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.

This study examined the effect of traumatic brain injury (TBI) in young children on sleep problems and the relationship of sleep problems to neuropsychological and psychosocial functioning. Participants were drawn from an ongoing longitudinal study of injury in young children recruited from 3 to 6 years of age. They constituted three groups: orthopedic injury (OI; n = 92), complicated mild/moderate TBI (mTBI; n = 55); and severe TBI (sTBI; n = 20). Caregivers completed the Children's Sleep Habits Questionnaire (CSHQ), as well as ratings of behavioral adjustment, adaptive functioning, and everyday executive function at 1, 6, 12, and 18 months postinjury. Retrospective ratings of preinjury sleep and psychosocial functioning were obtained at the initial assessment. Children completed neuropsychological testing at all occasions. Children with complicated mTBI demonstrated more total sleep problems than children with OI at 6 months postinjury, but not at 12 or 18 months. Children with sTBI displayed more bedtime resistance and shorter sleep duration than those with complicated mTBI or OI at several occasions. Across groups, total sleep problems predicted more emotional and behavioral problems and worse everyday executive function as rated by parents across follow-up occasions. In contrast, sleep problems were generally not related to neuropsychological test performance. The results suggest that young children with TBI demonstrate more sleep problems than children with injuries not involving the head. Sleep problems, in turn, significantly increase the risk of poor psychosocial outcomes across time, but are not associated with worse neuropsychological test performance.

Objective To compare the clinical course and outcome of patients diagnosed with one of four neonatal onset urea cycle disorders (UCDs), carbamyl phosphate synthase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthase (AS) or argininosuccinate lyase (AL) deficiency. Study design Clinical, biochemical, and neuropsychological data from 103 subjects with neonatal onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorder Consortium, one of the Rare Disease Clinical Research Networks. Results 88% of subjects presented clinically by age 7 days. Peak ammonia level was 963μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. 25% of subjects with CPSD/OTCD, 18% with ASD, and 67% with ALD had a honeymoon period, defined as time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/DQ < 70) was greatest in ALD (68%), followed by ASD (54%) and CPSD/OTCD (47%). This trend was not significant, but was observed in both the under age 4 years and 4 years and older category. Poor cognitive outcome did not correlate with peak ammonia level or length of initial admission. Conclusions Neurocognitive outcomes do not differ between those with proximal and distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal urea cycle disorders.

Objective To compare Executive Functioning (EF) profiles across several pediatric medical conditions and explored the influence of age of diagnosis and evaluation. Methods This was a retrospective, cross sectional study of 734 children ages 5-18 across five medical groups [brain tumor, leukemia (ALL), epilepsy (EPI), Neurofibromatosis Type 1 (NF1), and Ornithine Transcarbamylase Deficiency (OTC-D)], ADHD controls, and matched healthy controls. We compared groups across the subscales of a parent completed Behavior Rating Inventory of Executive Functioning (BRIEF) using MANOVA. Separate MANOVAs were conducted to look at age factors. Results The ADHD group differed from all other groups and had the highest level of reported EF problems. The NF1 and OTC-D groups differed significantly from the healthy comparison group for overall EF problems, while the EPI and cancer groups did not. Working Memory was the most elevated subscale across medical groups, followed by Plan/Organize. Children with medical disorders were two to four times as likely as healthy controls to have clinically significant problems in several EF domains. There was a main effect for age at diagnosis and age at evaluation.. Conclusions A subset of children with medical disorders were found to have parent reported EF difficulties, with particular vulnerability noted in working memory and organizational/planning skills. This has relevance for the development of interventions that may be helpful across disorders. Children with particular diagnoses and earlier age of diagnosis and evaluation had greater reported EF problems.