Disorders of Ornithine Metabolism

  • Vivian E. Shih
  • Matthias R. Baumgartner


Hyperornithinemia due to ornithine aminotransferase (OAT) deficiency is associated with gyrate atrophy of the choroid and retina. Patients usually become virtually blind by age 55. Treatment includes a low arginine diet and pharmacological doses of pyridoxine (vitamin B6). Long term compliance to an arginine-restricted diet, especially when started at a young age, can slow the progression of the chorioretinal lesions and loss of vision. Rarely, neonates can present with hyperammonemic encephalopathy, hypoargininemia, and hypoornithinemia and require arginine supplementation. In the hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome there is a wide spectrum of clinical manifestations, most of which are related to the toxicity of hyperammonemia. Progressive spastic paraparesis is often a late complication. Patients have a marked elevation of plasma ornithine associated with hyperammonemia and increased urinary excretion of homocitrulline. HHH results from a defect in the import of ornithine into the mitochondrion and consequent urea synthesis malfunction. Treatment is similar to that for patients with urea cycle disorders.

A newly recognized disorder, Δ 1-pyrroline-5-carboxylate synthase (P5CS) deficiency, has been described in two siblings with progressive neurodegeneration and peripheral neuropathy, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes mild hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia. This disorder underscores the importance of low levels of amino acids as markers of metabolic disease.


