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General introduction 131 (Figure 2). Personalized treatments vary from vitamins, diets, (repurposed) drugs, organ or stem cell transplants or therapy, to enzyme, RNA and gene therapy.25 Although often used interchangeably with precision medicine, personalized medicine refers to an N-of-1 approach that tailors interventions to the specific characteristics of an individual whereas precision medicine might be rather in line with an 1-of-N approach, using for example information from genomics, transcriptomics, metabolomics or proteomics to classify an individual into a subgroup. Personalized interventions include both targeted therapies when the intervention acts upon the underlying disease mechanism, and ‘untargeted’, taking into account the unique characteristics and needs of the affected individual. DNA RNA Protein Metabolite Neuropsychiatric problemsGene therapyGene editingAntisense oligonucleotide Enzymereplacement therapyDietSupplementationPharmacotherapyPsychotherapyTreatment targetsPossible interventionsFigure 2. Level of treatment targets (upper part) and examples of corresponding possible interventions (lower part) for brain manifestations in rare genetic neurodevelopmental disorders.Usually, multiple interventions focusing on both physical and mental health manifestations are applied in individuals with RGNDs and ID, throughout the entire lifespan. The neuropsychiatric manifestations are typically the greatest burden to the affected individuals and family.26–28 Interventions may include both pharmacological and behavioral interventions, with risk for both over- and undertreatment.29,30 Several targeted therapies and disease-modifying treatments are available with many more underway, such as mammalian target of rapamycin (mTOR) inhibitors for TSC or gene and enzyme therapies for metabolic disorders, including lysosomal storage disorders.31–35 Evidence for interventions is of great importance, especially for neuropsychiatric manifestations considering its burden and adverse effects of pharmacotherapy.26–28 Manifestations and effectiveness of interventions can differ between RGNDs, such as medication being specifically effective Annelieke Muller sHL.indd 13 14-11-2023 09:07