ASYMPTOMATIC AND LATE-ONSET ORNITHINE TRANSCARBAMYLASE (OTC) DEFICIENCY IN MALES OF A 5-GENERATION FAMILY, CAUSED BY AN A208T MUTATION

In a large five-generation Polish family, late-onset ornithine transca rbamylase (OTC) deficiency in males segregated with the missense mutat ion Ala208Thr (A208T), all all heterozygous females were asymptomatic. No other mutations were found in the coding sequences and intron-exon boundaries of the OTC gene. Surprisingly, the mutation originated fro m the great-grandfather of the index patient who died at age 59 of liv er carcinoma. He never had dietary restrictions or hyperammonemic spel ls throughout life and appears to be the oldest male reported with OTC deficiency. The index patient had a severe OTC deficiency (3% of norm al). Eight males died suddenly at ages 4 months to 23 years (average 1 4 years) after a foudroyant episode triggered by a common infection. T he patients remained undiagnosed for 28 years because a metabolic defe ct was not considered to be the cause of the acute episodes. Recogniti on of the familial pattern of inheritance was initially unnoticed sinc e the patients were admitted to eight different hospitals. DNA analysi s predicted that two 'healthy' boys also had OTC deficiency, which was confirmed by abnormal results of allopurinol challenge tests. Initial suspicion of OTC deficiency in such families is complicated, since sy mptoms can develop at any age, or even remain absent. This obscures th e typical pattern of X-linked inheritance in small families.