Fatal Initial Adult-Onset Presentation of Urea Cycle Defect

Abstract

Background: Ornithine transcarbamylase (OTC) deficiency presents most commonly with neonatal hyperammonemic coma. The gene is on the X chromosome, but the disease may manifest as a dominant trait. Mutations that lead to later-onset presentations may lead to life-threatening disease and may be unrecognized, particularly when the first clinical disease occurs in adulthood. Objective: To document the clinical and metabolic consequences of a mutation in the OTC gene. Design: Case reports. Setting: A metabolic/biochemical genetic referral service. Main Outcome Measures: Clinical and biochemical observations in 3 generations of a family. Results: A mutation in codon 208 of exon 6 in the OTC gene was found in a family in which the proband died of hyperammonemia at 52 years of age. Conclusions: Diagnosis of late-onset presentations of urea cycle defect in adults may be delayed. Heightened awareness could lead to effective treatment.

Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins’ diet

“…The present report is of great clinical importance because late-onset presentations of urea-cycle disorders often go unrecognized and may be life-threatening [5][6][7]. Early symptoms of confusion or neurological manifestations such as seizures may be followed by cerebral oedema and herniation.…”

“…The phenotype is extremely heterogeneous, ranging from complete absence of symptoms in hemizygous males who might become symptomatic only much later in life [5][6][7] to acute neonatal hyperammonemic coma. Researchers hypothesize that complete OCT deficiency is associated with neonatal disease and partial deficiency, with late-onset presentations.…”

“…Biochemical abnormalities include hyperammonemia, elevated plasma levels of glutamine, decreased level of citrulline and orotic aciduria [8]. Individuals who have mild molecular urea-cycle disorders can lead a relatively normal life until a severe environmental stress, such as infections, surgery, pregnancy or high-dose steroids trigger a hyperammonemic crisis [5][6][7]. The prompt recognition and treatment of such crises are essential for a good outcome.…”

A Case of Suspected Urea Cycle Dysfunction in a Patient with Unexplained Hyperammonemia

“…More than 340 mutations have been identified in families in which there was clinical OTC deficiency. 9 A patient with CPS I deficiency (autosomal recessive) would likely demonstrate mutation of the CPS I gene. Although the mutation was not detected in the liver biopsy of our patient, this condition cannot be excluded, as altered transcriptional regulation of CPS I expression by polymorphisms is possible and the genetic testing does not detect large heterozygous deletions, duplications, or mutations within the promoter or deep intronic regions.…”

Clinical Reasoning: A 27-year-old man with rapidly progressive coma

“…The disease tends to affect neonatal boys severely; however, adult-onset disease has been described. 3 In hyperammonemic crisis, rapidly progressive encephalopathy with signs of raised intracranial pressure is its most severe phenotype. Neurologic manifestations are common and include myoclonus, 4 seizure, and status epilepticus, among other signs of cortical dysfunction.…”