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Methylphenidate for ADHD in Smith-Magenis syndrome593enable measurement of clinically important changes. Such a personalized methodological approach has the potential of maximizing treatment adherence that is both patient-centered and evidence-based.21,22,23Rationale for N-of-1 designTrials in rare genetic neurodevelopmental disorders such as SMS pose specific challenges due to comorbidities and rarity of conditions.24,25 Singlecase experimental designs (SCEDs) provide an alternative to traditional parallel group randomized controlled trials (RCTs). Of SCEDs, the N-of-1 methodology provides the most rigorous evidence for treatment decisions at an individual level as replication is key for confirmation of causality. N-of-1 studies are randomized, controlled, multiple cross-over trials within individual patients26,27 and enhance precision when treatment effects are heterogeneous between individuals.28,29 Aggregating the results of several N-of-1 trials potentially yields treatment effect estimates that may be generalized at population level and may be as robust as traditional RCTs.30In particular, patients with rare disorders require individualized treatment interventions and outcomes due to their heterogeneity and vulnerability, which is facilitated by N-of-1 designs and consistent with the movement towards personalized care, providing a much needed bridge between practice and science.21ObjectivesThe main objective is to study the effectiveness of MPH for ADHD symptoms in individuals with SMS. Secondary objectives include assessment of the effect of MPH on emotion dysregulation, personalized goals that are specific and important to the patient, and side effects. To do this, we will perform a series of N-of-1 trials as these provide an excellent approach to study effectiveness of MPH on ADHD in SMS, given: (1) the chronic and relatively stable clinical course of ADHD, and (2) the rapid onset and termination of action of MPH.31Annelieke Muller sHL.indd 59 14-11-2023 09:07