A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome.

Angelman syndrome (AS) is due to deficient ubiquitin protein ligase 3a, the gene for which (UBE3A) maps to chromosome 15q11-q13 and is imprinted such that only the maternally inherited gene is expressed. The paternally inherited UBE3A gene is silenced, a process mediated by an antisense transcript. We conducted a trial using methylation-promoting dietary supplements (betaine, metafolin, creatine, and vitamin B(12) ) in an attempt to reduce antisense transcript production, increase UBE3A expression, and ameliorate the symptoms of AS. Neuropsychological evaluations, biochemical testing, and assessment of DNA methylation were performed at the beginning and at the end of 1 year of supplementation. The primary outcome measures were changes in the level of developmental function (cognitive, motor, and language) as measured using standardized instruments. The secondary outcomes measures were changes in biochemical parameters and global DNA methylation. These data were compared to those of a control group from a previous randomized double-blind trial using folic acid and betaine. There were no statistically significant changes in the developmental performance of children treated with supplements. There were no unexpected changes in biochemical parameters and no change in site-specific DNA methylation when comparing samples from before and after treatment. There were 10 adverse events that resulted in study withdrawal of 7 participants (worsening of seizures, onset, or worsening of sleep problems, constipation, and anorexia). Supplementation with betaine, metafolin, creatine, and vitamin B(12) appears safe but ineffective in decreasing the severity of AS.

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.

A modern approach to the treatment of mitochondrial disease.

The treatment of mitochondrial disease varies considerably. Most experts use a combination of vitamins, optimize patients' nutrition and general health, and prevent worsening of symptoms during times of illness and physiologic stress. We agree with this approach, and we agree that therapies using vitamins and cofactors have value, though there is debate about the choice of these agents and the doses prescribed. Despite the paucity of high-quality scientific evidence, these therapies are relatively harmless, may alleviate select clinical symptoms, and theoretically may offer a means of staving off disease progression. Like many other mitochondrial medicine physicians, we have observed significant (and at times life-altering) clinical responses to such pharmacologic interventions. However, it is not yet proven that these therapies truly alter the course of the disease, and some experts may choose not to use these medications at all. At present, the evidence of their effectiveness does not rise to the level required for universal use. Based on our clinical experience and judgment, however, we agree that a therapeutic trial of coenzyme Q10, along with other antioxidants, should be attempted. Although individual specialists differ as to the exact drug cocktail, a common approach involves combinations of antioxidants that may have a synergistic effect. Because almost all relevant therapies are classified as medical foods or over-the-counter supplements, most physicians also attempt to balance the apparent clinical benefit of mitochondrial cocktails with the cost burden that these supplements pose for the family.