Page 45 - Demo

N-of-1 studies in rare genetic neurodevelopmental disorders432DiscussionN-of-1 studies have been recommended for evaluating the efficacy of interventions in rare disorders.32,33 However, in this extensive review, only 12 studies complied with the fundamental N-of-1 criteria of a controlled multiple crossover trial, showing limited use and reporting of N-of-1 trials for rare genetic neurodevelopmental disorders. In addition to limitations in design and statistical analysis, generalizability and feasibility were particularly challenging. Below, limitations are discussed and recommendations are provided to implement and optimize future N-of-1 studies in this patient population (Figure 4).Although the genetic disorder and presence of ID were generally reported, diagnostic and eligibility criteria, comorbid conditions, and concurrent therapies were often unclear. Rare genetic neurodevelopmental disorders are often accompanied by various and often variable levels of ID and severe comorbidities. This intra- and interindividual heterogeneity can complicate generalization of findings to other patient populations. To optimize interpretation and generalizability, eligibility criteria and baseline characteristics pertaining to the study population as well as environment should be thoroughly described.The rationale for the intervention was well described in the reported studies. Distinction between disorder-specific and disease-modifying drugs was not performed by the authors. Categorization was difficult for some included studies as interventions may be disorder specific and not directly change its natural course by for example not targeting the primary underlying pathophysiology as exemplified by the study to L-arginine supplementation in ornithine transcarbamylase deficiency.28 Despite the fact that L-arginine supplementation does not target ornithine transcarbamylase itself but rather the consequences of the enzymatic deficiency, L-arginine ameliorates the overall function of the urea cycle by maintaining a normal rate of protein synthesis.28To optimize impact of N-of-1 studies, it is important to specify whether a trial will focus on syndrome-specific or more common manifestations. Annelieke Muller sHL.indd 43 14-11-2023 09:07