Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis.

OBJECT: Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model. METHODS: HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression. RESULTS: Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease. CONCLUSIONS: This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders.

Attention-deficit/hyperactivity disorder symptoms, adaptive functioning, and quality of life in children with autism spectrum disorder.

OBJECTIVE: The purpose of the current study was to evaluate the frequency of co-occurring attention-deficit/hyperactivity disorder (ADHD) symptoms in a well-defined cohort of children with autism spectrum disorders (ASDs) and to examine the relationship between ADHD symptoms and both adaptive functioning and health-related quality of life as reported by parents or other primary caregivers. METHODS: T scores on 2 ADHD-related scales from the Child Behavior Checklist were used to indicate the presence of ADHD symptoms. Participants were divided into groups based on whether their parents/caregivers rated them as having clinically significant T scores on the Attention Problem and Attention Deficit Hyperactivity Problem subscales. Standard scores from the Vineland Adaptive Behavior Scales, Second Edition and raw scores from the Pediatric Quality of Life Inventory were then compared between groups with the use of multivariate analyses. RESULTS: Approximately 40% of participants had 1 elevated T score, and 19% had both ADHD-related T scores elevated on the Child Behavior Checklist. The ASD + ADHD group had lower scores on the Vineland Adaptive Behavior Scales, Second Edition and the Pediatric Quality of Life Inventory in comparison with the ASD alone group. CONCLUSIONS: Results suggest greater impairment in adaptive functioning and a poorer health-related quality of life for children with ASDs and clinically significant ADHD symptoms in comparison with children with ASDs and fewer ADHD symptoms. Physicians are encouraged to evaluate for the presence of ADHD symptoms in their patients with ASDs and, if present, include symptom treatment in the overall care plan.

The relationship between sleep problems and daytime behavior in children of different ages with autism spectrum disorders.

BACKGROUND: The purpose of the current study was to evaluate the relationships among sleep problems and daytime behaviors in a large, well-defined cohort of children with autism spectrum disorder (ASD). METHODS: Out of a registry population of 3452 children with ASDs, a subset of 1193 children aged 4 to 10 years of age from 14 centers across the country was used to evaluate the relationship between varying levels of sleep problems and daytime behavior. Measures included Children's Sleep Habits Questionnaire, Vineland Adaptive Behavior Scales, Survey Interview Form, Second Edition, and Child Behavior Checklist. Multiple analysis of covariance was used to assess the association between sleep and behavior. RESULTS: Results suggest that sleep problems, as identified by parent report by use of the Children's Sleep Habits Questionnaire, have a negative relationship with daytime behavior. More specifically, children with ASDs and sleep problems had more internalizing and externalizing behavior problems, as measured by the Child Behavior Checklist, and poorer adaptive skill development, as measured by the Vineland Adaptive Behavior Scales, than children with ASDs and no sleep problems. Children with moderate to severe sleep problems had greater behavior difficulties, but not necessarily poorer adaptive functioning, than children with mild to moderate sleep problems. Both preschool- and school-aged children demonstrated a negative relationship between behavior and sleep, whereas the relationship between sleep and adaptive functioning was much more variable. CONCLUSIONS: These results suggest that, although sleep has a negative relationship with internalizing and externalizing behavior, it may have a different relationship with the acquisition of adaptive skills.

Which DSM-IV-TR criteria best differentiate high-functioning autism spectrum disorder from ADHD and anxiety disorders in older children?

Diagnosis of autism spectrum disorder (ASD) is often delayed in high-functioning children with milder and more varied forms of ASD. The substantial overlap between ASD and other psychiatric disorders is thought to contribute to this delay. This study examined the endorsement of DSM-IV-TR diagnostic criteria for ASD based on semi-structured parent interviews across three groups of older children referred to an ASD clinic: 55 children diagnosed with high-functioning ASD, 27 children diagnosed with attention-deficit/hyperactivity disorder (ADHD), and 23 children diagnosed with anxiety disorder. Results indicate that the criteria within the domains of communication and social relatedness were largely able to discriminate the high-functioning ASD group from the ADHD and anxiety disorder groups, but criteria within the domain of restricted/repetitive/stereotyped patterns were not.

Sex differences in autism spectrum disorder: an examination of developmental functioning, autistic symptoms, and coexisting behavior problems in toddlers.

Little is known about the female presentation of autism spectrum disorder (ASD) during early childhood. We investigated sex differences in developmental profiles using the Mullen Scales of Early Learning, autistic symptoms on the ADOS-G, and coexisting behavior problems on the CBCL in 157 boys and 42 girls with ASD aged 1.5-3.9 years. Overall, boys and girls evidenced a markedly similar pattern of developmental profiles, autism symptoms, and coexisting behavior problems, although subtle differences exist. Boys and girls evidenced a similar pattern of developmental strengths and weaknesses. Girls with ASD evidenced greater communication deficits than boys and boys evidenced more restricted, repetitive, and stereotyped behavior than girls. Girls exhibited more sleep problems and anxious or depressed affect than boys.

Does parent report of behavior differ across ADOS-G classifications: analysis of scores from the CBCL and GARS.

Behavior checklists are often utilized to screen for Autism Spectrum Disorders (ASDs) when comprehensive evaluations are unfeasible. The usefulness of two behavioral checklists, the Gilliam Autism Rating Scale (GARS) and Child Behavior Checklist (CBCL), in identifying ASDs was investigated among 109 children with Autism, 32 children with ASD, and 51 Non-Spectrum children based on Autism Diagnostic Observation Schedule-Generic classifications. The GARS did not distinguish children with ASDs from those without. The Withdrawn and Pervasive Developmental Problems subscales of the CBCL were higher among children with Autism than among Non-Spectrum children. These CBCL subscales also had better sensitivity and specificity in identifying children with Autism than the GARS. Results suggest that the CBCL is a useful behavioral checklist for screening ASDs.

The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive condition caused by a defect in cholesterol synthesis. Affected children often have malformations and mental retardation. Autistic behaviors also are evident. The purpose of the present study was to determine the prevalence of autism spectrum disorders (ASDs) in children with SLOS. Fourteen children, 3-16 years old, were evaluated using three different methods to document autistic symptoms: (a) parent interview, (b) direct observation, and (c) a behavior checklist. Blood sterols were also measured at regular intervals. Each subject was determined to have Autistic Disorder, Pervasive Developmental Disorder, not otherwise specified (PDD NOS), or no diagnosis on the autism spectrum, based on DSM-IV criteria. Correlations among variables were calculated, and blood sterol levels were compared between diagnostic groups. Approximately three-fourths of the children with SLOS (71-86% depending on the evaluation method) had an ASD, about 50% diagnosed with Autistic Disorder and the rest with PDD NOS. The children's baseline cholesterol, 7-dehydrocholesterol (7-DHC), and 8-dehydrocholesterol (8-DHC) levels, and cholesterol levels following supplementation did not correlate with the presence or severity of autistic symptoms. These results suggest that most children with SLOS have some variant of autism. SLOS appears to have the most consistent relationship with autism of any single gene disorder. Therefore, a link between cholesterol metabolism and autism is suggested. With further study, these findings, together with knowledge of the genetic and biochemical defects in SLOS, will likely provide valuable insights into the causes of autism in general.

Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome.

OBJECTIVE: Smith-Lemli-Opitz syndrome (SLOS) results in multiple malformations, growth deficiency, and mental retardation. Cholesterol supplementation has been used for several years to treat symptoms of SLOS. We assessed the developmental progress of children and adolescents with SLOS over a 6-year period. STUDY DESIGN: Patients with SLOS (n=14) received continuous cholesterol supplementation as part of a longitudinal study. Assessment of their developmental progress in the areas of cognitive, motor, and adaptive skills occurred every 6 to 12 months. The progress of each subject over time and the progress of the group as a whole were analyzed by using a repeated-measures design and multiple t tests. RESULTS: Developmental quotients did not improve over time for children with SLOS receiving cholesterol. In addition, baseline cholesterol levels, rather than age when supplementation began or increase in cholesterol levels, best predicted developmental outcome. CONCLUSIONS: These results suggest that cholesterol supplementation in its current form does not improve the developmental progress of children and adolescents with SLOS.