Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials.

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .

Child characteristics associated with child quality of life and parenting stress in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and behavioural issues. Little is known on child health-related quality of life (HRQoL) in AS. AS family studies have reported elevated parenting stress and a high impact of the child's syndrome on the parent. It is unclear which factors influence child HRQoL and parenting stress/impact in AS. METHODS: We collected data prospectively through standardised clinical assessments of children with AS at the ENCORE Expertise centre for Angelman Syndrome at the Erasmus MC Sophia Children's Hospital. A linear regression analysis was conducted for the following outcome variables: (1) child HRQoL (Infant and Toddler Quality of Life Questionnaire); (2) the impact of the child's syndrome on the parent (Infant and Toddler Quality of Life Questionnaire); and (3) parenting stress (Parenting Stress Index). Predictor variables were child genotype, epilepsy, sleeping problems (Sleep Disturbance Scale for Children), cognitive developmental level (Bayley Cognition Scale), autistic features (Autism Diagnostic Observation Schedule) and emotional/behavioural problems (Child Behaviour Checklist). Covariates were sex, age and socio-economic status. RESULTS: The study sample consisted of 73 children with AS, mean age = 9.1 years, range = 2-18 years. Emotional/behavioural problems were the strongest significant predictor of lowered child HRQoL. Internalising problems were driving this effect. In addition, having the deletion genotype and higher age was related to lower child HRQoL. Sleeping problems were related to a higher impact of the child's syndrome on the parent. Finally, emotional/behavioural problems were associated with higher parenting stress. Cognitive developmental level, autistic features and epilepsy were not a significant predictor of child HRQoL and parenting stress/impact. CONCLUSIONS: These results suggest that interventions aimed at increasing child HRQoL and decreasing parenting stress/impact in AS should focus on child emotional/behavioural problems and sleeping problems, using a family-centred approach.

[Fragile X syndrome: new therapeutic strategies]. / Fragiele-X-syndroom: nieuwe therapeutische strategieën.

BACKGROUND: Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy.
AIM: To present an overview of the development of targeted treatment for fxs.
METHOD: Several important publications were collected and indexed.
RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing.
CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement future therapeutic strategies and to facilitate research. In addition, this improves patient care, one example being the recent medical guideline for children with fxs.

Scar Perception in School-aged Children After Major Surgery in Infancy.

BACKGROUND: The long-term effects of childhood surgery scars on health status, quality of life (QoL), self-esteem, and body image remain uncertain. This study explores these effects in school-aged children. METHODS: We conducted a retrospective cohort study involving 454 children (58% boys; 8-17 years) who had undergone surgical correction of anatomical anomalies or neonatal ECMO. Data included patient-reported scar perception and scar-related embarrassment, along with psychological assessment via questionnaires. RESULTS: About 34% of children rated their scars as 'nice-looking', 49% as 'indifferent', and 12% as 'rather ugly'. Most children (91%) never experienced scar-related embarrassment, while frequent embarrassment was reported by 3%. Surgical scar correction was desired by 6% of the 8-year-olds and 19% of the 17-year-olds. Scar perception did not significantly affect health status or QoL. However, negative scar perception was associated with lower self-esteem in girls and a more negative body image in boys. Girls were more likely to report negative scar perception (OR: 1.54, 95%-CI: 1.06-2.24) and scar-related embarrassment (OR: 4.29, 95%-CI: 1.77-10.44). CONCLUSION: Children who underwent surgery in the neonatal period and subsequently grew up with scars resulting thereof, mostly perceive them either indifferently or positively, with minimal effect on health status and QoL. Nonetheless, some children, particularly girls, experienced negative perceptions of their scars, although scar-related embarrassment was rare. We recommend integrating scar assessment into routine follow-up at ages 12 and 17, and offering appropriate and timely guidance and support to children at risk for negative effects of scars. LEVEL OF EVIDENCE: III.

Associations between dietary factors and markers of NAFLD in a general Dutch adult population.

BACKGROUND/OBJECTIVES: The objective of this sudy was to assess the relationship between dietary intake and fatty liver as scored by the validated Fatty Liver Index (FLI) in a large cross-sectional study among a general Dutch adult population. Diet is known to affect liver fat accumulation in humans. SUBJECTS/METHODS: 1128 men and women aged 20-70 years were included. Dietary intake was assessed using a validated semiquantitative food frequency questionnaire. FLI was derived from body mass index (BMI), waist circumference, triglycerides and gamma-glutamyltransferase. Associations were adjusted for energy intake, alcohol intake, age, sex, education, smoking and prevalence of hypertension and diabetes. RESULTS: In this population (mean age 53.0±11.4 years; BMI 25.9±4.0 kg/m2; FLI 35.0±27.7), the prevalence of fatty liver as indicated by an FLI>60 was 21.5%. Subjects in the highest FLI category were more likely to be male, older and less physically active. Total protein intake and animal protein intake were positively associated with the highest FLI score versus the lowest (odds ratio (OR) 1.25 per 1 en%, 95% confidence interval (CI) 1.15-1.37 and OR 1.27, 95% CI 1.17-1.38, respectively); for vegetable protein, an inverse association was observed (OR 0.81, 95% CI 0.69-0.94). A similar positive association with FLI was observed when carbohydrates and fat were iso-calorically exchanged for total and animal proteins. CONCLUSIONS: Subjects in the high FLI group consumed more protein, especially from animal origin, less carbohydrates and less dietary fibre. The presence of fatty liver was associated with a higher intake of animal protein and total fat, soft drinks and snacks.

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.

High dietary protein intake, reducing or eliciting insulin resistance?

Dietary proteins have an insulinotropic effect and thus promote insulin secretion, which indeed leads to enhanced glucose clearance from the blood. In the long term, however, a high dietary protein intake is associated with an increased risk of type 2 diabetes. Moreover, branched-chain amino acids (BCAA), a prominent group of amino acids, were recently identified to be associated with diabetes. Observational data and intervention studies do not point in the same direction regarding the effect of protein intake on insulin sensitivity and diabetes risk. Therefore, the first aim of this review will be to discuss human studies addressing high dietary protein intake and insulin action, with special attention for BCAA. In the second part, we will highlight the (patho) physiological consequences of high-protein diets regarding insulin action, in particular the role of the mechanistic target of the rapamycin pathway.