Urea cycle disorders diagnosis

Brusilow SW, Maestri NE Urea cycle disorders diagnosis, pathophysiology and therapy. Adv Pediatr 43 127-170,1996. 

Haberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012 7 32. 

Summar ML, et al. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyper-ammonaemic episodes. Acta Paediatr. 2008 97(10) 1420-5. 

Amniotic fluid has limited value in prenatal diagnosis for the aminoacid-opathies. Unlike the organic acid disorders, in most amino acid disorders the metabolites do not accumulate before birth. Abnormal amino acid patterns in amniotic fluid have only been found in two of the urea cycle disorders, namely argininosuccinate lyase deficiency (argininosuccinic acidemia) and argininosuccinate synthetase deficiency (citrullinemia). 

Bachmann C. Urea cycle disorders. In Fernandes J, Saudubray J, Tada K, eds. Inborn metabolic diseases. Diagnosis and treatment. Springer-Verlag Berlin, Heidelberg 1990, pp 211-228... 

Citrulline is exchanged for ornithine across the inner mitochondrial membrane by ORNT-1. Ornithine is produced in the cytosol as the final step in the urea cycle and must be returned to the mitochondrial matrix for transcarbamoyla-tion by OTC. A second ornithine-citrulline antiporter (ORNT-2) is also expressed in the liver mitochondria and may attenuate the severity of disease in patients with HHH (Hyperammonemia, Hyperornithinemia, Homocitrullinuria) disease due to ORNT-1 deficiency. This disorder typically manifests later in life with intermittent hyperammonemic encephalopathy and protein aversion. Intramitochondrial ornithine deficiency causes both hyperammonemia and hyperornithinemia due to a lack of substrate for OTC. Homocitrullinuria occurs due to the use of lysine by OTC as an alternate substrate. The diagnosis is confirmed by mutation analysis. 

The determination of plasma ammonia is of great importance both for the diagnosis and for the treatment of hereditary metabolic disorders of the urea cycle. The level is always raised in these conditions since the other mechanisms for regulating blood ammonia mentioned above are not able by themselves to keep the ammonia level within normal limits. 

Antenatal diagnosis for fetuses at risk for the urea cycle enzyme disorders can be made by appropriate enzyme assays and DNA analysis in the cultured amniocytes. 

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