Introduction and background - UCD

Urea cycle disorders (UCD) are inborn errors of ammonia detoxification. The urea cycle is the main pathway to detoxify ammonia to form urea from waste nitrogen compounds. The urea cycle is present in the liver and located in mitochondria as well as in the cytosol of only periportal hepatocytes. The second function of the urea cycle is to synthesize arginine, which is the precursor amino acid for several important metabolites.

Due to defects in the metabolism of the extra nitrogen produced by the breakdown of protein and other nitrogen-containing molecules, the balance between ammonia production and detoxification can lead to hyperammoniamia. If any of these enzymes is deficient, the main resulting medical problem is hyperammonemia. Since ammonia is neurotoxic, life and mental status can be threatened in a few hours’ time.

Disease presentation and severity can vary from asymptomatic patients, picked up by Newborn screening until early onset patients that rapidly developed life-threatening. Infants with UCD often initially appear normal but rapidly develop very early after birth cerebral edema and the related signs of lethargy; anorexia; hyperventilation or hypoventilation; hypothermia, seizures and coma.

For approximately 50% of patients first symptoms appear after the neonatal period and can be triggered by any catabolic situation, for instance by infections or prolonged fasting due to reduction of number of feeds. The clinical manifestations of hyperammonemia are generally unspecific and mainly neurological, gastrointestinal or psychiatric. The main feature is unexplained change in consciousness.
In milder UCD ammonia, accumulation may be triggered by illness or stress at almost any time of life, resulting in mild elevations of plasma ammonia concentrations.

Major symptoms and range from subtile neurological changes (lethargy, headaches, tremor, changed personality or other psychiatric symptoms) to sub-acute loss of vision, seizures or coma.

Estimated incidence of the UCDs in total is approximately 1:8000 live births, but the exact prevalence is unknown.

References

E-IMD. Urea cycle disorders: quick reference guide. http://www.e-imd.org
Häberle J, Rubio V. Hyperammonemias and related disorders. In; Blau N (ed) Physician’s guide to the diagnosis, treatment and follow-up of inherited metabolic diseases, 2nd edn. Springer Heidelberg, 2014:47-62 Deodato F, Boenzi S et al. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet 2006;142C:104-112
Baumgartner et al. Orphanet Journal of Rare Diseased, 2014;9:130.

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