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Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma


IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

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2191-0251
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Volume 29, Issue 9

Issues

Hyperinsulinism-hyperammonemia syndrome: a de novo mutation of the GLUD1 gene in twins and a review of the literature

Dorotea NinkovićORCID iD: http://orcid.org/0000-0002-4239-519X / Vladimir Sarnavka / Anica Bašnec / Mario Ćuk
  • Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
  • University of Zagreb, School of Medicine, Zagreb, Croatia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Danijela Petković Ramadža / Ksenija Fumić / Vesna Kušec / René Santer / Ivo Barić
  • Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
  • University of Zagreb, School of Medicine, Zagreb, Croatia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-07-06 | DOI: https://doi.org/10.1515/jpem-2016-0086

Abstract

Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease characterized by recurrent hypoglycemia and persistent mild elevation of plasma ammonia. HI/HA syndrome is one of the more common forms of congenital hyperinsulinism (CHI), caused by activating mutations within the GLUD1 gene that encodes the mitochondrial enzyme glutamate dehydrogenase (GDH). We report here on monozygotic twin girls presented with fasting- and protein-induced hypoglycemia and mild persistent hyperammonemia. Genetic analysis revealed that both girls were heterozygous for a novel missense mutation within exon 11 [c.1499A>T, p.(R443W)] of the GLUD1 gene. Despite early treatment with diazoxide and a low protein diet, they both developed non-hypoglycemic seizures in early childhood followed by cognitive impairment. In addition to their clinical course, a review of the literature on HI/HA syndrome is provided.

Keywords: cognitive impairment; epilepsy; GLUD1 gene; glutamate dehydrogenase; hyperammonemia; hypoglycemia

References

  • 1.

    Stanley CA, Leiu YK, Hsu BY, Burlina AB, Greenberg CR, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of glutamate dehydrogenase gene. N Engl J Med 1998;338:1352–7.Google Scholar

  • 2.

    De Leon DD, Stanley CA. Mechanism of disease: advanced in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab 2007;3:57–68.Google Scholar

  • 3.

    MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, et al. Hyperinsulinism-hyperammonemia syndrome in children with regulatory mutations in inhibitory GDP binding domain of glutamate dehydrogenase gene. J Clin Endocrinol Metab 2001;86:1782–7.Google Scholar

  • 4.

    Stanley CA. Two genetic forms of hyperinsulinemic hypoglycemia caused by dysregulation of glutamate dehydrogenase. Neurochem Int 2011;59:465–72.Google Scholar

  • 5.

    Stanley CA, Fang J, Kutyna K, Hsu BY, Ming JE, et al. Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators. Diabetes 2000;49:667–73.Google Scholar

  • 6.

    Santer R, Kinner M, Passarge M, Superti-Furga A, Mayatepek E, et al. Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. Hum Genet 2001;108:66–71.Google Scholar

  • 7.

    Kapoor RR, Flanagan SE, Fulton P, Chakrapani A, Chadefaux B, et al. Hyperinsulinism-hyperammonemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations. Eur J Endocrinol 2009;161:731–5.Google Scholar

  • 8.

    Stanley CA. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 2004;81:45–5.Google Scholar

  • 9.

    Bahi-Buisson N, El Sabbagh S, Soufflet C, Escande F, Boddaert N, et al. Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase. Seizure 2008;17:658–64.Google Scholar

  • 10.

    Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, et al. Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 2005;146:388–94.Google Scholar

  • 11.

    Bahi-Buisson N, Roze E, Dionisi C, Escande F, Valayannopoulos V, et al. Neurological aspects of hyperinsulinism-hyperammonemia syndrome. Dev Med Child Neurol 2008;50:945–9.Google Scholar

  • 12.

    Li C, Chen P, Palladino A, Narayan S, Russell LK, et al. Mechanism of hyperinsulinism in short-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency involves the activation of glutamate dehydrogenase. J Biol Chem 2010;285:31806–18.Google Scholar

  • 13.

    Flanagan SE, Patch AM, Locke JM, Akcay T, Simsek E, et al. Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. J Clin Endocrinol Metab 2011;96:498–502.Google Scholar

  • 14.

    Stanley CA. Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children. Am J Clin Nutr 2009;90:862–6.Google Scholar

  • 15.

    Kibbey RG, Choi CS, Lee HY, Cabrera O, Pongratz RL, et al. Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release. Diabetes 2014;63:4218–29.Google Scholar

  • 16.

    Li M, Li C, Allen A, Stanley CA, Smith TJ. Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis. Neurochem Res 2014;39:433–45.Google Scholar

  • 17.

    Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT. Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/ hyperammonemia syndrome. Am J Physiol Endocrinol Metab 2010;298:1219–25.Google Scholar

  • 18.

    Meissner T, Mayatepek E, Kinner M, Santer R. Urinary alpha-ketoglutarate is elevated in patients with hyperinsulinism-hyperammonemia syndrome. Clin Chim Acta 2004;341:23–6.Google Scholar

  • 19.

    Cochrane WA, Peyne WW, Simkiss MJ, Woolf LI. Familial hypoglycemia precipitated by aminoacids. J Clin Invest 1956;35:411–22.Google Scholar

  • 20.

    Zammarchi E, Filippi L, Novembre E, Donati MA. Biochemical evaluation of a patient with a familial form of leucine sensitive hypoglycemia and concomitant hyperammonemia. Metabolism 1996;45:957–60.Google Scholar

  • 21.

    Miki Y, Taki T, Ohura T, Kato H, Yanagisawa M, et al. Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism–hyperammonemia syndrome. J Pediatr 2000;136:69–72.Google Scholar

  • 22.

    De Lonlay P, Benelli C, Fouque F, Ganguly A, Aral B, et al. Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. Pediatr Res 2001;50:353–7.Google Scholar

  • 23.

    Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, et al. Clinical and molecular characterization of 300 patients with congenital hyperinsulinism. Eur J Endocrinol 2013;168:557–64.Google Scholar

  • 24.

    Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab 2013;98:355–63.Google Scholar

  • 25.

    Aso K, Okano Y, Takeda T, Sakamoto O, Ban K, et al. Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome. Osaka City Med J 2011;57:1–9.Google Scholar

  • 26.

    Faletra F, Athanasakis E, Morgan A, Biarnés X, Fornasier F, et al. Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort. Gene 2013;521:160–5.Google Scholar

  • 27.

    Sang Y, Xu Z, Liu M, Yan J, Wu Y, et al. Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A and GCK genes in 30 Chinese patients with congenital hyperinsulinism. Endocr J 2014;61:901–10.Google Scholar

  • 28.

    de las Heras J, Garin I, de Nanclares GP, Aguayo A, Rica I, et al. Familial hyperinsulinism-hyperammonemia syndrome in a family with seizures: case report. J Pediatr Endocrinol Metab 2010;23:827–30.Google Scholar

  • 29.

    Diao C, Chen S, Xiao X, Wang T, Sun X, et al. Two unrelated Chinese patients with hyperinsulinism/hyperammonemia (HI/HA) syndrome due to mutations in glutamate dehydrogenase gene. J Pediatr Endocrinol Metab 2010;23:733–8.Google Scholar

  • 30.

    Balasubramaniam S, Kapoor R, Yeow JH, Lim PG, Flanagan S, et al. Biochemical evaluation of an infant with hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene and hyperinsulinism-hyperammonemia syndrome. J Pediatr Endocrinol Metab 2011;24:573–7.Google Scholar

  • 31.

    Pérez Errazquin F, Sempere Fernández J, García Martín G, Chamorro Muñoz MI, Romero Acebal M. Hyperinsulinism and hyperammonemia syndrome and severe myoclonic epilepsy of infancy. Neurologia 2011;26:248–52.Google Scholar

  • 32.

    Corrêa-Giannella ML, Freire DS, Cavaleiro AM, Fortes MA, Giorgi RR, et al. Hyperinsulinism/hyperammonemia (HI/HA) syndrome due to a mutation in the glutamate dehydrogenase gene. Arq Bras Endocrinol Metabol 2012;56:485–9.Google Scholar

  • 33.

    Nakano K, Kobayashi K, Okano Y, Aso K, Ohtsuka Y. Intractable absence seizures in hyperinsulinism-hyperammonemia syndrome. Pediatr Neurol 2012;47:119–22.Google Scholar

  • 34.

    Tran C, Konstantopoulou V, Mecjia M, Perlman K, Mercimek-Mahmutoglu S, et al. Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene. J Pediatr Endocrinol Metab 2015;28:873–6.Google Scholar

  • 35.

    Fang C, Ding X, Huang Y, Huang J, Zhao P, et al. A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA). J Pediatr Endocrinol Metab 2016;29:385–8.Google Scholar

  • 36.

    Komlos D, Mann KD, Zhuo Y, Ricupero CL, Hart RP, et al. Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia 2013;61:394–408.Google Scholar

About the article

Received: 2016-03-12

Accepted: 2016-05-09

Published Online: 2016-07-06

Published in Print: 2016-09-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: This work is part of the project “InNerMeD-I-Network” which was funded by the European Union, in the framework of the Health Programme. Sole responsibility lies with the author and the Executive Agency is not responsible for any use that may be made of the information contained therein.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 29, Issue 9, Pages 1083–1088, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2016-0086.

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