Taking the dietary supplements oral betaine and Metafolin (L-methylfolate, the active form of folic acid) cannot effectively ease developmental symptoms of children with Angelman syndrome, a small clinical study contends.
Two pairs of identical twins were treated either with oral betaine and Metafolin or placebo for one year, but no changes were seen in measures of speech and communication, cognitive or daily living abilities, between the groups.
The study, “A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome” was published in the Orphanet Journal of Rare Diseases.
Angelman syndrome (AS), a disease characterized by several physical and intellectual disabilities, is caused by genetic defects that turn off (inactivate) or delete the UBE3A gene.
A person generally inherits one copy of each gene — including UBE3A — from each parent. Both UBE3A copies are active in most tissues in the body, driving the production of an enzyme called ubiquitin protein ligase E3A.
However, in selected regions of the brain, only the UBE3A copy inherited from the mother (maternal copy) is active and driving the production of the enzyme in nerve cells.
That happens because during development a process called genomic imprinting silences the copy of the gene inherited from a person’s father (paternal copy) in some areas of the brain.
Due to that, loss of the maternal copy prevents the ubiquitin protein ligase E3A from being produced in certain brain regions, likely causing Angelman syndrome. If unsilenced, the paternal copy could be a source of active enzyme for patients. In fact, the activation of the paternally inherited UBE3A copy is deemed as a potential strategy to lessen disease symptoms.
Paternal silencing, or imprinting, is thought to be carried out by a genetic “roadblock” called UBE3A antisense transcript (ATS). So, trying to override UBE3A-ATS may lead to new ways to treat AS.
A potential strategy is to increase the methylation of UBE3A-ATS to inhibit its action and prevent its ability to silence the paternal copy of UBE3A. (Methylation is the addition of chemical groups of methyl to other molecules.)
In line with this approach, researchers at the University of California at Irvine analyzed the effects of one year of supplementation with betaine and folic acid, two natural substances present in food and known to increase methylation in the body.
The study was part of a larger trial (NCT00348933) evaluating dietary supplements to treat Angelman symptoms.
The study’s main goal was to verify if these two supplements could promote a global rise in brain methylation levels in an attempt to activate the paternal copy of UBE3A.
Two pairs of identical twin male siblings with Angelman syndrome were enrolled. Researchers chose to study twins as a way to limit biological and environmental variability. The disease was caused by UBE3A deletions in all patients.
For each twin pair, one of the siblings was assigned daily oral supplements of betain and Metafolin (L-methylfolate, the active form of folic acid, or folate) and the other patient was given a placebo, over 12 months.
In one pair, one of the twins was enrolled at age 8 (placebo) and the other when he was 5 months old (supplementation). In the other pair, one of the twins entered the study at age 5 (placebo) and the other at age 7 (supplementation).
At the beginning of the study, and then at six and 12 months, patients underwent several clinical and developmental tests; four different scales were used to assess cognitive and motor and communication skills. Parents also completed a questionnaire about the child’s behavior. Blood and urine tests determined the levels of folate and betaine, and other parameters.
The study’s results showed that supplementations did not lead to any significant developmental improvements in any of the twin pairs.
The findings agree with a prior trial in which 48 children with AS had no significant clinical benefits from treatment with betaine and folic acid.
“[I]n our study, data from the [identical] twins minimized confounding variables, such as age, gender, cultural, environmental, or genetic factors, and allowed for reliable conclusions. We however did not find significant improvements with the betaine and folic acid treatment, nor did we find negative effects of the treatment in the treated twins,” the researchers concluded.