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 .

Consensus recommendations on organization of care for individuals with Phelan-McDermid syndrome.

The manifestations of Phelan-McDermid syndrome (PMS) are complex, warranting expert and multidisciplinary care in all life stages. In the present paper we propose consensus recommendations on the organization of care for individuals with PMS. We indicate that care should consider all life domains, which can be done within the framework of the International Classification of Functioning, Disability and Health (ICF). This framework assesses disability and functioning as the outcome of the individual's interactions with other factors. The different roles within care, such as performed by a centre of expertise, by regional health care providers and by a coordinating physician are addressed. A surveillance scheme and emergency card is provided and disciplines participating in a multidisciplinary team for PMS are described. Additionally, recommendations are provided for transition from paediatric to adult care. This care proposition may also be useful for individuals with other rare genetic neurodevelopmental disorders.

Methylphenidate for attention-deficit/hyperactivity disorder in patients with Smith-Magenis syndrome: protocol for a series of N-of-1 trials.

BACKGROUND: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations. METHODS AND ANALYSIS: We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level. CONCLUSIONS: This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care. TRIAL REGISTRATION: This study is registered in the Netherlands Trial Register (NTR9125).

Growing up with Fragile X Syndrome: Concerns and Care Needs of Young Adult Patients and Their Parents.

Little is known about care needs of young adults with Fragile X Syndrome (FXS). Patient-driven information is needed to improve understanding and support of young adults with FXS. A qualitative study was performed in 5 young adult patients (aged 18-30), and 33 parents of young adults. Concerns and care needs were categorized using the International Classification of Functioning, Disability, and Health. Results indicated concerns on 14 domains for males, and 13 domains for females, including physical, psychological and socio-economical issues. In both groups parents reported high stress levels and a lack of knowledge of FXS in adult care providers. This study revealed concerns on various domains, requiring gender-specific, multidisciplinary transitional care and adult follow-up for patients with FXS.

[Somatic comorbidity in children and adults with intellectual disability and mental health problems.] / Somatische comorbiditeit bij kinderen en volwassenen met een verstandelijke beperking en een psychiatrische aandoening.

BACKGROUND: People with intellectual disability (id) frequently suffer from somatic and psychiatric comorbidity. Somatic morbidity can be the cause and the result of mental health problems. Timely diagnosis and interdisciplinary management are essential for optimal health, development and quality of life.
AIM: To improve interdisciplinary cooperation of professionals involved in care for patients with id, with emphasis on prevalence, diagnosis, and treatment of somatic comorbidity.
METHOD: Literature review and expert opinion.
RESULTS: Epidemiology, diagnostics, and treatment of somatic comorbidity in patients with id are discussed. Additionally, roles and responsibilities of involved professionals are addressed.
CONCLUSION: Somatic comorbidity is highly prevalent in patients with id. People with id should be regularly screened for somatic comorbidity, and re-evaluated in case of behavioral changes. Where available, an id physician can be included in the interdisciplinary care team.

[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.

Costello syndrome: report and review.

We describe a 34-year-old woman with mental retardation, short stature, macrocephaly, a "coarse" face, hoarse voice, and redundant skin with deep palmar and plantar creases who had evident Costello syndrome. Lacking papillomata, she had wart-like lesions of the skin. The previously reported patients with Costello syndrome are reviewed. Costello syndrome is probably an autosomal dominant disorder, either caused by a mutation in a single gene or by microdeletion.