Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00672360 |
| Other study ID # |
H-20959 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
May 2007 |
| Est. completion date |
February 2015 |
Study information
| Verified date |
October 2020 |
| Source |
Baylor College of Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
New evidence suggests that autistic disorder (AD) may be associated with abnormalities in
folate metabolism, which is a process that affects genetic expression by facilitating the
formation of methyl donors for DNA methylation. Limited data show that some children with AD
show behavioral improvements with folic acid (FA) therapy, while others show a worsening
effect. If behavioral worsening is linked with abnormalities in folate metabolism, then
nutritional modifications could normalize these processes and result in clinical
improvements. To address this premise, we propose a randomized, placebo-controlled crossover
pilot study with two phases. The first phase will focus on the behavioral and biochemical
responses of children with AD to high-dose folic acid supplementation. Because FA is an
inactive folate that requires biochemical conversion to become active, and select genotypes
impede this conversion, our general hypothesis is that FA will yield behavioral improvements
in some children but exacerbate problem behaviors in others. During the second phase,
children who had a worsened behavioral response to FA during phase 1 will participate in an
open-label trial of high-dose Metafolin® supplementation. The focus here would similarly be
on the behavioral and biochemical outcomes of participating children following treatment with
the study supplement. Because Metafolin® is an active folate metabolite that should not be
affected by genotypes in the folate pathway, our general hypothesis for phase 2 is that
Metafolin® would yield behavioral improvements without the risk for behavioral worsening.
Results from this project may provide support for continued study of the potential
relationship between folate metabolism and problem behaviors among children with AD,
potentially justifying the need to examine effects of folate supplementation among a larger
sample of affected children.
Description:
There are limited data on the use of folic acid as a treatment for children with autistic
disorder (AD). Most experimentation thus far has focused on the effects of folic acid
supplementation in small samples of males with fragile X syndrome (FRAX), and many of these
participants did not meet criteria for AD but were said to exhibit autistic-like features.
Initial case reports suggested folic acid might be an effective treatment for FRAX, some of
which noted a reduced expression of the fragile site Xq27 in blood cultures. Subsequent work
found that high doses of folic acid supplementation reduced the percentage of FRAX positive
cells and increased plasma-folate concentrations among 9 males with FRAX. Autistic-like
behaviors were said to improve for the 5 youngest participants (age range 3 years, 5 months
to 9 years, 10 months); however, one adult, aged 49, developed an increase in motor activity
and aggressiveness during treatment. His behavior returned to pretreatment levels following
discontinuation of folic acid. In similar work, researchers employed a crossover design using
4 boys (ages 6 to 14) with comorbid autism and FRAX to assess efficacy of folic acid
supplementation. Favorable behavioral changes were noted for 3 boys; however, for 2 of them,
carryover effects of folic acid into the placebo period may have clouded the magnitude of
potential differences in folic acid versus placebo effects. No changes throughout the trial
were evidenced for the fourth child, who was also the oldest and the only one to have
commenced puberty.
Overall, investigations on folic acid supplementation with small groups of FRAX participants
have yielded inconsistent findings, with favorable behavioral and/or biochemical effects for
some but not others. Moreover, the findings cannot be generalized to the broader population
of children with AD who do not have FRAX. Our search of the literature uncovered only one
report of folic acid treatment prescribed for 2 children without FRAX, one of whom was
described as psychotic with mental retardation and the other, as having a diagnosis of
autism. For both children, behaviors were notably improved with treatment and returned to
problematic levels when folic acid therapy stopped.
In addition to these few empirical studies, there are numerous anecdotal reports of families
using folate treatments with their children, most of which are promulgated through Internet
websites and the Autism Research Institute's (ARI) publication, Autism Research Review
International. For the most part, these reports are favorable. Additionally, the ARI recently
published findings from their web-based investigation on the parent-reported use and efficacy
of a wide range of treatments for children with AD. Of the 1437 families who indicated use of
folic acid as a therapeutic supplement, 42% said their children got better, 54% said their
children did not exhibit noticeable changes, and 3% said their children got worse. Taken
together, these limited data support the possibility for folic acid and other folates to
generate favorable outcomes among children with AD; this may hold true particularly for
pre-adolescent children.
