![]() ![]() ![]() There remains a group of patients with AS with no identifiable molecular abnormality (10–14%). Haploinsufficiency for genes adjacent to UBE3A may contribute to a more severe phenotype in deletion cases. Treatment for this condition is supportive and mainly consists of controlling seizures and employing rehabilitative therapies.ĪS is caused by several recognized mechanisms, which reduce the expression of UBE3A: (1) 5–6 Mb deletions of the maternal 15q11–q13 region (65–75%) (2) paternal uniparental disomy (pUPD) with two copies of paternally inherited 15q11–q13 and no copy of maternally inherited 15q11–q13 (3–5%) (3) imprinting defects where the maternally inherited UBE3A has the methylation and gene expression pattern of a paternally inherited UBE3A, thereby rendering the maternally inherited gene inactive (6–8%) and (4) loss-of-function point mutations or intragenic deletions in the maternally inherited UBE3A gene (4–6%). The clinical phenotype of Angelman syndrome (AS) includes global developmental delay, minimal or absent speech, seizures, ataxia, sleep disturbance, and an unique behavioral profile consisting of happy demeanor, easily provoked or inappropriate laughter, hypermotoric behaviors, and excessive mouthing behaviors. There were no statistically significant changes between treated and untreated children however, in a small subset of patients we observed some positive trends. We report herein the data on 48 children with AS who were enrolled in a double-blind placebo-controlled protocol using betaine and folic acid for 1 year. We performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. We conducted a trial using two dietary supplements, betaine and folic acid to promote global levels of methylation and attempt to activate the paternally inherited UBE3A gene. We hypothesized that increasing methylation might reduce expression of the antisense UBE3A RNA, thereby increasing UBE3A expression from the paternal gene and ameliorating the clinical phenotype. ![]() Expression of UBE3A from the maternal chromosome is essential to prevent AS, because the paternally inherited gene is not expressed, probably mediated by antisense UBE3A RNA. ![]() UBE3A is subject to genomic imprinting in neurons in most regions of the brain. Angelman syndrome (AS) is caused by reduced or absent expression of the maternally inherited ubiquitin protein ligase 3A gene ( UBE3A), which maps to chromosome 15q11–q13. ![]()
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