ABSTRACT Ornithine transcarbamylase (OTC) deficiency can present during the neonatal period, infancy, or adulthood. Late‐onset phenotypes are influenced by residual enzyme activity and OTC gene expression. The objective of this study was to assess the pathogenicity of a rare promoter region variant, c.‐106C>A. We reviewed three independent pedigrees harboring the c.‐106C>A variant. Retrospective chart reviews were conducted for 16 affected males to evaluate biochemical and clinical features. Functional OTC enzyme data were obtained from the liver biopsy of three affected males. The median age of diagnosis for symptomatic males was 15 years (range: 0.08–55). All 21 heterozygous females have been asymptomatic to date. Of the 16 hemizygous males, seven have experienced at least one episode of hyperammonemia, and eight have remained asymptomatic. The proband from Family A presented at age 55, with a peak ammonia level of 694 μmol/L. His OTC activity was 8.2 μmol/g liver/min (control: 94.9 μmol/g liver/min). The proband from Family B presented at age 15 with an ammonia level of 1568 μmol/L and later died from cerebral edema. His OTC activity was 2.2 μmol/g liver/min (control: 73.2 μmol/g liver/min). The proband from Family C presented at age 24 with hyperammonemia and later died following withdrawal of care. His liver punch biopsy OTC enzyme activity was measured to be 0 μmol/g liver/min (control range: 25–31.7 μmol/g liver/min). For most affected males, ammonia scavenger therapy has successfully prevented recurrent decompensation. The combined biochemical, clinical, and enzymatic data strongly support the pathogenicity of the c.‐106C>A OTC promoter region variant in late‐onset OTC deficiency.
Tholl et al. (Thu,) studied this question.