Abstract
BackgroundThe principal aim of this study was to investigate the long-term outcomes of a large cohort of patients with ornithine transcarbamylase deficiency (OTCD) who were followed up at a single medical center.MethodsWe analyzed clinical, biochemical and genetic parameters of 90 patients (84 families, 48 males and 42 females) with OTCD between 1971 and 2011.ResultsTwenty-seven patients (22 boys, 5 girls) had a neonatal presentation; 52 patients had an “intermediate” late-onset form of the disease (21 boys, 31 girls) that was revealed between 1 month and 16 years; and 11 patients (5 boys, 6 girls) presented in adulthood (16 to 55 years). Patients with a neonatal presentation had increased mortality (90% versus 13% in late-onset forms) and peak plasma ammonium (mean value: 960 μmol/L versus 500 μmol/L) and glutamine (mean value: 4110 μmol/L versus 1000 μmol/L) levels at diagnosis. All of the neonatal forms displayed a greater number of acute decompensations (mean value: 6.2/patient versus 2.5 and 1.4 in infants and adults, respectively). In the adult group, some patients even recently died at the time of presentation during their first episode of coma. Molecular analyses identified a deleterious mutation in 59/68 patients investigated. Single base substitutions were detected more frequently than deletions (69% and 12%, respectively), with a recurrent mutation identified in the late-onset groups (pArg40 His; 13% in infants, 57% in adults); inherited mutations represented half of the cases. The neurological score did not differ significantly between the patients who were alive in the neonatal or late-onset groups and did not correlate with the peak ammonia and plasma glutamine concentrations at diagnosis. However, in late-onset forms of the disease, ammonia levels adjusted according to the glutamine/citrulline ratio at diagnosis were borderline predictors of low IQ (p = 0.12 by logistic regression; area under the receiver operating characteristic curve of 76%, p <0.05).ConclusionsOTCD remains a severe disease, even in adult-onset patients for whom the prevention of metabolic decompensations is crucial. The combination of biochemical markers warrants further investigations to provide additional prognostic information regarding the neurological outcomes of patients with OTCD.
Highlights
Ornithine transcarbamylase deficiency (OTCD), an Xlinked disorder, is the most common urea cycle disorder (UCD) with an incidence between 1/17 000 in the USA [1] and 1/60 000 in Finland [2], whereas the overall frequency of urea cycle disorders is approximately 1 in 8000 newborns [3]
ornithine transcarbamylase deficiency (OTCD) impairs the synthesis of citrulline and urea, which leads to the accumulation of ammonium, glutamine, and other amino acids, contrasting with the low levels of citrulline and diversion of carbamoylphosphate into pyrimidine synthesis and leading to an increase in the excretion of urinary orotic acid [4]
We investigated potential correlations between plasma markers at diagnosis and survival, and we found no differences in the ammonemia or glutamine levels between patients with a neonatal presentation that survived less vs those that survived more than 1 week
Summary
Ornithine transcarbamylase deficiency (OTCD), an Xlinked disorder, is the most common urea cycle disorder (UCD) with an incidence between 1/17 000 in the USA [1] and 1/60 000 in Finland [2], whereas the overall frequency of urea cycle disorders is approximately 1 in 8000 newborns [3]. The gene encoding OTC is located on Xp21.1, and the enzyme is expressed in the liver and gut. The clinical presentation of OTCD is very heterogeneous. Affected hemizygous males usually present in the neonatal period with acute hyperammonemic coma due to a severe enzymatic deficiency, whereas the clinical severity of heterozygous affected females varies considerably, depending partially on the pattern of inactivation of the X chromosome. When the enzymatic deficiency is partial, the onset of symptoms can be delayed to childhood or adult age for males and females. The principal aim of this study was to investigate the long-term outcomes of a large cohort of patients with ornithine transcarbamylase deficiency (OTCD) who were followed up at a single medical center
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