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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). |