Double-blind therapeutic trial in Angelman syndrome using betaine and folic acid.
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. UBE3A is subject to genomic imprinting in neurons in most regions of the brain. 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. 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. 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 performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. 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. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends.
Peters
Sarika U
SU
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Bird
Lynne M
LM
Kimonis
Virginia
V
Glaze
Daniel G
DG
Shinawi
Lina M
LM
Bichell
Terry Jo
TJ
Barbieri-Welge
Rene
R
Nespeca
Mark
M
Anselm
Irina
I
Waisbren
Susan
S
Sanborn
Erica
E
Sun
Qin
Q
O'Brien
William E
WE
Beaudet
Arthur L
AL
Bacino
Carlos A
CA
D000293:Adolescent; D017204:Angelman Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001622:Betaine / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D019175:DNA Methylation; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008082:Lipotropic Agents / Q000627:therapeutic use; D008297:Male; D010641:Phenotype; D010919:Placebos; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D014803:Vitamin B Complex / Q000627:therapeutic use
D004338:Drug Combinations; D008082:Lipotropic Agents; D010919:Placebos; D014803:Vitamin B Complex; D001622:Betaine; D005492:Folic Acid; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases