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

Brassier A, Gobin S, Arnoux JB, Valayannopoulos V, Habarou F, Kossorotoff M, Servais A, Barbier V, Dubois S, Touati G, Barouki R, Lesage F, Dupic L, Bonnefont JP, Ottolenghi C, De Lonlay P - Orphanet J Rare Dis (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Reference Center of Inherited Metabolic Diseases and units of metabolism and neurology, 149 rue de Sèvres, 75015, Paris, France. anais.brassier@nck.aphp.fr.

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.

No MeSH data available.


Related in: MedlinePlus

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).
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Fig3: 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).

Mentions: The mean peak of ammonemia at diagnosis was much higher in the neonatal group after the exclusion of the patients who were diagnosed antenatally (mean value = 960 μmol/L and median value = 925 μmol/L) than in the pooled late-onset groups (mean value = 500 μmol/L and median value = 240 μmol/L). The plasma glutamine levels at diagnosis correlated with the ammonia levels and were much higher in the neonatal group (mean and median values = 4110 μmol/L) than in the late-onset groups (mean and median values = 1000 μmol/L) Figure 3. The degree of plasma citrulline depletion was more marked than that of plasma arginine in all of the patients (data not shown). The plasma concentration of citrulline was lower in the neonatal group (median value = 5 μmol/L and undetectable in 8 patients) than in the late-onset groups (median values = 15 μmol/L in patients in the 1 month – 16 year group and 14 μmol/L in patients in the greater than 16 year group). There was no correlation between the biochemical parameters at diagnosis (plasma ammonia, glutamine and citrulline) and the neurological outcome in the 1 m-16 y group (Figure 4a). Therefore, in patients with the late-onset form (1 mth-16 y), we attempted to combine three relevant biomarkers into a predictive score by regressing the plasma ammonia levels on the glutamine/citrulline ratio (intended as a better indicator of the glutamine response to ammonia rather than to other factors such as the fasting time). The resulting residuals can be rationalized as the among-patient variation of ammonemia relative to the glutamine levels, with higher values representing a reduced capacity to incorporate ammonemia into glutamine. The values for this score at diagnosis were borderline predictive of IQ, with an odds ratio of 3.3 (0.7 -14.5; p = 0.12) and area under the receiver operating characteristic curve of 76% (p < 0.05; Figure 4b).Figure 3


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

Brassier A, Gobin S, Arnoux JB, Valayannopoulos V, Habarou F, Kossorotoff M, Servais A, Barbier V, Dubois S, Touati G, Barouki R, Lesage F, Dupic L, Bonnefont JP, Ottolenghi C, De Lonlay P - Orphanet J Rare Dis (2015)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4443534&req=5

Fig3: 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).
Mentions: The mean peak of ammonemia at diagnosis was much higher in the neonatal group after the exclusion of the patients who were diagnosed antenatally (mean value = 960 μmol/L and median value = 925 μmol/L) than in the pooled late-onset groups (mean value = 500 μmol/L and median value = 240 μmol/L). The plasma glutamine levels at diagnosis correlated with the ammonia levels and were much higher in the neonatal group (mean and median values = 4110 μmol/L) than in the late-onset groups (mean and median values = 1000 μmol/L) Figure 3. The degree of plasma citrulline depletion was more marked than that of plasma arginine in all of the patients (data not shown). The plasma concentration of citrulline was lower in the neonatal group (median value = 5 μmol/L and undetectable in 8 patients) than in the late-onset groups (median values = 15 μmol/L in patients in the 1 month – 16 year group and 14 μmol/L in patients in the greater than 16 year group). There was no correlation between the biochemical parameters at diagnosis (plasma ammonia, glutamine and citrulline) and the neurological outcome in the 1 m-16 y group (Figure 4a). Therefore, in patients with the late-onset form (1 mth-16 y), we attempted to combine three relevant biomarkers into a predictive score by regressing the plasma ammonia levels on the glutamine/citrulline ratio (intended as a better indicator of the glutamine response to ammonia rather than to other factors such as the fasting time). The resulting residuals can be rationalized as the among-patient variation of ammonemia relative to the glutamine levels, with higher values representing a reduced capacity to incorporate ammonemia into glutamine. The values for this score at diagnosis were borderline predictive of IQ, with an odds ratio of 3.3 (0.7 -14.5; p = 0.12) and area under the receiver operating characteristic curve of 76% (p < 0.05; Figure 4b).Figure 3

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Reference Center of Inherited Metabolic Diseases and units of metabolism and neurology, 149 rue de Sèvres, 75015, Paris, France. anais.brassier@nck.aphp.fr.

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.

No MeSH data available.


Related in: MedlinePlus