Kinder- und Jugendmedizin 2015; 15(02): 119-125
DOI: 10.1055/s-0038-1629258
Stoffwechsel
Schattauer GmbH

Diagnose und Therapie der Harnstoffzyklusdefekte

Diagnosis and therapy of urea cycle defects
J. Häberle
1   Kinderspital Zürich, Abteilung Stoffwechselkrankheiten
› Institutsangaben
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Publikationsverlauf

Eingereicht am: 27. Februar 2014

angenommen am: 11. März 2014

Publikationsdatum:
31. Januar 2018 (online)

Zusammenfassung

Harnstoffzyklusdefekte sind seltene, vererbte Fehlfunktionen des Harnstoffzyklus in der Leber. Dabei ist die Ammoniakentgiftung aufgrund von Defekten in einem von fünf Hauptenzymen, einem Aktivierungsenzym oder einem Transportprotein gestört. Die kumulative Inzidenz aller Harnstoffzyklusdefekte beträgt ca. 1 : 35 000. Bei etwa der Hälfte der Betroffenen manifestiert sich die Krankheit in den ersten Tagen nach der Geburt. Die Patienten entwickeln eine Hyperammonämie, die zu schwerwiegenden und oft leider irreversiblen neurologischen Schädigungen bis hin zum Tod führen kann. Die Diagnose erfolgt oft sehr spät oder gar nicht und das Outcome ist häufig unbefriedigend. Entscheidend für die Prognose sind die rechtzeitige Erkennung der Situation und eine schnelle Absenkung der Ammoniakkonzentration, um Folgeschäden des Gehirns zu vermeiden. Derzeit ist die Lebertransplantation die einzige kurative Therapie. In der Neugeborenen-phase ist eine Lebertransplantation jedoch ein Risikoeingriff mit relativ hoher Morbidität und Mortalität. Daher wird derzeit eine alternative Therapieoption, die Leberzelltherapie, im Rahmen eines klinischen Studienprogramms untersucht.

Summary

Urea Cycle Defects (UCDs) are rare, inherited disorders of the urea cycle in the liver. These inborn errors of ammonia detoxification are caused by defects in one of five key enzymes, an activating enzyme or a transport protein. The estimated cumulative incidence of all UCDs is 1 : 35 000. In about half of the patients, first symptoms occur only few days after birth – due to hyperammonemia, which often leads to severe and unfortunately irreversible neurological damage, depending on the severity of the underlying defect. UCDs are often diagnosed too late or not at all, and in many cases the outcome is disappointing. Identifying the disease early enough and providing patients with rapid and targeted treatment are critical for prognosis: during the acute phase, ammonia levels need to be reduced to normal levels very quickly in order to avoid brain damage. Currently, the only curative therapy is liver transplantation. However, for newborns, liver transplantation is an intervention with a relatively high morbidity and mortality rate. Therefore, liver cell therapy is currently being investigated within a clinical trial program as an alternative treatment option.

 
  • Literatur

  • 1 Brusilow S, Horwich A. Urea cycle enzymes. In. Scriver C, Beaudet A, Sly W, Valle D. (eds) The metabolic & molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001: 1909-1963.
  • 2 Rüegger CM, Lindner M, Ballhausen D. et al. Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. J Inherit Metab Dis 2014; 37: 21-30.
  • 3 Summar ML, Koelker S, Freedenberg D. et al. The incidence of urea cycle disorders. Mol Genet Metab 2013; 110: 179-180.
  • 4 Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 2003; 162: 410-416.
  • 5 Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999; 134: 268-272.
  • 6 Msall M, Batshaw ML, Suss R. et al. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 1984; 310: 1500-1505.
  • 7 Nassogne MC, Heron B, Touati G. et al. Urea cycle defects: management and outcome. J Inherit Metab Dis 2005; 28: 407-414.
  • 8 Harada E, Nishiyori A, Tokunaga Y. et al. Late-onset ornithine transcarbamylase deficiency in male patients: prognostic factors and characteristics of plasma amino acid profile. Pediatr Int 2006; 48: 105-111.
  • 9 Nicolaides P, Liebsch D, Dale N. et al. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child 2002; 86: 54-56.
  • 10 Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 1998; (Suppl. 21) Suppl 1: 151-159.
  • 11 Enns GM. Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol 2008; 15: 132-139.
  • 12 Häberle J, Boddaert N, Burlina A. et al. Suggested Guidelines For The Diagnosis And Management Of Urea Cycle Disorders. Orphanet J Rare Dis 2012; 7: 32.
  • 13 Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr 2011; 170: 21-34.
  • 14 Deutsche Gesellschaft für Kinder- und Jugendmedizin (2012) Diagnostik und Therapie von Harnstoffzyklusstörungen A-L-. http://www.awmf.org/leitlinien/detail/II/027-006.html AWMF Düsseldorf, letzter Zugriff: 30.11.2013.
  • 15 Enns GM, Berry SA, Berry GT. et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007; 356: 2282-2292.
  • 16 Picca S, Dionisi-Vici C, Abeni D. et al. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol 2001; 16: 862-867.
  • 17 Schaefer F, Straube E, Oh J. et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant 1999; 14: 910-918.
  • 18 Dixon M. Disorders of amino acid metabolism, organic acidemias and urea cycle defects. Organic acidemias and urea cycle disorders. In. Shaw V, Lawson M. (eds) Clinical Pediatric Dietetics. 2007: 357-389.
  • 19 Häberle J. Grundsätzliche und praktische Aspekte zur Hyperammonämie im Kindesalter. Kinder- und Jugendmedizin 2006; 6: 233-240.
  • 20 Häberle J. Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Therapeutics and clinical risk management 2011; 7: 1-6.
  • 21 Singh RH. Nutrition management of patients with inherited disorders of urea cycle enzymes. In. Acosta PB. (ed) Nutrition management of patients with inherited metabolic disorders. Sudbury: Jones & Bartlett Learning; 2009: 405-429.
  • 22 Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001; 138 (Suppl. 01) Suppl S56-60. discussion S-1.
  • 23 WHO Technical Report Series. Protein and amino acid requirement in human nutrition. 2007
  • 24 Bourdeaux C, Darwish A, Jamart J. et al. Living-related versus deceased donor pediatric liver transplantation: a multivariate analysis of technical and immunological complications in 235 recipients. Am J Transplant 2007; 7: 440-447.
  • 25 Morioka D, Kasahara M, Takada Y. et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl 2005; 11: 1332-1342.
  • 26 McBride KL, Miller G, Carter S. et al. Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics 2004; 114: e523-526.
  • 27 Noujaim HM, Mayer DA, Buckles JA. et al. Techniques for and outcome of liver transplantation in neonates and infants weighing up to 5 kilograms. J Pediatr Surg 2002; 37: 159-164.
  • 28 Sundaram SS, Alonso EM, Whitington PF. Liver transplantation in neonates. Liver Transpl 2003; 9: 783-788.
  • 29 Meyburg J, Das AM, Hoerster F. et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 2009; 87: 636-641.
  • 30 Enns GM, Millan MT. Cell-based therapies for metabolic liver disease. Mol Genet Metab 2008; 95: 3-10.
  • 31 Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis 2006; 29: 431-435.
  • 32 Meyburg J, Hoffmann GF. Liver cell transplantation for the treatment of inborn errors of metabolism. J Inherit Metab Dis 2008; 31: 164-172.
  • 33 Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010; 100 (Suppl. 01) Suppl S77-83.
  • 34 Häberle J. Varianten von Harnstoffzyklusstörungen. Monatsschr Kinderheilkd 2011; 159: 834-841.