Orotic Acid Urea Cycle Disorder Ornithine Aminotransferase Gyrate Atrophy Orotic Aciduria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Takahashi O, Hayasaka S, Kiyosawa M et al (1985) Gyrate atrophy of choroid and retina complicated by vitreous hemorrhage. Jpn J Ophthalmol 29:170–176PubMedGoogle Scholar
  2. 2.
    Cleary MA, Dorland L, de Koning TJ et al (2005) Ornithine aminotransferase deficiency: diagnostic difficulties in neonatal presentation. J Inherit Metab Dis 28:673–679PubMedCrossRefGoogle Scholar
  3. 3.
    Webster M, Allen J, Rawlinson D et al (1999) Ornithine Aminotransferase Deficiency presenting with hyperammonaemia in a premature newborn. J Inherit Metab Dis 22[Suppl 1]:80Google Scholar
  4. 4.
    Champion MP, Bird S, Fensom T, Dalton RN (2002) Ornithine aminotransferase deficiency (gyrate atrophy) presenting with hyperammonaemic encephalopathy. J Inherit Metab Dis 25[Suppl 1]:29Google Scholar
  5. 5.
    Wilson DJ, Weleber RG, Green WR (1991) Ocular clinicopathologic study of gyrate atrophy. Am J Ophthalmol 111:24–33PubMedGoogle Scholar
  6. 6.
    Arshinoff SA, McCulloch JC, Matuk Y et al (1979) Amino-acid meta bolism and liver ultrastructure in hyperornithinemia with gyrate atrophy of the choroid and retina. Metabolism 28:979–988PubMedCrossRefGoogle Scholar
  7. 7.
    Kaiser-Kupfer MI, Kuwabara T, Askanas V (1981) Systemic manifestations of gyrate atrophy of the choroid and retina. Ophthalmology 88:918–928Google Scholar
  8. 8.
    Valtonen M, Nanto-Salonen K, Jaaskelainen S et al (1999) Central nervous system involvement in gyrate atrophy of the choroids and retina with hyperornithinaemia. J Inherit Metab Dis 22:855–866PubMedCrossRefGoogle Scholar
  9. 9.
    Peltola KE, Jaaskelainen S, Heinonen OJ et al (2002) Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 59:735–740PubMedGoogle Scholar
  10. 10.
    Trijbels JMF, Sengers RCA, Bakkaren JAJM et al (1977) L-Ornithineketoacidtransaminase deficiency in cultured fibroblasts of a patient with hyperornithinemia and gyrate atrophy of the choroids and retina. Clin Chim Acta 79:371–377PubMedCrossRefGoogle Scholar
  11. 11.
    Wang T, Lawler AM, Steel G et al (1995) Mice lacking ornithinedelta-aminotransferase have paradoxical neonatal hypoornithinaemia and retinal degeneration. Nat Genet 11:185–190PubMedCrossRefGoogle Scholar
  12. 12.
    Vannas-Sulonen K, Simell O, Sipila I (1987) Gyrate atrophy of the choroid and retina. The ocular disease progresses in juvenile patients despite normal or near normal plasma ornithine concentration. Ophthalmology 94:1428–1433PubMedGoogle Scholar
  13. 13.
    Nanto-Salonen K, Komu M, Lundbom N et al (1999) Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 53:303–307PubMedGoogle Scholar
  14. 14.
    Takki K (1974) Gyrate atrophy of the choroid and retina associated with hyperornithinaemia. Br J Ophthalmol 58:3PubMedGoogle Scholar
  15. 15.
    Ramesh V, Gusella JF, Shih VE (1991) Molecular pathology of gyrate atrophy of the choroid and retina due to ornithine aminotransferase deficiency. Mol Biol Med 8:81–94PubMedGoogle Scholar
  16. 16.
    Valle D, Walser M, Brusilow SW, Kaiser-Kupfer M (1980) Gyrate atrophy of the choroid and retina: amino acid metabolism and correction of hyperornithinemia with an arginine-deficient diet. J Clin Invest 65:371–378PubMedCrossRefGoogle Scholar
  17. 17.
    McInnes RR, Arshinoff SA, Bell L et al (1981) Hyperornithinaemia and gyrate atrophy of the retina: improvement of vision during treatment with a low-arginine diet. Lancet 1:513–516PubMedCrossRefGoogle Scholar
  18. 18.
    Kennaway NG, Weleber RG, Buist NRM (1980) Gyrate atrophy of the choroid and retina with hyperornithinemia: Biochemical and histologic studies and repsonse to vitamin B6. Am J Hum Genet 32:529PubMedGoogle Scholar
  19. 19.
    Hayasaka S, Saito T, Nakajima H et al (1985) Clinical trials of vitamin B6 and proline supplementation for gyrate atrophy of the choroids and retina. Br J Ophthalmol 69:283–290PubMedGoogle Scholar
  20. 20.
    Shih VE, Berson EL, Gargiulo M (1981) Reduction of hyperornithinemia with a low protein, low arginine diet and pyridoxine in patients with a deficiency of ornithine-ketoacid transaminase (OKT) activity and gyrate atrophy of the choroid and retina. Clin Chim Acta 113:243–251PubMedCrossRefGoogle Scholar
  21. 21.
    Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF (2004) Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol 122:982–984PubMedCrossRefGoogle Scholar
  22. 22.
    Kaiser-Kupfer MI, Caruso RC, Valle D (2002) Gyrate atrophy of the choroid and retina: further experience with long-term re duction of ornithine levels in children. Arch Ophthalmol 120:146–153PubMedGoogle Scholar
  23. 23.
    Santinelli R, Costagliola C, Tolone C et al (2004) Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: a twenty-six-year follow-up. J Inherit Metab Dis 27:187–196PubMedCrossRefGoogle Scholar
  24. 24.
    Heinanen K, Nanto-Salonen K, Komu M et al (1999) Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia. Eur J Clin Invest 29:1060–1065PubMedCrossRefGoogle Scholar
  25. 25.
    Elpeleg N, Korman SH (2001) Sustained oral lysine supplementation in ornithine delta-aminotransferase deficiency. J Inherit Metab Dis 24:423–424PubMedCrossRefGoogle Scholar
  26. 26.
    Shih VE, Efron ML, Moser HW (1969) Hyperornithinemia, hyperammonemia, and homocitrullinuria: A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation. Am J Dis Child 117:83PubMedGoogle Scholar
  27. 27.
    Shih VE, Laframboise R, Mandell R, Pichette J (1992) Neonatal form of the hyperornithinemia, hyperammonemia and homocitrullinuria (HHH) syndrome and prenatal diagnosis. Prenat Diagn 12:717–723PubMedGoogle Scholar
  28. 28.
    Salvi S, Dionisi-Vici C, Bertini E et al (2001) Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Hum Mutat 18:460PubMedCrossRefGoogle Scholar
  29. 29.
    Dionisi Vici C, Bachmann C, Gambarara M et al (1987) Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement. Pediatr Res 22:364–367PubMedGoogle Scholar
  30. 30.
    Smith L, Lambert MA, Brochu P et al (1992) Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy. J Pediatr Gastroenterol Nutr 15:431–436PubMedCrossRefGoogle Scholar
  31. 31.
    Tuchman M, Knopman DS, Shih VE (1990) Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Arch Neurol 47:1134–1137PubMedGoogle Scholar
  32. 32.
    Camacho JA, Obie C, Biery B et al (1999) Hyperornithinaemiahyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 22:151–158PubMedCrossRefGoogle Scholar
  33. 33.
    Miyamoto T, Kanazawa N, Kato S et al (2001) Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. J Hum Genet 46:260–262PubMedCrossRefGoogle Scholar
  34. 34.
    Shih VE, Mandell R, Herzfeld A (1982) Defective ornithine metabolism in cultured skin fibroblasts from patients with the syndrome of hyperornithinemia, hyperammonemia and homocitrullinuria. Clin Chim Acta 118:149PubMedCrossRefGoogle Scholar
  35. 35.
    Chadefaux B, Bonnefont JP, Shih VE, Saudubray JM (1989) Potential for the prenatal diagnosis of hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Am J Med Genet 32:264PubMedCrossRefGoogle Scholar
  36. 36.
    Zammarchi E, Ciani R, Pasquini E et al (1997) Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with favourable outcome. J Pediatr 131:440–443PubMedGoogle Scholar
  37. 37.
    Gaye AM, Wong PWK, Kang DS et al (1983) Treatment of hyperornithinemia, hyperammonemia and homocitrullinuria (HHH) during pregnancy. Clin Res 31:787AGoogle Scholar
  38. 38.
    Baumgartner MR, Rabier D, Nassogne MC et al (2005) Delta1-pyrroline-5-carboxylate synthase deficiency: Neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonemia and reduced ornithine, citrulline, arginine and proline. Eur J Pediatr 164:31–36PubMedCrossRefGoogle Scholar
  39. 39.
    Baumgartner MR, Hu CA, Almashanu S et al (2000) Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. Hum Mol Genet 9:2853–2858PubMedCrossRefGoogle Scholar
  40. 40.
    Wakabayashi Y, Yamada E, Hasegawa T, Yamada R (1991) Enzymological evidence for the indispensability of small intestine in the synthesis of arginine from glutamate. I. Pyrroline-5-carboxylate synthase. Arch Biochem Biophys 291:1–8PubMedCrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag Heidelberg 2006

Authors and Affiliations

  • Vivian E. Shih
    • 1
  • Matthias R. Baumgartner
    • 2
  1. 1.Amino Acid Disorder Laboratory, Pediatrics and Neurology ServicesMassachusetts General HospitalBostonUSA
  2. 2.Division of Metabolism and Molecular PediatricsUniversity Children’s HospitalZürichSwitzerland

Personalised recommendations