Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders.

Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA.
Pediatric Research (Impact Factor: 2.84). 04/2009; 66(1):96-101. DOI: 10.1203/PDR.0b013e3181a27a16
Source: PubMed

ABSTRACT Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain and result in high rates of mortality and neurodevelopmental disability. This study seeks to characterize the cognitive, adaptive, and emotional/behavioral functioning of children with urea cycle disorders (UCDs). These domains were measured through testing and parent questionnaires in 92 children with UCDs [33 neonatal onset (NO), 59 late onset (LO)]. Results indicate that children who present with NO have poorer outcome than those who present later in childhood. Approximately half of the children with NO performed in the range of intellectual disability (ID), including a substantial number ( approximately 30%) who were severely impaired. In comparison, only a quarter of the LO group was in the range of ID. There is also evidence that the UCD group has difficulties in aspects of emotional/behavioral and executive skills domains. In conclusion, children with UCDs present with a wide spectrum of cognitive outcomes. Children with NO disease have a much higher likelihood of having an ID, which becomes even more evident with increasing age. However, even children with LO UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning.

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    ABSTRACT: Background In recent decades, considerable progress in diagnosis and treatment of patients with intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders (UCD), organic acidurias (OA), maple syrup urine disease (MSUD), or tyrosinemia type 1 (TYR 1) has resulted in a growing group of long-term survivors. However, IT-IEM still require intense patient and caregiver effort in terms of strict dietetic and pharmacological treatment, and the threat of metabolic crises is always present. Furthermore, crises can affect the central nervous system (CNS), leading to cognitive, behavioural and psychiatric sequelae. Consequently, the well-being of the patients warrants consideration from both a medical and a psychosocial viewpoint by assessing health-related quality of life (HrQoL), psychological adjustment, and adaptive functioning. To date, an overview of findings on these topics for IT-IEM is lacking. We therefore aimed to systematically review the research on HrQoL, psychological adjustment, and adaptive functioning in patients with IT-IEM.Methods Relevant databases were searched with predefined keywords. Study selection was conducted in two steps based on predefined criteria. Two independent reviewers completed the selection and data extraction.ResultsEleven articles met the inclusion criteria. Studies were of varying methodological quality and used different assessment measures. Findings on HrQoL were inconsistent, with some showing lower and others showing higher or equal HrQoL for IT-IEM patients compared to norms. Findings on psychological adjustment and adaptive functioning were more consistent, showing mostly either no difference or worse adjustment of IT-IEM patients compared to norms. Single medical risk factors for HrQoL, psychological adjustment, or adaptive functioning have been addressed, while psychosocial risk factors have not been addressed.Conclusion Data on HrQoL, psychological adjustment, and adaptive functioning for IT-IEM are sparse. Studies are inconsistent in their methodological approaches, assessment instruments and norm populations. A disease-specific standard assessment procedure for HrQoL is not available. Psychosocial risk factors for HrQoL, psychological adjustment, or adaptive functioning have not been investigated. Considering psychosocial variables and their corresponding risk factors for IT-IEM would allow evaluation of outcomes and treatments as well as the planning of effective social and psychological interventions to enhance the patients¿ HrQoL.
    Orphanet Journal of Rare Diseases 10/2014; 9(1):159. DOI:10.1186/s13023-014-0159-8 · 3.96 Impact Factor
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    ABSTRACT: Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans.
    PLoS ONE 02/2015; 10(2):e0116594. DOI:10.1371/journal.pone.0116594 · 3.53 Impact Factor
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    ABSTRACT: The Urea Cycle Disorders Consortium (UCDC) is a member of the NIH funded Rare Diseases Clinical Research Network and is performing a longitudinal study of 8 urea cycle disorders (UCDs) with initial enrollment beginning in 2006. The consortium consists of 14 sites in the U.S., Canada and Europe. This report summarizes data mining studies of 614 patients with UCDs enrolled in the UCDC's longitudinal study protocol. The most common disorder is ornithine transcarbamylase deficiency, accounting for more than half of the participants. We calculated the overall prevalence of urea cycle disorders to be 1/35,000, with 2/3rds presenting initial symptoms after the newborn period. We found the mortality rate to be 24% in neonatal onset cases and 11% in late onset cases. The most common precipitant of clinical hyperammonemic episodes in the post-neonatal period was intercurrent infections. Elevations in both blood ammonia and glutamine appeared to be biomarkers for neurocognitive outcome. In terms of chronic treatment, low protein diet appeared to result in normal weight but decreased linear growth while N-scavenger therapy with phenylbutyrate resulted in low levels of branched chain amino acids. Finally, we found an unexpectedly high risk for hepatic dysfunction in patients with ornithine transcarbamylase deficiency. This natural history study illustrates how a collaborative study of a rare genetic disorder can result in an improved understanding of morbidity and disease outcome.
    Molecular Genetics and Metabolism 08/2014; 113(1-2). DOI:10.1016/j.ymgme.2014.08.001 · 2.83 Impact Factor

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