European Journal of Pediatrics

, Volume 164, Issue 1, pp 31–36 | Cite as

Δ1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline

  • Matthias R. Baumgartner
  • Daniel Rabier
  • Marie-Cécile Nassogne
  • Jean-Louis Dufier
  • Jean-Paul Padovani
  • Pierre Kamoun
  • David Valle
  • Jean-Marie Saudubray
Original Paper


Δ1-pyrroline-5-carboxylate synthase (P5CS) catalyses the reduction of glutamate to Δ1-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine. Recently, we reported a newly recognised inborn error due to deficiency of P5CS in two sibs, one presenting at birth with hypotonia, dysmorphic signs, pes planus and clonic seizures. Both developed progressive neurodegeneration and peripheral neuropathy, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes mild hyperammonaemia, hypo-ornithinaemia, hypocitrullinaemia, hypo-argininaemia and hypoprolinaemia. Incorporation of 3H-proline into protein was deficient in fibroblasts incubated with 3H-glutamate. Both patients are homozygous for the missense mutation R84Q in P5CS. Here, we describe the clinical phenotype of the sibs in detail and show that a relative deficiency of urea cycle intermediates (ornithine, citrulline and arginine) during fasting periods results in a paradoxical hyperammonaemia. Furthermore, we show the results of ornithine loading tests and indirect enzyme studies corroborating the biological significance of the defect in P5CS in vivo. Conclusion:The metabolic phenotype of Δ1-pyrroline-5-carboxylate synthase deficiency is easily missed. The combination of low levels of ornithine, citrulline, arginine and proline plus a tendency to hyperammonaemia or one of the above together with a clinical phenotype of neurodegeneration with peripheral neuropathy and/or cataracts and connective tissue manifestations should suggest this disorder. Early recognition would allow a therapeutic trial with citrulline and proline.


Cataracts Δ1-pyrroline-5-carboxylate synthase Hyperammonaemia Hypocitrullinaemia Inborn error 





Δ1-pyrroline-5-carboxylate synthase


ornithine δ-aminotransferase


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Matthias R. Baumgartner
    • 1
  • Daniel Rabier
    • 2
  • Marie-Cécile Nassogne
    • 3
  • Jean-Louis Dufier
    • 4
  • Jean-Paul Padovani
    • 5
  • Pierre Kamoun
    • 2
  • David Valle
    • 6
  • Jean-Marie Saudubray
    • 3
  1. 1.Division of Metabolism and Molecular PaediatricsUniversity Children’s HospitalZürich Switzerland
  2. 2.Laboratoire de Biochimie Médicale BHôpital Necker-Enfants MaladesParis France
  3. 3.Service des Maladies MétaboliquesHôpital Necker-Enfants MaladesParis France
  4. 4.Service d’OphtalmologieHôpital Necker-Enfants MaladesParis France
  5. 5.Service d’OrthopédieHôpital Necker-Enfants MaladesParis France
  6. 6.McKusick-Nathans Institute of Genetic Medicine and Howard Hughes Medical InstituteJohns Hopkins UniversityBaltimore USA

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