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
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.
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.
Available from: Jean-Marie Tonnelier
- "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 . Les antécédents familiaux sont inconstants. "
Available from: Jean-Marc Nuoffer
- "The phenotype is extremely heterogeneous, ranging from complete absence of symptoms in hemizygous males who might become symptomatic only much later in life    to acute neonatal hyperammonemic coma. Researchers hypothesize that complete OCT deficiency is associated with neonatal disease and partial deficiency, with late-onset presentations. "
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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.
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ABSTRACT: Significant advances in the understanding of the biochemical and molecular basis of inherited metabolic disorders have led to major improvements in their diagnosis, management, and treatment. With expansion of newborn screening and identification of children prior to their initial crisis, there is hope for a more optimistic outcome for the individuals with inherited metabolic disorders. Individual diet management is central to the treatment of most metabolic disorders. This article reviews the basic principles of management and steps necessary to minimize the frequency, duration, and severity of catabolic crisis in infants and children, with an emphasis on the use of total parenteral nutrition.
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