hypoglycaemic episodes continued after surgery. The parents of other patient refused surgery, the medical treatment was continued, nevertheless, severe motor and mental retardation developed. At follow-up, 23.5% of the patients were found to have mild or moderate psychomotor retardation, and 23.5% developed epilepsy. There was no marked difference in neurological results between cases with onset in the neonatal period or in infancy. Conclusions: Clinical course and treatment response in HIH cases are very heterogeneous. Long-term careful monitoring is needed to detect and treat the complications. Conflict of interest:None declared.
    Journal of Clinical Research in Pediatric Endocrinology 09/2013; 5(3):150-5. DOI:10.4274/Jcrpe.991
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    • "The second mechanism is supported by the reduction in the concentration of blood ammonia on administration of N-carbamylglutamate (an analogue of N-acetylglutamate) (17, 18). There has been one other report of two patients (father and son) with HI due to the R269H mutation in the GLUD1 gene and normal serum ammonia concentrations (35 and 28 μmol/l) (19). Our patient with the novel P436L mutation had a completely normal serum ammonia concentration (highest being 41 μmol/l) that led to a delay in establishing the molecular diagnosis. "
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    ABSTRACT: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism-hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. To study the genotype-phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 micromol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.
    European Journal of Endocrinology 08/2009; 161(5):731-5. DOI:10.1530/EJE-09-0615 · 4.07 Impact Factor
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