Title:
Inborn errors of nitrogen metabolism – clinical practice and scientific bases

Johannes Haberle
University Children’s Hospital Zurich, Switzerland

Abstract:
Hyperammonemia is the hallmark of many disorders of nitrogen metabolism and can occur in inherited as well as in acquired disorders. Thus, hyperammonemia is an unspecific laboratory sign. It is defined as a plasma ammonia level > 50 μmol/L (and > 100 μmol/L in newborns) and should always be regarded as an emergency situation. Hyperammonemia can occur when there is an increased production of ammonia (possible causes comprise e.g. intestinal bacterial overgrowth, neurogenic bladder) or if the detoxification is affected (possible causes include e.g. decreased urea cycle flux, blood bypass of the liver or insufficient action of glutamine synthetase). Often, endogenous protein catabolism triggers an increase of ammonia such as during infections or due to any other energy deficit. Detoxification of ammonia is mainly achieved in periportal hepatocytes within the urea cycle. A defect of any of the involved enzymes or transporters and also inhibition of the urea cycle through metabolites or by substrate deficiencies can affect ammonia detoxification.
In addition, various other situations such as organic acidemias, fatty acid oxidation defects, some rare diseases such as pyrroline-5-carboxylate synthetase deficiency and the hyperammonemia-hyperinsulinism syndrome, as well as some drugs such as valproic acid or cyclophosphamide can cause hyperammonemia. While the aforementioned conditions lead to a secondary impairment of urea cycle function which might manifest at any age, patients with a primary urea cycle defect are also threatened by irreversible hyperammonemic brain edema during their entire life.
Early recognition of a hyperammonemic state and initiation of specific treatment are of utmost importance. In particular, this should be acknowledged by neonatologists treating sick newborns considered initially as bacterial sepsis cases. The main prognostic factors are, irrespective of the underlying cause, the duration of the hyperammonemic coma and the extent of ammonia accumulation. The talk will discuss the biochemical background of primary and secondary hyperammonemia, give an overview on the various underlying disorders including their genetic backgrounds, and will summarize the diagnostic and therapeutic strategies.

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