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The hyperinsulinism/hyperammonemia syndrome

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Abstract

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism (HI). Children affected by this syndrome have both fasting and protein sensitive hypoglycemia combined with persistently elevated ammonia levels. Gain of function mutations in the mitochondrial enzyme glutamate dehydrogenase (GDH) are responsible for the HI/HA syndrome. GDH is expressed in liver, kidney, brain, and pancreatic beta-cells. Patients with the HI/HA syndrome have an increased frequency of generalized seizures, especially absence-type seizures, in the absence of hypoglycemia. The hypoglycemia of the HI/HA syndrome is well controlled with diazoxide, a KATP channel agonist. GDH has also been implicated in another form of HI, short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency associated HI. The HI/HA syndrome provides a rare example of an inborn error of intermediary metabolism in which the effect of the mutation on enzyme activity is a gain of function.

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References

  1. Cochrane WA, Payne WW, Simpkiss MJ, Woolf LI. Familial hypoglycemia precipitated by amino acids. J Clin Invest. 1956;35:411–22.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Stanley CA, Lieu YK, Hsu BYL, Burlina AB, Greenberg CR, Hopwood NJ, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998;338:1352–7.

    Article  CAS  PubMed  Google Scholar 

  4. Stanley CA. The hyperinsulinism-hyperammonemia syndrome: gain of function mutations of glutamate dehydrogenase. In: Dunger DB, editor. Genetic insights in paediatric endocrinology and metabolism. Bristol: BioScientifica; 2000. p. 23–30.

    Google Scholar 

  5. MacMullen C, Fang J, Hsu BYL, Kelly A, deLonlay-Debeney P, Saudubray JM, et al. Hyperinsulinism/Hyperammonemia syndrome in children with regulatory mutations in the inhibitory GTP binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001;86:1782–7

    Google Scholar 

  6. Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr. 2001;138:383–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Huijmans JGM, Duran M, DeKlerk JBC, Rovers MJ, Scholte HR. Functional hyperactivity of hepatic glutamate dehydrogenase as a cause of the hyperinsulinism/hyperammonemia syndrome: effect of treatment. Pediatrics. 2000;106:596–600.

    Article  CAS  PubMed  Google Scholar 

  9. Weinzimer SA, Stanley CA, Berry GT, Yudkoff M, Tuchman M, Thornton PS. A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr. 1997;130:661–4.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  11. Kelly A, Ng D, Ferry Jr RJ, Grimberg A, Koo-McCoy S, Thornton PS, et al. Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome. J Clin Endocrinol Metab. 2001;86:3724–8.

    Article  CAS  PubMed  Google Scholar 

  12. Stewart PM, Walser M. Short term regulation of ureagenesis. J Biol Chem. 1980;255:5270–80.

    CAS  PubMed  Google Scholar 

  13. 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:E1219–25.

    Article  CAS  PubMed  Google Scholar 

  14. Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, Kelly A. Central Nervous System hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr. 2005;146:388–94.

    Article  CAS  PubMed  Google Scholar 

  15. Li C, Najafi H, Daikhin Y, Nissim IB, Collins HW, Yudkoff M, et al. Regulation of leucine-stimulated insulin secretion and glutamine metabolism in isolated rat islets. J Biol Chem. 2003;278:2853–8.

    Article  CAS  PubMed  Google Scholar 

  16. Hudson RC, Daniel RM. L-glutamate dehydrogenases: distribution, properties and mechanism. Comp Biochem Physiol B. 1993;106:767–92.

    Article  CAS  PubMed  Google Scholar 

  17. Smith TJ, Peterson PE, Schmidt T, Fang J, Stanley CA. Structures of bovine glutamate dehydrogenase complexes elucidate the mechanism of purine regulation. J Mol Biol. 2001;23:707–20.

    Article  Google Scholar 

  18. Smith TJ, Stanley CA. Untangling the glutamate dehydrogenase allosteric nightmare. Trends Biochem Sci. 2008;33:557–64.

    Article  CAS  PubMed  Google Scholar 

  19. Fang J, Hsu BY, MacMullen CM, Poncz M, Smith TJ, Stanley CA. Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations. Biochem J. 2002;363:81–7.

    Article  CAS  PubMed  Google Scholar 

  20. Bahi-Buisson N, Roze E, Dionisi C, Escande F, Boddaert N, Valayannopoulos V, et al. Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase. Seizure. 2008;17:658–64.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Google Scholar 

  24. Kapoor RR, James C, Flanagan SE, Ellard S, Eaton S, Hussain K. 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. J Clin Endocrinol Metab. 2009;94:2221–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the NIH (UL1 RR024134, RO1 DK 56268, RO1 DK 53012 to CAS) and from the Society for Inherited Metabolic Disorders.

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  1. The Children’s Hospital of Philadelphia, Division of Endocrinology and Diabetes, University of Pennsylvania, School of Medicine, 34th Street and Civic Center Boulevard, Philadelphia, PA, 19104, USA

    Andrew A. Palladino & Charles A. Stanley

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  1. Andrew A. Palladino
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  2. Charles A. Stanley
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Correspondence to Andrew A. Palladino.

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Palladino, A.A., Stanley, C.A. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord 11, 171–178 (2010). https://doi.org/10.1007/s11154-010-9146-0

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