The lack of empirically sound information about folic-acid efficacy among children with AD,
however, also leaves open the possibility that increased supplementation may not be helpful
and could, in fact, be harmful. There is some evidence to suggest that high doses of folic
acid supplementation produce negative physiological and/or behavioral responses, such as
gastrointestinal disturbances, sleep difficulties, malaise/irritability, and
excitability/overactivity in a sample of typical adults. Many of these symptoms are similar
if not identical to those described more generally in children with AD. Additionally, just as
there are favorable anecdotal reports of folic acid treatment, there are negative ones, as
well. For example, parents of one teenager with AD told us that, when their son participated
in a stepwise-administered supplement program and folic acid was administered as the final
supplement, he became extremely agitated, self-injurious, aggressive toward parents, prone to
frantic gesturing, and developed sleep difficulties. When the folic acid was withdrawn, his
behaviors gradually subsided to a pre-supplementation level (personal communication,
September 27, 2003).
As to whether folic acid supplementation might be "good" or "bad," an alternative explanation
is that folic acid may be beneficial in some circumstances and harmful in others. This
explanation is potentially attractive if one hypothesizes that the conversion of homocysteine
to methionine (for which folate is necessary) is beneficial, but that high doses of folic
acid can lead to anti-folate effects by accumulation of "free folic acid." For individuals
with an imbalanced metabolic profile but adequate levels of B12, it seems that folic acid
supplementation would yield favorable effects by normalizing this profile. However, folic
acid supplementation could lead to problematic behaviors through any one or combination of
biological scenarios, including accumulation of unmetabolized pteroylglutamic acid (PGA) in
serum, B12 deficiency, and/or genotypes known to impede the biochemical conversion of folic
acid. Given that negative responses to folic acid supplementation have typically been
reported among adolescents and adults, it is further possible that this phenomenon is
regulated by maturational processes.
One possibility for achieving maximum folate benefit without the risk of anti-folate effects
is through supplementation with a form of folate, Metafolin, that can serve directly as a
methyl donor. Metafolin is the L-form isomer of 5- methyltetrahydrofolate (5-MTHF) and,
presumably, a more active compound than folic acid or folinic acid (leucovorin). Metafolin
has been approved for use in the U.S. as a dietary supplement since 2001. While studies
around the globe have tested the safety of 5-MTHF at doses up to 17mg, there have not yet
been any studies to examine its efficacy as a therapeutic agent in specific
neurodevelopmental disorders. However, folinic acid (5,10- MTHF), which immediately precedes
5-MTHF in the folate-metabolism cycle, has been investigated repeatedly as a potential
therapeutic agent for this population. In one such study, James et al. examined the
biochemical effects of folinic acid supplementation in conjunction with betaine and vitamin
B12 on the biochemical outcomes of children with imbalanced metabolic profiles. This team
initially discovered that, compared with a control group, children with AD had significantly
lower baseline concentrations of methionine, S-adenosylmethionine (SAM), and homocysteine and
significantly higher concentrations of S-adenosylhomocysteine (SAH) and adenosine--a
metabolic profile that is consistent with impaired capacity for methylation. Following
supplementation with the study treatments, the metabolic imbalance within the AD group was
normalized. This same research team recently published results from an extension of this work
in which they assessed levels of folate-related metabolites and genotypes for select enzymes.
Approximately 50% of children with AD had severely abnormal metabolic profiles; additionally,
"...several susceptibility alleles that perturb a common metabolic pathway were increased
among the autistic children. The hypothesis that a genetic component of autism could involve
multiple susceptibility alleles that interact to create a fragile, environmentally sensitive
metabolic imbalance is worthy of further pursuit," (electronic copy; no page number
available).
