Abstract: Urea cycle disorders (UCDs) are a group of autosomal or X-linked,
recessively inherited errors of metabolism that lead to severe neurological
disease due to insufficient detoxification of excess nitrogen. The resulting
hyperammonemia is the key feature of UCDs, but at the same time only a
surrogate marker. In the majority of cases, a sole biochemical analysis is
indicative but not diagnostic. Therefore, additional means are required and
mutation analysis is the method of choice for confirmation in most cases of
UCD. In addition to confirming the diagnosis, mutation analysis enables genetic
counseling and prenatal testing and contributes to new research approaches. All
genes involved in any of the enzymatic (namely the genes for N-acetylglutamate
synthase, NAGS; carbamoylphosphate synthetase, CPS1; ornithine
transcarbamylase, OTC; argininosuccinate synthetase, ASS1; argininosuccinate
lyase, ASL; arginase, ARG1) or transporter steps (namely the genes for the
ornithine/citrulline antiporter ORNT1, SLC25A15; glutamate/aspartate antiporter
citrin, SLC25A13) of the urea cycle are known and thus accessible for genetic
testing. In most situations, direct Sanger sequencing using DNA from peripheral
blood cells can be done but there are exceptions to this such as in the case of
the relatively large CPS1 gene which renders RNA based mutation analysis an
attractive alternative. With this review, we provide an overview on the current
methods used for mutation analysis of each UCD gene, we mention possible
pitfalls and their solutions, and discuss alternative methods which may become
standard in the future.
Keywords: Urea cycle, mutation analysis, hyperammonemia, inborn error of metabolism
