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 (ϳ30%) 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. of the six enzymes and two transport proteins involved in urea biosynthesis. The specific disorders are: N-acetylglutamate synthase deficiency, carbamyl phosphate synthetase I deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase (AS) deficiency (citrullinemia), argininosuccinate lyase (AL) deficiency (argininosuccinic aciduria), arginase deficiency (argininemia), hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (or mitochondrial ornithine carrier deficiency-ORNT), and citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency-CITR). UCDs are inherited as autosomal recessive traits, except for OTC deficiency, which is X-linked. Because of the absence of nationwide newborn screening for these disorders, the true incidence of UCD is unknown. Based on case reports and data from referred patients, the estimated combined incidence for all UCDs has ranged from 1 in 8,200 to 1 in 30,000 (1,2).Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain and clinically present as recurrent episodes of hyperammonemia manifested by vomiting, lethargy, and coma. Infants with complete enzyme deficiencies (other than argininemia) commonly present in the newborn period with hyperammonemic coma. Despite aggressive treatment with hemodialysis, the mortality in the newborn period for proximal urea cycle defects (OTC deficiency and CPSI deficiency) has been reported to approach 50% (3). As reported in our previous studies, virtually all survivors have developmental disabilities that correlate with the number, severity, and duration of hyperammonemic episodes (4,5). Studies of children with neonatal UCDs have shown variable intellectual outcomes, based broadly on develop...
The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDC's accomplishments over the first six years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.
Background Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. Methods We report the results of a pivotal phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3-AUC0-24hr), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of 4 studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Results Glycerol phenylbutyrate was non-inferior to NaPBA with respect to ammonia control in the pivotal study, with mean (SD) NH3-AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing 3 similarly designed short term comparisons of glycerol phenylbutyrate versus NaPBA, NH3-AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (p<0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with slow release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning and self-monitoring, was significantly improved. Conclusions Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297).
Children who sustain severe TBI are at elevated risk for post-injury sleep problems. Because sleep problems may result in daytime impairments and family distress, additional clinical and research attention is warranted.
The current pilot study examined functional magnetic resonance imaging (fMRI) activation in children with mild traumatic brain injury (mTBI) during tasks of working memory and inhibitory control, both of which are vulnerable to impairment following mTBI. Thirteen children with symptomatic mTBI and a group of controls completed a version of the Tasks of Executive Control (TEC) during fMRI scanning. Both groups showed greater prefrontal activation in response to increased working memory load. Activation patterns did not differ between groups on the working memory aspects of the task, but children with mTBI showed greater activation in the posterior cerebellum with the addition of a demand for inhibitory control. Children with mTBI showed greater impairment on symptom report and "real world" measures of executive functioning, but not on traditional "paper and pencil" tasks. Likewise, cognitive testing did not correlate significantly with imaging results, whereas increased report of post-concussive symptoms were correlated with increased cerebellar activation. Overall, results provide some evidence for the utility of symptom report as an indicator of recovery and the hypothesis that children with mTBI may experience disrupted neural circuitry during recovery. Limitations of the study included a small sample size, wide age range, and lack of in-scanner accuracy data.
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