Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation

Abstract

A large family with ornithine transcarbamylase deficiency due to mutation R141Q was ascertained through a propositus who presented with acute neonatal hyperammonemic coma. Of 13 females at risk, 11 were evaluated clinically and had laboratory studies performed. Seven were found to be heterozygous for the mutation. Of these seven, five had chronic clinical symptoms and two were asymptomatic. None of the heterozygotes had elevated plasma ammonia on random testing. Of the five symptomatic females, three had markedly elevated plasma glutamine levels on random testing, while two had levels in the upper range of normal. Plasma citrulline and arginine levels were somewhat lower in the symptomatic individuals but still within the normal range. Five heterozygotes who were tested had either spontaneous orotic aciduria or elevated orotic acid following ingestion of allopurinol, whereas one unaffected female and one unaffected male had normal allopurinol tests. A higher than expected proportion of female heterozygous for the R141Q mutation were clinically and biochemically symptomatic but remained undiagnosed for many years. Plasma glutamine determination and allopurinol testing should be performed in females who present with a combination of relatively non-specific symptoms detailed in this report.

Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision

“…Postpartum coma has been reported as a first manifestation in females with partial OTCD, CPS1D, and ASSD . Manifestations of partial UCDs can vary among individuals having the same mutant genotype, exemplified best with partial OTCD and CPS1D in different members of the same family …”

“…[62][63][64] Manifestations of partial UCDs can vary among individuals having the same mutant genotype, exemplified best with partial OTCD and CPS1D in different members of the same family. [65][66][67] The family history may indicate X-linked inheritance for OTCD and show consanguinity in other UCDs, all of which are autosomal recessive conditions. It is mandatory with suspected UCD patients to take a careful medical history, investigating the occurrence in the family of unexplained neonatal deaths, of neurological disorders, or of protein avoidance, and asking about drug intake by the patient.…”

The Diagnosis and Management of Ornithine Transcarbamylase Deficiency in Pregnancy: A Case Report

“…[5] Diagnosis may be late as symptoms in some heterozygote patients are non-specific. [6] The general purposes of the treatment in urea cycle disorders are to fix biochemical disorder and to provide body balance by meeting nutrition requirements. It is aimed to keep plasma ammoniac levels below 80 micromole/L and plasma glutamine levels below 800 micromole/L and essential amino acids at normal levels.…”

Neuropsychiatric Manifestations in Late-Onset Urea Cycle Disorder Patients

“…1 Among heterozygous females with ornithine transcarbamylase deficiency, mental retardation has been widely investigated. 2,3 Other neuropsychiatric traits, such as autism and psychotic signs, have been described as the first manifestation of urea cycle disorders, mainly in the reporting of single cases. 4,5 In the current study, we review a series of patients with late-onset urea cycle disorder to highlight neuropsychiatric/neurodevelopmental symptoms as initial manifestations among this group, with the aim of increasing awareness among physicians.…”