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We tested the hypothesis that increasing methyl-group pools might promote transcriptional repression by other methyl-binding proteins or by mutant methyl-CpG-binding protein 2 with altered affinity, ameliorating the clinical features of Rett syndrome. A 12-month, double-blind, placebocontrolled folate-betaine trial enrolled 73 methyl-CpG-binding protein 2 mutation positive female participants meeting consensus criteria for Rett syndrome. Participants were randomized as young (< age 5 years) or old (≥ age 5 years). Structured clinical assessments occurred at baseline, 3, 6, and 12 months. Primary outcome measures included quantitative evaluation of breathing and hand movements during wakefulness, growth, anthropometry, motor/behavioral function, and qualitative evaluations from electroencephalograms and parent questionnaires. In all, 68 participants completed the study. Objective evidence of improvement was not found. Subjective improvement from parent questionnaires was noted for the <5 years group. This study should inform future treatment trials regarding balancing participants with specific mutations and comparable severity to minimize selection bias. KeywordsRett syndrome; MECP2; methylation; folate; betaine ; vitamin B 12 Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females following apparently normal psychomotor development during the first 6 months of life. The principal features of Rett syndrome include loss of speech and purposeful hand use, stereotypic hand movements, gait dyspraxia, and deceleration in the rate of head growth. 1 Seizures, abnormal breathing (apnea and hyperventilation) during wakefulness, autonomic nervous system dysfunction, and growth failure may be noted.Amir et al 2 reported several mutations in the methyl-CpG-binding protein 2 gene in individuals with Rett syndrome. At present, >95% of those meeting clinical criteria for Rett syndrome have 1 of more than 200 mutations of which 8 common mutations account for about 65% of the total. Methyl-CpG-binding protein 2 gene encodes methyl-CpG-binding protein 2, a member of a family of proteins known to bind specifically to methylated DNA CpGs and to be capable of repressing transcription. [3][4][5] Methyl-CpG-binding protein 2 is expressed in all human tissues but is more abundant in brain. Study DesignWe enrolled 73 female participants with Rett syndrome. To be eligible for enrollment, participants were required to meet the consensus criteria for Rett syndrome and to have a methyl-CpG-binding protein 2 gene mutation. They were categorized as young if less than (<) 5 years of age or old if equal to or greater than (≥) 5 years of age. All participants were stable clinically. We selected this age stratification scheme based on experience with a previous trial. 13 Prior to age 5 years is the period of rapid regression or dynamic changes. The period after age 5 years is associated with stabilization and improved interaction and attentiveness. Failure to stratify in the previous study skewed the d...

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