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 .

Background Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to measure the impact of TSC manifestations on daily functioning. The aim of this study was to develop a TSC-specific PROM for adults that captures the impact of TSC on physical functions, mental functions, activity and participation, and the social support individuals with TSC receive, called the TSC-PROM. Methods COSMIN methodology was used to develop a self-reported and proxy-reported version. Development and validation consisted of the following studies: PROM development, content validity, structural validity, internal consistency, and construct validity. The International Classification of Functioning and Disability was used as a framework. Content validity was examined by a multidisciplinary expert group and cognitive interview study. Structural and construct validity, and internal consistency were examined in a large cohort, using confirmatory factor analysis, hypotheses testing, and Cronbach’s alpha. Results The study resulted in an 82-item self version and 75-item proxy version of the TSC-PROM with four subscales (physical functions 18 and 19 items, mental functions 37 and 28 items, activities and participation 13 and 14 items, social support 13 items, for self version and proxy version respectively). Sufficient results were found for structural validity with sufficient unidimensionality for each subscale. With regard to construct validity, 82% of the hypotheses were met for the self version and 59% for the proxy version. The PROM showed good internal consistency (Cronbach’s alpha 0.78–0.97). Conclusions We developed a PROM for adults with TSC, named TSC-PROM, showing sufficient evidence for reliability and validity that can be used in clinical and research settings to systematically gain insight into their experiences. It is the first PROM in TSC that addresses the impact of specific TSC manifestations on functioning, providing a valuable, patient-centered addition to the current clinical outcomes.

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.

Purpose: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). Method: In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score =3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of =3 (i.e., at least "minimal improvement") and =2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range.Results: Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2-3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study.Conclusions: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants.

AIM:To identify meaningful outcomes of children and their caregivers attending a paediatric brain centre.METHOD:We compiled a long list of outcomes of health and functioning of children with brain-related disorders such as cerebral palsy, spina bifida, (genetic) neurodevelopmental disorders, and acquired brain injury. We incorporated three perspectives: patients, health care professionals, and published outcome sets. An aggregated list was categorized using the International Classification of Functioning, Disability, and Health: Children and Youth version in a patient validation survey for children and parent-caregivers to prioritize outcomes. Outcomes were considered meaningful when ranked 'very important' by 70% or more of the participants.RESULTS:We identified 104 outcomes from the three perspectives. After categorizing, 59 outcomes were included in the survey. Thirty-three surveys were completed by children (n = 4), caregivers (n = 24), and parent-caregivers together with their child (n = 5). Respondents prioritized 27 meaningful outcomes covering various aspects of health and functioning: emotional well-being, quality of life, mental and sensory functions, pain, physical health, and activities (communication, mobility, self-care, interpersonal relationships). Parent-caregiver concerns and environmental factors were newly identified outcomes.INTERPRETATION:Children and parent-caregivers identified meaningful outcomes covering various aspects of health and functioning, including caregiver concerns and environmental factors. We propose including those in future outcome sets for children with neurodisability.WHAT THIS PAPER ADDS:Outcomes that children with brain-related disorders and their parent-caregivers consider to be the most meaningful cover a wide range of aspects of functioning. Involving these children and their parent-caregivers resulted in the identification of important outcomes that were not covered by professionals and the literature. Parent-caregiver-related factors (coping, burden of care) and environmental factors (support, attitudes, and [health care] services) were identified as meaningful.

Differentiation between acute flaccid myelitis (AFM) and Guillain–Barré syndrome (GBS) can be difficult, particularly in children. Our objective was to improve the diagnostic accuracy by giving recommendations based on a comparison of clinical features and diagnostic criteria in children with AFM or GBS.

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

Novel clinical evaluation strategies are needed to fulfil the potential of targeted therapies for rare neurodevelopmental disorders.

Background: Tuberous sclerosis complex (TSC) is a highly variable condition and its clinical features cannot reliably be predicted from the genotype. Counselling of parents of a child with TSC is challenging because of the variability of the condition and the changing outlook due to new treatment options. This study explored current counselling strategies in TSC in the Netherlands, with the aim of developing a recommendation for counselling. Method: We performed a nationwide survey using digital questionnaires. Questionnaires were sent to parents of children diagnosed with TSC, and to medical doctors involved in counselling, both no more than ten years prior to the study. Questions focused on general information about the child with TSC, medical doctors involved in counselling, type of information provided, mode of providing information, and recommendations for improvement of counselling. Results: Parents of 34 children diagnosed with TSC (7 prenatally) and 18 medical doctors from different departments responded to the questionnaires. Almost all parents were informed on the neurological and cardiac symptoms of TSC, other symptoms were mentioned less often. Satisfaction on counselling was higher when more information on the variability of TSC was provided, preferentially during a clinical visit, when emotional support was provided, and when parents were notified of the TSC patient society. Conclusions: Information on the variability in expression and quality of life is highly demanded by (expecting) parents of a child with TSC. Furthermore, reference should be made to institutions such as the support organisation for patients and social services for questions and support. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Introduction Transitioning into adulthood and from pediatric services to adult healthcare are both challenging processes for young adults with rare chronic disorders such as tuberous sclerosis complex (TSC) and their parents. Adult healthcare systems are often less family-oriented and lack multidisciplinary care and experience with TSC, which can result in increased health risks and morbidity. Patient-driven data on care needs are necessary to optimize support for this vulnerable patient group. Aim The aim of this study was to explore the concerns and care needs of young adult patients with TSC in medical, psychological, and socioeconomical domains. Method A qualitative study was performed using semistructured interviews with 16 patients (median age: 21 years; range: 17 to 30) and 12 parents. Concerns and care needs were organized using the International Classification of Functioning, Disability, and Health (ICF). Results Main concerns involved mental and physical health, participation, self-management skills, family planning, and side effects of medications. Patients expressed the need for multidisciplinary care that is well-informed, easily accessible, and focused on the patient as a whole, including his/her family. Parents reported high stress levels. Conclusion The current study provides patient-driven information, allowing recommendations to facilitate the (transition of) care for young adults with TSC. In addition to seizures, tumor growth, and TSC-associated neuropsychiatric disorders (TAND), more attention is needed for concerns and care needs specific to the transitional period, participation, and environmental factors. Adult healthcare providers should offer expert multidisciplinary care for adult patients with TSC, including attention for parental stress.

Paired associative stimulation (PAS) is a frequently used TMS paradigm that induces long-term potentiation in the human cortex. However, little is known about the within-subject consistency of PAS-induced effects. We determined PAS-induced effects and their consistency in healthy volunteers between two PAS sessions. Additionally, we assessed the benefit of applying linear mixed models (LMMs) to PAS data. Thirty-eight healthy volunteers underwent two identical PAS sessions with a >1 week interval. During each session, motor evoked potentials (MEPs) were assessed once before PAS induction and 3 times after at 30 min intervals. We did not detect any significant potentiation of MEP size after PAS induction. However, MEP size during PAS induction showed significant potentiation over time in both sessions (LR(1)=13.36, p<0.001). Nevertheless, there was poor within-subject consistency of PAS-induced effects both during (ICC=0.15) and after induction (ICC=0.04-0.09). Additionally, statistical model selection procedures demonstrate that a LMM with an unstructured covariance matrix better estimated PAS-induced effects than one with a conventional compound symmetry matrix (LR(34)=214.73, p<0.001). While our results are supportive of a high intra-individual variability of PAS-induced effects, the generalizability of our results is unclear, as we were only partially successful in replicating results from previous PAS studies typically showing potentiation of MEPs during and after PAS induction. We do, however, demonstrate that linear mixed models can improve the reliability of PAS-induced effects estimation.

EXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures.After completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3-15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR).Of 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2-36.1; N = 352) at week 18, 46.6% (95% CI, 40.9-52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7-65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5-36.1) at week 18, 46.7% (95% CI, 40.2-54) at 1 year, and 56.9% (95% CI, 50-68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5-35.2; N = 361) at week 18, 38.8% (95% CI, 33.7-44.1; N = 358) at 1 year, and 41% (95% CI, 34.6-47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock).Sustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns.This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.

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.

Objective: To define age-specific reference values for cerebrospinal fluid (CSF) total protein levels for children and validate these values in children with Guillain-Barre syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS).Methods: Reference values for CSF total protein levels were determined in an extensive cohort of diagnostic samples from children (<18 year) evaluated at Erasmus Medical Center/Sophia Children's Hospital. These reference values were confirmed in children diagnosed with disorders unrelated to raised CSF total protein level and validated in children with GBS, ADEM and MS.Results: The test results of 6145 diagnostic CSF samples from 3623 children were used to define reference values. The reference values based on the upper limit of the 95% CI (i.e. upper limit of normal) were for 6 months-2 years 0.25 g/L, 2-6 years 0.25 g/L, 6-12 years 0.28 g/L, 12-18 years 0.34 g/L. These reference values were confirmed in a subgr oup of 378 children diagnosed with disorders that are not typically associated with increased CSF total protein. In addition, the CSF total protein levels in these children in the first 6 months after birth were highly variable (median 0.47 g/L, IQR 0.26-0.65). According to these new reference values, CSF total protein level was elevated in 85% of children with GBS, 66% with ADEM and 23% with MS.Conclusion: More accurate age-specific reference values for CSF total protein levels in children were determined. These new reference values are more sensitive than currently used values for diagnosing GBS and ADEM in children. (C) 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.