Interdependence of clinical factors predicting cognition in children with tuberous sclerosis complex

Cognitive development in patients with tuberous sclerosis complex is highly variable. Predictors in the infant years would be valuable to counsel parents and to support development. The aim of this study was to confirm factors that have been reported to be independently correlated with cognitive development. 102 patients included in this study were treated at the ENCORE-TSC expertise center of the Erasmus Medical Center-Sophia Children’s Hospital. Data from the first 24 months of life were used, including details on epilepsy, motor development and mutation status. Outcome was defined as cognitive development (intellectual equivalent, IE) as measured using tests appropriate to the patients age and cognitive abilities (median age at testing 8.2 years, IQR 4.7–12.0). Univariable and multivariable regression analyses were used. In a univariable analysis, predictors of lower IE were: the presence of infantile spasms (β = −18.3, p = 0.000), a larger number of antiepileptic drugs used (β = −6.3, p = 0.000), vigabatrin not used as first drug (β = −14.6, p = 0.020), corticosteroid treatment (β = −33.2, p = 0.005), and a later age at which the child could walk independently (β = −2.1, p = 0.000). An older age at seizure onset predicted higher IE (β = 1.7, p = 0.000). In a multivariable analysis, only age at seizure onset was significantly correlated to IE (β = 1.2, p = 0.005), contributing to 28% of the variation in IE. In our cohort, age at seizure onset was the only variable that independently predicted IE. Factors predicting cognitive development could aid parents and physicians in finding the appropriate support and schooling for these patients

Design and Cohort Characteristics of the Social Spectrum Study: A Multicenter Study of the Autism Spectrum Among Clinically Referred Children

This paper provides an overview of the design and cohort characteristics of the Social Spectrum Study: a clinical cohort study that used a two-phase sampling design to identify children at risk for ASD. After screening 1281 children aged 2.5–10 years who had been consecutively referred to one of six mental health services in the Netherlands, children who screened positive for ASD (n = 428) and a random selection of screen negatives (n = 240) were invited to participate in diagnostic assessments and questionnaires regarding the child, family and society. A 1-year follow-up was also conducted. Results from this study may contribute to knowledge of the identification and characterization of children with ASD, family processes, and the impact of ASD on the family and society

Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1)

In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)—and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1

An overview of health issues and development in a large clinical cohort of children with Angelman syndrome

This study presents a broad overview of health issues and psychomotor development of 100 children with Angelman syndrome (AS), seen at the ENCORE Expertise Center for AS in Rotterdam, the Netherlands. We aimed to further delineate the phenotype of AS, to evaluate the association of the phenotype with genotype and other determinants such as epilepsy and to get insight in possible targets for intervention. We confirmed the presence of a more severe phenotype in the 15q11.2-q13 deletion subtype. Novel findings were an association of (early onset of) epilepsy with a negative effect on development, a high occurrence of nonconvulsive status epilepticus, a high rate of crouch gait in the older children with risk of deterioration of mobility, a relatively low occurrence of microcephaly, a higher mean weight for height in all genetic subtypes with a significant higher mean in the nondeletion children, and a high occurrence of hyperphagia across all genetic subtypes. Natural history data are needed to design future trials. With this large clinical cohort with structured prospective and multidisciplinary follow-up, we provide unbiased data on AS to support further intervention studies to optimize outcome and quality of life of children with AS and their family

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. Methods: We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. Results: Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population. Conclusions: The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5–2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability

Clinical aspects of a large group of adults with Angelman syndrome

Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe