Abstract
BackgroundSmith–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 analysisWe 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.ConclusionsThis 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).
Highlights
Smith–Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances
SMS is caused by a deletion on chromosome 17 (17p11.2) or a pathogenic mutation in the RAI1 gene located within this region
Treatment is focused on appropriate management of sleeping pattern, concomitant somatic comorbidities, psychoeducation and professional guidance for parents and caregivers aimed at symptom reduction and optimizing quality of life of both the patient and their family [10,11,12,13]
Summary
Smith–Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Treatment is focused on appropriate management of sleeping pattern, concomitant somatic comorbidities, psychoeducation and professional guidance for parents and caregivers aimed at symptom reduction and optimizing quality of life of both the patient and their family [10,11,12,13]. Often, this does not suffice, resulting in the prescription of psychotropic drugs in the vast majority of children and adults with SMS, including stimulants, antidepressants, antipsychotics, mood stabilizers, alfa agonists, sleep aids, and benzodiazepines [14]
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