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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

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.
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Fig1: 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.

Mentions: Mortality was much higher in the neonatal group (20/27 or 74% deceased at diagnosis or during follow-up) than in the late-onset forms (8/63 or 13% deceased overall, p < 0.0001; cf Figure 1). In fact, mortality reached 90% in the neonatal-onset group when the 6 patients diagnosed antenatally were removed from this group. As summarized in Table 1, in the neonatal group, 13 patients died early in the neonatal period; 3 died after postoperative liver transplantation at 3.5 years of age; 1 died of Reye syndrome at 4 years of age; and 3 died after infection with neurological signs and coma, and psychiatric signs in one patient, at ages 2, 6, and 7 years. To summarize, 60% of the cases with a neonatal presentation died at presentation, and 75% of the survivors subsequently died between 1 and 7 years of age. In the late-onset forms of the disease, 6 patients died at presentation during the first acute metabolic crisis between 9.3 and 55 years; 1 girl died at 12 years of age with a diagnosis of fibrolamellar hepatocellular carcinoma that was resistant to chemotherapy (her OTCD was diagnosed at age 11); and 1 girl died at 4 months of age after an infection that led to a hyperammonemic coma. This result indicates that for the late-onset form, deaths were rare during infancy, whereas a peak in mortality occurred at adolescence (9-14 years) in the 1 mth-16 y group (Figure 2; Fisher’s exact test, p < 0.01).Figure 1


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)

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

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

Fig1: 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.
Mentions: Mortality was much higher in the neonatal group (20/27 or 74% deceased at diagnosis or during follow-up) than in the late-onset forms (8/63 or 13% deceased overall, p < 0.0001; cf Figure 1). In fact, mortality reached 90% in the neonatal-onset group when the 6 patients diagnosed antenatally were removed from this group. As summarized in Table 1, in the neonatal group, 13 patients died early in the neonatal period; 3 died after postoperative liver transplantation at 3.5 years of age; 1 died of Reye syndrome at 4 years of age; and 3 died after infection with neurological signs and coma, and psychiatric signs in one patient, at ages 2, 6, and 7 years. To summarize, 60% of the cases with a neonatal presentation died at presentation, and 75% of the survivors subsequently died between 1 and 7 years of age. In the late-onset forms of the disease, 6 patients died at presentation during the first acute metabolic crisis between 9.3 and 55 years; 1 girl died at 12 years of age with a diagnosis of fibrolamellar hepatocellular carcinoma that was resistant to chemotherapy (her OTCD was diagnosed at age 11); and 1 girl died at 4 months of age after an infection that led to a hyperammonemic coma. This result indicates that for the late-onset form, deaths were rare during infancy, whereas a peak in mortality occurred at adolescence (9-14 years) in the 1 mth-16 y group (Figure 2; Fisher’s exact test, p < 0.01).Figure 1

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