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N-of-1 studies in rare genetic neurodevelopmental disorders392Table 2. Characteristics of N-of-1 Studies in Rare Genetic Neurodevelopmental Disorders.Study Diagnosis Number of partici,pantsAverage age of par,ticipants (range); yIntervention Primary and secondary outcome measures1 Assessed byBawden et al. (55) Williams syndrome 4 11 (9-13) Methylphenidate Child Behavior Checklist, Conners’ Parent/ Teacher Questionnaire, Side Effects Questionnaire, cognitive psychometric measuresCaregiverByiers et al. (56) Rett syndrome 3 30 (15-47) Functional communication trainingCommunicative behaviour InvestigatorCamfield et al. (21) Cerebellar hypoplasia tapetoretinal degeneration syndrome6 7 (3-13) Melatonin Average number of hours asleep per 24 hours, and the number of awakenings and nights without arousalsCaregiver, parentsCrook et al. (57) Down syndrome 5 59 (55-63) Cognitive stimulation therapyDementia Care Mapping CaregiverFisch et al. (26) Fragile X syndrome 6 8 (3-15) Folic acid Vineland Adaptive Behavior Scales, Autistic Descriptors Checklist, questionnaire about noticed changes in behavior, red blood cell folate levelsCaregiver, parentsGiffin et al. (27) Phenylketonuria 3 15 (9-21) Phenylalanine restrictionVisual attention, plasma phenylalanine and tyrosine levelsInvestigatorHackett et al. (28)Ornithine transcarbamylase deficiency1 48 L-arginine Quality of life/mood assessment questionnaire, plasma glutamine and arginine levelsPatient, investigatorKhasnavis et al. (30) Lesch-Nyhan disease 9 10 (6-22) Ecopipam Behavior Problems Inventory, Clinical Global Impression scale, adverse events Caregiver, study staffLuciano et al. (29) Myoclonus-dystonia syndrome 2 29 (28-31) Tetrabenazine Global Dystonia rating scale, Fahn-Marsden rating scale, Unified Myoclonus rating scale InvestigatorMarholin et al. (25) Phenylketonuria 6 36 (19-53) Low phenylalanine diet and behavior modificationSocial and motor behavior, serum phenylalanine levelsInvestigatorSimacek et al. (20) Rett syndrome 3 3 (3-4) Functional communication trainingIdiosyncratic responses and augmentative and alternative communication requestsInvestigatorTierney et al. (31) Smith-Lemli-Opitz syndrome 10 11 (5-20) Cholesterol -- easy eggs liquid egg yolksAberrant Behavior Checklist (ABC) Caregiver1Underlined when indicated as a primary outcome measure by the authors. y, year.Table 3. Methodological Characteristics of the 12 Included N-of-1 Studies.Study (first author)Design Periods Duration active interventionTotal trial durationRandomization Blinding Comparator(s) Type of analysesBawden ABAB / ABBA / BAAB 5 1 week 5 weeks Yes Double-blind Placebo TabularByiers ABAB 4 15-35 minutes 2-3 days No Not blinded Alternate treatment Graphical, non-overlap of all pairsCamfield ABABABABAB 10 1 week 10 weeks Yes Double-blind Placebo TabularCrook AA[AAABBBCCC] 11 30 minutes 11 days Yes Not blinded Alternate treatment + no interventionGraphical, tabular, statistics ((non-)parametric)Fisch ABA / BAB 3 4 months 12 months Yes Double-blind Placebo Graphical, tabularGiffin ABA 3 8-14 weeks 16-26 weeksNo Patient and observerAlternate treatment Statistics ((non-)parametric), graphicalHackett ABABAB 6 1 week 7 weeks Yes Double-blind Placebo Statistics ((non-)parametric), tabularKhasnavis ABA / BAB + A (follow-up) + openlabel extension5 6 weeks 17 months Yes Double-blind Placebo + no interventionTabular, graphicalLuciano ABAB 4 <1 day 3 days No Clinician only No intervention TabularMarholin ABA 3 56 days (range 53-59)Not reportedNo Double-blind No intervention GraphicalABCADAD 7 2-11 days 45 days No Not blinded No intervention GraphicalSimacek ABAB 8 5 minutes Not reportedNo Not blinded Treatment as usual GraphicalTierney ABACA / ACABA (with washout)5 2 weeks 10 weeks Yes Double-blind Placebo + treatment as usualStatistics ((non-)parametric), graphicalAnnelieke Muller sHL.indd 39 16-11-2023 09:50