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.
We are grateful to Katja Dumić Kubat for her help with the literature.
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.
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;338:1352–7.10.1056/NEJM199805073381904Search in Google Scholar PubMed
2. De Leon DD, Stanley CA. Mechanism of disease: advanced in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab 2007;3:57–68.10.1038/ncpendmet0368Search in Google Scholar PubMed
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.Search in Google Scholar
4. Stanley CA. Two genetic forms of hyperinsulinemic hypoglycemia caused by dysregulation of glutamate dehydrogenase. Neurochem Int 2011;59:465–72.10.1016/j.neuint.2010.11.017Search in Google Scholar PubMed PubMed Central
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;49:667–73.10.2337/diabetes.49.4.667Search in Google Scholar PubMed
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;108:66–71.10.1007/s004390000432Search in Google Scholar PubMed
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;161:731–5.10.1530/EJE-09-0615Search in Google Scholar PubMed PubMed Central
8. Stanley CA. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 2004;81:45–5.10.1016/j.ymgme.2003.10.013Search in Google Scholar PubMed
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;17:658–64.10.1016/j.seizure.2008.01.005Search in Google Scholar PubMed
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;146:388–94.10.1016/j.jpeds.2004.10.040Search in Google Scholar PubMed
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;50:945–9.10.1111/j.1469-8749.2008.03114.xSearch in Google Scholar PubMed
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;285:31806–18.10.1074/jbc.M110.123638Search in 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;96:498–502.10.1210/jc.2010-1906Search in Google Scholar
14. Stanley CA. Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children. Am J Clin Nutr 2009;90:862–6.10.3945/ajcn.2009.27462AASearch in 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;63:4218–29.10.2337/db14-0783Search in 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;39:433–45.10.1007/s11064-013-1173-2Search in 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;298:1219–25.10.1152/ajpendo.00028.2010Search in 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;341:23–6.10.1016/j.cccn.2003.10.023Search in Google Scholar
19. Cochrane WA, Peyne WW, Simkiss MJ, Woolf LI. Familial hypoglycemia precipitated by aminoacids. J Clin Invest 1956;35:411–22.10.1172/JCI103292Search in 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;45:957–60.10.1016/S0026-0495(96)90262-0Search in 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;136:69–72.10.1016/S0022-3476(00)90052-0Search in 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;50:353–7.10.1203/00006450-200109000-00010Search in Google Scholar PubMed
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;168:557–64.10.1530/EJE-12-0673Search in Google Scholar PubMed PubMed Central
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;98:355–63.10.1210/jc.2012-2169Search in Google Scholar PubMed PubMed Central
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.Search in 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;521:160–5.10.1016/j.gene.2013.03.021Search in Google Scholar PubMed
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;61:901–10.10.1507/endocrj.EJ13-0398Search in 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;23:827–30.10.1515/jpem.2010.132Search in Google Scholar PubMed
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;23:733–8.10.1515/JPEM.2010.23.7.733Search in 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;24:573–7.10.1515/jpem.2011.057Search in Google Scholar PubMed
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;26:248–52.10.1016/j.nrl.2010.09.024Search in Google Scholar PubMed
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;56:485–9.10.1590/S0004-27302012000800004Search in Google Scholar PubMed
33. Nakano K, Kobayashi K, Okano Y, Aso K, Ohtsuka Y. Intractable absence seizures in hyperinsulinism-hyperammonemia syndrome. Pediatr Neurol 2012;47:119–22.10.1016/j.pediatrneurol.2012.04.019Search in Google Scholar PubMed
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;28:873–6.10.1515/jpem-2014-0441Search in Google Scholar PubMed
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;29:385–8.10.1515/jpem-2015-0276Search in Google Scholar PubMed
36. Komlos D, Mann KD, Zhuo Y, Ricupero CL, Hart RP, et al. Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia 2013;61:394–408.10.1002/glia.22442Search in Google Scholar PubMed PubMed Central
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