Ornithine transcarbamylase deficiency, the most common urea cycle disorder, is an X‐linked trait displaying large heterogeneity, including cases of symptomatic heterozygotes and very mild hemizygous individuals. A wide mutational spectrum, comprising more than 500 disease‐associated mutations, is currently known. More than two‐thirds of the mutations are nucleotide replacements at the coding region of the gene. De novo mutations are common being responsible for as much as three‐fourths of female abnormal chromosomes. Recurrent mutations found in different human populations are associated with hypermutable CpG dinucleotides, and these features render diagnosis and genetic counselling, particularly challenging. The responsible gene is, however, an excellent model for research on human mutation, owing to (1) the mode of transmission (allowing direct haplotype ascertainment and evaluation of the role of recombination) and (2) the abundance and diversity of mutations. Treatment strategies involve reduction of protein level intake and stimulation of alternative metabolic pathways or liver transplantation.

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