Fatal Initial Adult-Onset Presentation of Urea Cycle Defect

Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0830, USA.
JAMA Neurology (Impact Factor: 7.42). 01/2008; 64(12):1777-9. DOI: 10.1001/archneur.64.12.1777
Source: PubMed


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.
To document the clinical and metabolic consequences of a mutation in the OTC gene.
Case reports.
A metabolic/biochemical genetic referral service.
Clinical and biochemical observations in 3 generations of a family.
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.
Diagnosis of late-onset presentations of urea cycle defect in adults may be delayed. Heightened awareness could lead to effective treatment.

2 Reads
  • Source
    • "Il faut donc connaître ces situations à risque pour prévenir une éventuelle décompensation. Étant donné la pénétrance incomplète et l'expressivité variable de cette maladie, une enquête familiale doit être entreprise [13]. Les antécédents familiaux sont inconstants. "
    La Presse Médicale 04/2014; · 1.08 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Late-onset symptoms of urea-cycle disorder may lead to a life-threatening disease which is often undetected. We report the clinical and metabolic manifestations of acute hyperammonemic encephalopathy in a 47-year-old asymptomatic man with ornithine transcarbamylase (OTC) deficiency. The hyperammonemic encephalopathy was unmasked by a high-protein Atkins diet. Genetic analysis of the patient's family, 89 unrelated Ashkenazi Jewish and 50 unrelated Europeans subjects was performed using polymerase chain reaction amplification and DNA sequencing of the OTC gene. Treatment with hemodialysis, provision of adequate calories to prevent catabolism, and protein elimination for 24h followed by protein restriction and ammonia scavenging medications effectively lowered the patient's plasma ammonia level and resulted in full recovery. Genetic analysis of the OTC gene revealed a novel hemizygous missense mutation in exon 5 (c.477T>G), leading to an isoleucine-to-methionine substitution in codon 159 (Ile159Met). Further genetic analysis of the patient's family yielded the mutation in many of them, although findings were negative in 89 unrelated Ashkenazi Jewish and 50 unrelated Europeans subjects. This is the first reported case of an adult urea-cycle defect unmasked by the Atkins diet. Measurements of serum ammonia level must be part of the basic work-up in all patients presenting with encephalopathy of unknown origin even in the absence of liver dysfunction. Awareness of this important association can contribute to prompt diagnosis and life-saving treatment. Correct diagnosis is also important to prevent future recurrences and to provide genetic counselling for family members.
    Journal of Hepatology 02/2010; 52(2):292-5. DOI:10.1016/j.jhep.2009.11.014 · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a lack of awareness of acutely presenting inborn errors of metabolism in adults, of which the X-linked urea cycle defect ornithine transcarbamylase (OTC) deficiency is an example, many comparatively mild mutations having been identified. In male hemizygotes clinical manifestations and age at presentation vary and depend on the mutation. In female heterozygotes the clinical spectrum depends on the extent to which the abnormal gene is expressed. Milder versions of the defect may not cause clear clinical symptoms and may remain unrecognized until the person is subjected to an unusually high nitrogen load when they develop severe hyperammonaemia. During acute episodes liver enzymes may be normal or only slightly elevated and occasionally accompanied by coagulopathy, but the key finding is hyperammonaemia. Boys with these milder forms may exhibit abnormal behaviour and be diagnosed with attention deficit hyperactivity disorder. This case illustrates how late presentation of OTC deficiency in a non-specialist centre can be difficult to differentiate from drug abuse, psychiatric illness or encephalopathy. Failure to measure blood ammonia in adults with unexplained key symptoms - particularly prolonged vomiting without diarrhoea and altered mental state/hallucinations, or to recognize the significance of elevated blood ammonia without evidence of liver decompensation can lead to delayed or missed diagnosis.
    Annals of Clinical Biochemistry 05/2010; 47(Pt 3):279-81. DOI:10.1258/acb.2010.009250 · 2.34 Impact Factor
Show more