Page 46 - Demo

Chapter 244Now that disease-modifying drugs are becoming increasingly available,18 consideration of disorder-specific effects is especially important with regard to generalizability to other patient populations. Also, diseasemodifying drugs may have age- or comorbidity-dependent effects. For example, therapeutic effects of mammalian target of rapamycin inhibitors for tuberous sclerosis complex might differ over time, across patients, and across manifestations.34,35 This emphasizes the need for detailed baseline characteristics.The interventions of the included studies were mainly directed to neurobehavioral manifestations such as improving cognition, behavior, and quality of life, underlining the great burden of neuropsychiatric symptoms for patients as well as caregivers in patients with rare genetic neurodevelopmental disorders.36 Considering the high burden of shared neuropsychiatric comorbidity, symptomatic interventions are of pivotal importance as their effect may be disorder transcending. Hence, especially symptomatic drug and nondrug trials should discuss generalizability of their intervention to other populations, taking disorder-specific effects and side effects into account. The critical need for well-controlled studies before interventions becomes established as standard of care was underscored by a negative caretaker bias encountered in 1 study.31Only 2 studies were explicitly identified by the authors as an N-of-1 trial, underlining the need of a common terminology. The rationale for the N-of1 design was generally not specified. Other limitations regarding the trial design were observed including unclear justification of trial and intervention duration, lack of run-in periods, carryover effects, randomization, and blinding.It has been proposed that conditions should be stable over time to be eligible for conducting an N-of-1 study.37 IEMs are however typically (neuro)degenerative disorders resulting in an unstable and often variable natural course across patients. As the natural history of other types of neurodevelopmental disorders unfolds, this variable course increasingly applies to many other genetic neurodevelopmental disorders.38,39 However, even for unstable manifestations, effects may be observed by tracing the Annelieke Muller sHL.indd 44 14-11-2023 09:07