Asymptomatic and late‐onset ornithine transcarbamylase (OTC) deficiency in males of a five‐generation family, caused by an A208T mutation

Abstract

In a large five‐generation Polish family, late‐onset ornithine transcarbamylase (OTC) deficiency in males segregated with the missense mutation Ala208Thr (A208T), and 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 from the great‐grandfather of the index patient who died at age 59 of liver carcinoma. He never had dietary restrictions or hyperammonemic spells throughout life and appears to be the oldest male reported with OTC deficiency. The index patient had a severe OTC deficiency (3% of normal). Eight males died suddenly at ages 4 months to 23 years (average 14 years) after a foudroyant episode triggered by a common infection. The patients remained undiagnosed for 28 years because a metabolic defect was not considered to be the cause of the acute episodes. Recognition of the familial pattern of inheritance was initially unnoticed since the patients were admitted to eight different hospitals. DNA analysis 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 symptoms can develop at any age, or even remain absent. This obscures the typical pattern of X‐linked inheritance in small families.

Estimation of the total number of disease‐causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential

“…The very characteristic mild mutations p.Arg40His and p.Ala208Thr are also represented in our sample, in patients 11 and 17, respectively. These mutations have been reported in paternal transmission and were found to cause overt disease only in some males (Matsuda et al 1996;Van Diggelen et al 1996). The latter is also observed here in patient 11, who has a healthy 4-year-old brother carrying the p.Arg40His mutation.…”

Fatal Initial Adult-Onset Presentation of Urea Cycle Defect

“…In both of these kindreds, 9,10 all of the female heterozygotes were asymptomatic, as was the patient in case 1 in this report. We expect that the 2 sisters of case 1 will remain asymptomatic.…”

“…Other families have been described in whom the A208T mutation has been found. In one 5-generation family, 9 the 59-year-old great-grandfather was homozygous for the mutation, but he has never had hyperammonemia or dietary restriction; nevertheless, 8 males had died suddenly at 4 months to 23 years of age. In another 4-generation family, 10 there was an asymptomatic 97-year-old hemizygous man, whereas the proband was his 10-year-old grandson, who had a fatal episode of hyperammonemia as his initial presentation.…”

Déficit de ornitina transcarbamilasa. Caso clínico

“…A208T, descrita en 1996 por Van Diggelen, está asociada al debut tardío y la conservación de cierta actividad enzimática residual. 8,9 Los portadores de esta mutación se encuentran en permanente riesgo de descompensación aguda y potencialmente grave ante cualquier estado hipercatabólico. Esto justifica la evolución tardía de nuestro paciente y la reflexión sobre el beneficio que hubiera supuesto haberlo diagnosticado de manera precoz.…”