Long-term outcomes in Ornithine Transcarbamylase deficiency: a series of 90 patients

Abstract

Background: 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.

Methods: We analyzed clinical, biochemical and genetic parameters of 90 patients (84 families, 48 males and 42 females) with OTCD between 1971 and 2011.

Results: Twenty-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).

Conclusions: OTCD 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.

Figure 1

Survival of OTCD patients by age of onset. Comparison of survival between the 1 mth-16 y and neonatal group. In the 1 mth-16 y group, the “critical” period (risk of death) is that between the first severe symptoms and diagnosis. In the neonatal form, there are two high-risk age intervals: the first days of life and the period between 1 and 7 years of age.

Figure 2

Age at diagnosis, length of follow-up, and mortality in the 1 mth-16 y group. A peak of mortality was noted approaching and during adolescence.

Figure 3

Comparison of biochemical parameters at diagnosis (plasma ammonemia, plasma glutamine and urinary orotic acid) in the neonatal group versus the late-onset groups (1 mth-16 y and >16 y groups).

Figure 4

Initial plasma markers (plasma ammonemia, glutamine and citrulline) compared to the control group and cognitive outcome in the 1 mth-16 y group. Cognitive outcome was based on an IQ < 80 or >80, revealing extensive overlap of the values among patients with different outcomes. a: Individual markers shown separately (in μM). b: A combined score based on ammonia, glutamine and citrulline levels at diagnosis as a borderline predictor of IQ in the 1 mth-16 y group (see text).

Figure 5

Biochemical markers in the different groups of patients with different clinical forms based on age at diagnosis as indicated. a: Plasma ammonia in μM. b: Plasma glutamine in μM. Red circles indicate female patients, and blue circles are male patients. The boxed color codes are approximate indications of the clinical severity (blue: moderate; yellow: severe; red: early severe).

Figure 6

Biplot of CSF (Y-axis) vs plasma (X-axis) glutamine in paired samples from our hospital cohort (bilog transformation). Empty circles are the reference hospital population, and colored circles represent urea cycle disorders as indicated. The black solid line is the regression line for urea cycle disorder, the blue solid line is the regression line for the reference population (calculated based on samples with CSF glutamine levels less than 1000 μM), and the dotted line is the theoretical equality line between the CSF and plasma.