Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon

We report on late-onset ornithine transcarbamylase (OTC) deficiency in two families with mutations in the same codon, but different base substitutions . Onset of symptoms showed great variation, and five hemizygotes finally di ed. Clinical diagnosis was late and difficult. In family A, 1 patient also developed the signs of Gilbert's disease. In fa mily B, the index case came to attention as OTC deficiency, after the trans plantation of his liver when the recipient died of cerebral edema and hyper ammonemia. In family A, the hemizygote males died at the ages of 12 and 18 years; in family B, they died at the ages of 20, 26, and 30 years, respecti vely. Diagnosis was confirmed by reduced OTC activity in liver specimens. T he residual activity in autopsy liver of the index patient in family A was less than the activity in the biopsy of the transplanted liver of the index patient in family B. The molecular investigations showed mutations in exon 2 at codon 40 in the OTC gene in both families. However, different bases w ere substituted. In family A, the single-base mutation was a cytosine-to-th ymine transition (Arg 40 Cys); in family B, it was a guanine-to-adenine tra nsition (Arg 40 His). Published data on in vitro expression studies of the recurrent OTC mutation Arg 40 His have shown little effect on the protein structure of the enzyme . These studies would fit well with our observation of higher OTC activity and later age of onset of symptoms in family B.