Genotype spectrum of ornithine transcarbamylase deficiency: Correlation with the clinical and biochemical phenotype

Ornithine transcarbamylase (OTC) deficiency, a partially dominant X-linked disorder, is the most common inherited defect of the urea cycle. Previous r eports suggested a variable phenotypic spectrum, and several studies docume nted different "private" mutations in the OTC genes of patients. Our labora tory identified disease-causing mutations in 157 families with OTC deficien cy, 100 of which came to medical attention through a hemizygous propositus and in 57 the index case was a heterozygous female. We correlated the genot ype with age of onset, liver OTC activity, incorporation of nitrogen into u rea, and peak plasma ammonia levels. The "neonatal onset" group has a homog enous clinical and biochemical phenotype, whereas the "late onset" group sh ows an extremely wide phenotype; 60% of the mutations are associated exclus ively with acute neonatal hyperammonemic coma. The remaining mutations caus ed a nonuniform phenotype ranging from severe disease to no symptoms; 31% o f the mutations in the OTC gene occur in CpG; dinucleotides (methylation-me diated deamination), and none of them accounted for more than 4% of the tot al. Eighty-six percent of the mutations represented single-base substitutio ns and 68% of the substitutions were transitions. G-to-A and C-to-T transit ions were the most frequent substitutions (34 and 21%, respectively) wherea s C-to-A, A-to-C, C-to-G;, and T-to-A transversions were the least common ( 1.5-3%). Twenty percent of propositi and 77% of propositae carried new muta tions. Forty percent of female germinal mutations were in CpG: dinucleotide s whereas this number appears much smaller in male germinal mutations. Thes e data allow classification of patients with OTC deficiency into at least t wo groups who have discordant disease course and prognoses. In addition, th ey improve our understanding on the origin of mutations in the OTC gene and allow better counseling of affected families. (C) 2000 Wiley-Liss, Inc.