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Neuropsychological attributes of urea cycle disorders: A systematic review of the literature.

ABSTRACT: Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35?000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the eight UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and compared for each UCD. Since diagnoses for UCDs tended to occur earlier and better treatments became more readily available after the turn of the century, this assessment will characterize the extent that current management strategies have improved neuropsychological outcomes. The pooled sample included data on cognitive abilities of 1649 individuals reported in 58 citations. A total of 556 patients (34%) functioned in the range of intellectual disabilities. The decline in the proportion of intellectual disabilities in six disorders, ranged from 7% to 41%. Results from various studies differed and the cohorts varied with respect to age at symptom onset, age at diagnosis and treatment initiation, current age, severity of the metabolic deficiency, management strategies, and ethnic origins. The proportion of cases with intellectual disabilities ranged from 9% to 65% after 2000 in the seven UCDs associated with cognitive deficits. Positive outcomes from some studies suggest that it is possible to prevent or reverse the adverse impact of UCDs on neuropsychological functioning. It is time to "raise the bar" in terms of expectations for treatment effectiveness.

SUBMITTER: Waisbren SE

PROVIDER: S-EPMC7250134 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Neuropsychological attributes of urea cycle disorders: A systematic review of the literature.

Waisbren Susan E SE Stefanatos Arianna K AK Kok Teresa M Y TMY Ozturk-Hismi Burcu B

Journal of inherited metabolic disease 20190801 6

Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35 000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the eight UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and c ...[more]

PMID: 31268178

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Project description:Urea cycle disorders are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia. Clinical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synthesis and urea cycle-specific nitrogen flux would correlate with both phenotypic severity and carrier status in patients with a variety of different enzymatic deficiencies of the urea cycle. We studied control subjects, patients, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet. On a separate occasion the subjects either received a higher protein intake or were treated with an alternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources was determined from [(18)O]urea labeling, and the utilization of peripheral nitrogen was estimated from the relative isotopic enrichments of [(15)N]urea and [(15)N]glutamine during i.v. co-infusions of [5-(amide)(15)N]glutamine and [(18)O]urea. The ratio of the isotopic enrichments of (15)N-urea/(15)N-glutamine distinguished normal control subjects (ratio = 0.42 +/- 0.06) from urea cycle patients with late (0.17 +/- 0.03) and neonatal (0.003 +/- 0.007) presentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0. 22 +/- 0.03), argininosuccinate lyase deficiency (0.35 +/- 0.11), and partial ornithine transcarbamylase deficiency (0.26 +/- 0.06) from normal controls. Administration of Ucephan lowered, and arginine increased, urea synthesis to the degree predicted from their respective rates of metabolism. The (15)N-urea/(15)N-glutamine ratio is a sensitive index of in vivo urea cycle activity and correlates with clinical severity. Urea synthesis is altered by alternative route medications and arginine supplementation to the degree that is to be expected from theory. This stable isotope protocol provides a sensitive tool for evaluating the efficacy of therapeutic modalities and acts as an aid to the diagnosis and management of urea cycle patients.

Project description:BackgroundTreatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes.ResultsOverall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions.ConclusionsThis study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations.

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Neuropsychological attributes of urea cycle disorders: A systematic review of the literature.

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Neuropsychological attributes of urea cycle disorders: A systematic review of the literature.

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