Requirement of argininosuccinate lyase for systemic nitric oxide production

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases

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

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. The current 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, 59 late onset). Results indicate that children who present with neonatal onset have poorer outcome than those who present later in childhood. Approximately half of the children with neonatal onset performed in the range of intellectual disability (ID), including a substantial number (~30%) who were severely impaired. In comparison, only a quarter of the late onset group were 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 neonatal onset disease have a much higher likelihood of having an intellectual disability, which becomes even more evident with increasing age. However, even children with late onset UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning

Brief report: Parental report of sleep behaviors following moderate or severe pediatric traumatic brain injury

OBJECTIVE: Determine the effect of moderate and severe traumatic brain injuries (TBI) on the sleep of school-aged children. METHODS: A concurrent cohort-prospective design compared children aged 6–12 years who sustained moderate TBI (baseline n=56), severe TBI (n= 53), or only orthopedic injuries (n= 80). Retrospective parental report of pre-injury sleep was collected about 3 weeks post-injury. Post-injury assessments occurred prospectively a mean of 6, 12, and 48 months later. RESULTS: Growth curve analyses compared the groups over time. The moderate TBI group had worse pre-injury sleep than the other groups. The moderate TBI and orthopedic injury groups displayed a small decline in sleep problems from pre- to post-injury. Children with severe TBI displayed increased post-injury sleep problems. CONCLUSIONS: 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

Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors.

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

Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium

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 6years, 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

Intellectual, Adaptive, and Behavioral Functioning in Children With Urea Cycle Disorders

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. The current 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, 59 late onset). Results indicate that children who present with neonatal onset have poorer outcome than those who present later in childhood. Approximately half of the children with neonatal onset performed in the range of intellectual disability (ID), including a substantial number (~30%) who were severely impaired. In comparison, only a quarter of the late onset group were 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 neonatal onset disease have a much higher likelihood of having an intellectual disability, which becomes even more evident with increasing age. However, even children with late onset UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning