1. health and fitness
2. disease
3. autism and pdd

Autism and Vitamin D
by John J. Canneii, MD
Any theory of autism's etiology must
take into account its strong genetic
basis, but also explain how genetics
interacts with the environment to
produce autism's unusual epidemiology.
Activated vitamin D, calcitriol, is a potent
neurosteroid hormone with critical
roles in mammalian brain development.
Calcitriol's physiology is unique among
the steroid hormones, because normal
steroid feedback kinetics does not regulate
neural levels of calcitriol; human behavior
does so. The apparent dramatic increase
in the prevalence of autism and other
neurodevelopmental disorders over the
last 20 years corresponds with the medical
profession's increasing advice to avoid the
sun during that same time, advice that may
have dramatically lowered brain calcitriol
levels. Estrogen and testosterone have very
different effects on calcitriol's metabolism,
differences that may explain the striking
male/female sex ratios in autism. Cognitive
abilities are positively associated with
vitamin D levels, even after correction
for sun exposure. Autistic individuals
have immunological abnormalities that
are similar to those produced by vitamin
D deficiency Calcttrioi downregulates
production of inflammatory cytokines in
the brain, which have consistently been
associated with cognitive impairment.
Severe maternal vitamin D deficiency
leads to rat pups with increased brain size
and enlarged ventricles, abnormalities
similar to those found in autistic children.
Vitamin D deficiency impairs glutathione
metabolism, which may explain the
link between oxidative stress, mercury
accumulation, and autism. Multivitamins
containing vitamin D reduce symptoms
of autism and increase cognitive abilities
in children. Consumption of vitamin
D-containing fish during pregnancy
reduces autistic symptoms in children.
Most studies show autistic births are
higher in the winter, especially in March,
when vitamin D levels are their lowest.
TOWNSEND LETTER - APRIL 2008
Neurodevelopmental abnormalities appear
to be higher among those with low vitamin
D levels, such as African Americans,
and maternal vitamin D deficiency is
exceptionally common, especially among
"Always observe the
physician with the
same diligence as he
the disease."
John Donne(1623)
African Americans, regardless of prenatal
vitamin use. While future epidemiological,
genetic, and interventional studies
should test this theory, physicians should
diagnose and treat vitamin D deficiency
during pregnancy and childhood now.
Introduction
Arguably, the five most striking
epidemiological aspects of autism are
its high monozygotic (407o-90%) vs.
dizygotic (0% -10%) twin concordance
rates,'
widely
varying
phenotypic
expression even among monozygotic
twins,^ striking male/female ratio (-3:1},
apparent increased prevalence in African
Americans, and apparent rapid increase
in incidence rates over the last 20 years.
Whatever its genetic roots, and they are
strong, autism hardly follows classic
Mendelian inheritance. A useful theory of
causation must explain all these discrepant
epidemiological observations - and
should do so parsimoniously.
When a disease with strong genetic
roots displays such peculiar epidemiology,
it is reasonable to seek an explanation
amongenvi ronmental genetic contri butors.
While the predisposing autistic lesion
is genetic, the above epidemiological
observations indicate the environment
is dramatically affecting phenotypic
expression. That is, the environment
is altering the brain, epigenetically, or
through gene-environment interactions.
Environmental genetic contributors
directly influence the genome, but the
environment directly influences them as
well, the neurosteroid hormones being one
example. Furthermore, if current claims
of increasing prevalence rates of autism
and other neurodevelopmental disorders
over the last 20 years (Figure 1)' are due
to some actual increases in incidence and this seems increasingly likely^ - then
it is reasonable to search for neurosteroids
that have changed over the same time
autism has increased. Furthermore, if a
neurosteroid exists that profoundly affects
brain development, whose metabolism
is different in males and females, whose
levels are lov^^er in African Americans than
Whites, whose levels are directly affected
by diet or human behavior, and whose
brain levels have dramatically decreased in
the last 20 years, surely that neurosteroid
is a prime causation candidate.
In a recent article discussing aulism
and genetics, Herbert et <il. warned that
"'environmentally responsive genes,' not
specifically associated with the nervous
system, but potentially associated with
systemic changes in autism, have not
hitherto received sufficient attention in
autism genetics investigations"'' (p. 671).
Although not among their final candidate
genes, they could not have better
described the genes that code for various
components of the hormone system whose
end-product is the neurosteroid, calcitriol,
or activated vitamin D.
Of the neurosteroids involveii in
brain development, calcitriol is unique
- the least understood but arguably one
of the most profound. McGrath et a!,
alerted us to this fact in 2001, pointing
out that vitamin D is "the neglected
neurosteroid."*' In the same paper, the
authors poinled out that calcitriol is a
potent up-regulator of nerve growth factor
and that the vitamin D receptor (VDR)
91
Autism & Vitamin D
is found in a wide variety of brain tissue
quite early in embryogenesis. These two
facts alone led them to conclude that
"hypovitaminosis D should be examined
in more detail as a candidate risk factor for
neurodevelopmental...disorders" (p. 571).
In 2006, Kalueff et al. went
further, suggesting vitamin D offers
"neuroprotection, antiepiieptic effects,
immunomodulation, possible interplay
with several brain neurotransmitter system
and hormones, as well as regulation of
behaviors"' (p. 363). In 2007, Kalueff
and Tuohimaa reviewed the nootropic
properties of vitamin D in even more
detail and concluded the data "stress
the importance of vitamin D prenatal,
neonatal, and postnatal supplementation
for normal brain functioning"^ (p. 16).
tf true, then candidate genes for
autism should include all those that
code for the various proteins involved in
the metabolism, catabolism, transport,
or binding of calcitriol. For example,
expression and nuclear activation of the
Childhood Autism
'^
Cohort
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5'
5
10
Age, y
Autism Spectrum Disorder
VDR are necessary for the effects of vitamin
D. Several DNA sequence variations polymorphisms - occur frequently in
the population and may have biological
effects.'' Their abundance in the human
genome as well as the high frequency
with which VDR polymorphisms occur in
humans make them candidates to explain
variation in risk, but the influence such
polymorphisms have on function is largely
unknown.'"
A pilot study of VDR receptor
variants using a robotically enhanced
multiplexed scanning method did not
detect mutational abnormalities in 24
autistic individuals, but they did not
assess for VDR polymorphisms." VDR
polymorphisms are not associated with
schizophrenia, but a highly significant
association exists between one VDR
polymorphism and larger head size.'^
Mean head circumference is larger and
rates of macrocephaly higher in autism,"
Vitamin D pseudodeficiency, an
inborn error of metabolism involving
the defective conversion of 25(OH)D
to calcitriol, which should lower brain
calcitriol, has never been studied in
relationship to autism other than afflicted
children have the hypotonia, decreased
activity, developmental motor delay,
listlessness, and failure to thrive seen
in common rickets {see Vitamin D and
Autism below). However, children with
the Williams syndrome,'* who often
have elevated calcitriol levels for several
months in very early life,''' usually present
in later life with remarkable sociability,
overfriendliness, empathy, and willingness
to initiate social interaction,'* strikingly
the opposite phenotype of autism.
Vitamin D
Perhaps because the term, vitamin D,
contains the word "vitamin," many people
wrongly assume it is a vitamin. Instead,
vitamin D is the only known
substrate for a steroid hormone
system that - until recent sun
-1
U
Û.
Age, y
Figure 1 : Time trend of autism spectrum disorder and
childhood autism among children born in Denmark,
1990 to 1999, and reported 1995 to 2004: cumulative
incidence proportion (per 10,0000) for each two-year
analytic birth cohort for each disorder. (Reproduced
will permission of American Medical Association,
Atladottiretal., 2007).
.
I
avoidance campaigns - always
began in the skin, not in the
mouth. Ninety percent of human
vitamin D stores come from skin
production, not oral intake.'^'^
Large populations of people
putting small amounts in their
mouths, instead of generating
large amounts in their skins, is
novel to both human experience
and human brain development.
Obviously,
for
such a
change to be compensatory,
oral intake must be adequate to
18000
make up for diminished skin production.
But the skin's production of vitamin D
is rapid and robust, easily exceeding
recognized dietary sources by an order
of magnitude.''' For example, when fairskinned adults sunbathe in the summer
(one, full-body, minimal erythemal dose
of ultraviolet light), for 20 minutes, they
deliver about 20,000 units of vitamin D
to their systemic circulation within 24
hours.^'^ A pregnant woman would have to
drink two hundred glasses of milk or take
50 prenatal multivitamins to do the same.
Equally novel to human experience is
recent advice that humans should avoid
the sun, advice widely and successfully
promulgated by medical and governmental
bodies since the late 1980s. The increase
in autism appears to have begun at the
same time.-' Indeed, most of the popular
graphs showing rising prevalence rates
of autism over the last 20 years (Figure
2) would be strikingly similar to graphs
showing the rising rates of programs
promulgating sun avoidance.
No longitudinal studies of vitamin D
levels exist; that is, we don't know how
successful sun avoidance campaigns
have been in lowering vitamin D levels.
However, if one assumes that at least some
Americans follow their government's and
their physician's advice, then a subgroup
must have had declining vitamin D levels
over time - unless they took enough
supplemental vitamin D to make up for
lack of sun exposure, but few people take
the thousands of daily units needed to do
that.
Certainly, there is evidence that
prominent medical organizations targeted
sun-avoidance campaigns to infants and
children." For example, in 1989, around
the time autism rates began to dramatically
rise, the American Medical Association's
(AMA) Counci I on Scientific Affairs warned
Number of Cases of Autism
U.S. Sduul Ysui 1992-2005 - Agca 6-22
iO sum, p.c., A PuEIIo RicD
'*^
'^"*"
g """"^
I *""
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^ *""
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"^ "
Figure 2: Time trend of autism prevalence for the 50 states and
Puerto Rico. (Reproduced with permission. Fighting Autism, http;//
www.fightingautism.org/idea/autism.php, accessed 5/8/07.)
TOWNSEND LETTER - APRIL 2008
about the dangers of sun exposure and
advised mothers to, "keep infants out of
the sun as much as possible" •'' {p. 383). in
1999, the American Academy of Pediatrics
went further, advising mothers to always
keep infants out of direct sunlight, use
sun-protective clothes and sunblock, and
make sure children's activities In general
minimize sunlight exposure. Furthermore,
quite inexplicably, they reported there was
"no evidence" such procedures would
affect vitamin D levels (p. 330). By 2002,
the Centers for Disease Control (CDC)
reported the efforts were quite successful;
"protection from sun exposure is reported
for a high proportion of children"" {p.
360).
Apparently, no effort was made to
counteract the vitamin D deficiency such
sun protection would predictably induce.
For example, when the AMA's Council on
Scientific Affairs - cited above - warned
about the dangers of sunlight, they did
not even mention that sunlight triggers the
formation of vitamin D. Furthermore, the
Food and Nutrition Board's (FNB) vitamin
D recommendations for young women,
pregnant women, infants, and children
did not change during the decades of sun
avoidance advice (200 units per day for
all children, pregnant women, and young
adults - regardless of weight. That is, they
did and do recommend the same daily
200 units for two kg infants as they do for
100 kg pregnant women). Unfortunately,
in 2003, the American Academy of
Pediatrics cut their longstanding 400
units per day recommendation in half,
apparently simply to comply with FNB
recommendations, and did so despite
their advice four years earlier that infants
and children should avoid sunlight.
Among the body's steroid hormone
systems, the vitamin D system is unique.
Unlike other steroids, the body cannot
make calcitriol de novo from cholesterol to
meet its needs; all of the body's calcitriol
must come from vitamin D, either made
in the skin or ingested orally. Furthermore,
besides its endocrine role in maintaining
the calcium economy, calcitriol has
multiple independent autocrine hormonal
functions, if enough vitamin D substrate is
available.-'''
Most importantly, unlike any other
steroid hormone, the enzyme that first
hydroxylates vitamin D in the liver and
the enzyme that makes calcitrio! in the
tissues both operate below their respective
Michaelis-Menten constants throughout
the full range of their normal substrate
concentrations.^* That means tissue levels
of calcitrioi during brain development
TOWNSEND LETTER - APRIL 2008
directly depend on maternal 25(OH)
D blood levels, which, in turn, directly
depend on the amount of vitamin D the
mother makes in her skin or puts in her
mouth. That is, the rate-limiting step for the
production of this neurosteroid is unique;
concentrations of brain calcitriol literally
depend on human behavior, be it the step
into the sun, the step to the supplements,
the step into the shade, or the step to the
sunscreen.
Calcitriol and the Developing Brain
Like ail steroid hormones (hormone:
from the Greek, to urge on), calcitriol
binds to a member of nuclear hormone
receptor superfamily where the complex
then acts as a molecular switch to signal
its target genes; about 0.57o of the
human genome (200 genes) are primary
targets of calcitriol, and the list is steadily
growing. (Kalueff et al., 2006) If, and only
if, adequate substrate is available, most
organs in the human body produce their
own calcitriol, have a VDR, regulate their
own needs in an autocrine manner, and
thus do not depend on hematogenous
endocrine supply of calcitriol from the
kidney." The brain is such an organ, and
the developing brain is heavily invested
in calcitriol from very early gestation.^"
Both the VDR and the enzyme necessary
to make calcitriol are present in a wide
variety of human brain tissues."
Serum calcitriol levels increase by
50-1007o by the second trimester and by
100% during the third trimester, probably
of placental origin.^" The enzyme
necessary to make calcitriol in human
placenta and decidua increases by several
orders of magnitude starting in very early
gestation.^' Expression of the VDR in the
developing mammalian brain rises steadily
beginning several weeks after conception
where calcitriol induces the expression
of nerve growth factor and stimulates
neuronal cell growth.'- For a review of
vitamin D's multiple effects on brain
development and function, se Brächet et
al. "
In a series of recent animal experiments,
an Australian group found severe maternal
vitamin D deficiency in rats produce
offspring with aberrant apoptosis and
cell proliferation at both the cellular and
molecular level,''' reduced expression of
a number of genes involved in neuronal
structure,"
hyperlocomotion,'*"
and
subtle alterations in both learning and
memory." When vitamin D deficiency
is restricted to late gestation only, such
deficiencies are sufficient to disrupt
adult brain functioning.'^ Recently, a
Autism & Vitamin D
French group confirmed the Australian's
discoveries,
finding
developmental
vitamin D deficiency dysregulates 36
proteins involved in mammalian brain
development,
including
biological
pathways for oxidative phosphorylation,
redox balance, cytoskeleton maintenance,
calcium
homeostasis,
chaperoning,
post-translational modification, synaptic
plasticity, and neurotransmission.'''Severe
maternal vitamin D deficiency leads to
rat pups with increased brain size and
enlarged ventricles (Eyies et al., 2005),
abnormalities similar to those found in
autistic children.""**'
Dysregulated immune responses are
associated with both autism and vitamin
D deficiency. For example, autistic
individuals have T-cell abnormalities and
cytokine excesses'- that show a striking
similarity to that produced by vitamin D
deficiency.*" Animal evidence indicates
some vitamin D deficiency-induced
brain damage may be malleable; that is,
vitamin D may partially reverse the brain
damage, if done early enough.*** These
studies offer hope that exogenous vitamin
D, especially in young autistic children,
may have a treatment effect.
Both the brain and the blood of
autistic individuals show evidence of
chronic inflammation and oxidative stress
no
= TOO
Sqjtcmbcr
June
120
100
Vitamin / Mineral Supplimcni
Placebo
September
June
Figure
3:
Influence
of
vitamin/mineral
supplementation versus placebo on verbal and nonverbal intelligence of 60 English schoolchildren.
p<0.01, (Reprinted with permission from Elsevier,
Benton and Roberts. 1988)
Autism & Vitamin D
(Herbert et al.). Hope for a nootropic
treatment effect lies in calcilriol's
powerful anti-inflammatory properties; its
administration down-regulates production
of inflammatory cytokines in the brain,
which have consistently been associated
with cognitive impairment."''' Furthermore,
calcitriol is remarkably neuroprotective by
stimulating neurotropin release, reducing
toxic calcium levels in the brain, and
inhibiting the production of nitrous oxide;
by its immunomodulating propertiesespecially in reducing inflammatory
cytokines''^; and by increasing brain
glutathione.""^
This last function of vitamin D,
increasing brain levels of glutathione,
may explain the purported link between
heavy metals, oxidative stress, and autism.
The primary route for the neurotoxicity of
most heavy metals is through depletion of
glutathione and subsequent generation of
reactive oxygen and nitrogen species.^^
Furthermore, besides its function as a
master antioxidant, glutathione acts as
a cheldting agent to remove mercury,
cadmium, and nickel. ""^ Kern and Jones
review several studies indicating autistic
individuals have difficulty excreting heavy
metals, especially mercury. If calcitrioldeficient brains are unable to utilize
glutathione properly, and thus unable
to remove heavy metals, they may be
oxidatively damaged by heavy metal loads
normal children easily excrete. It bears
repeating that the amount of calcitriol in
the brain directly depends on how much
vitamin D is made in the skin or put in the
mouth.
Vitamin D and Autism
Although no studies associating
vitamin D levels with cognitive abilities
exist for children, several studies
%
10
Season of Birth
: 11
;iil 1
1 • • • II
1
1
Figure 4: Proportion of birth dates per month of the
passive subgroup of 131 children with autism using
Wing's Autistic Disorder interview Checklist, sociai
functioning classification, {Reprinted with permission,
Tayior and Francis, Stevens et ai,, 2000.)
94
have found significant associations in
adults.^"'^'" Recently, Vanlintand Nugent
reported a very high incidence of vitamin
D deficiency among 337 individuals
with intellectual disabilities in residential
care.^^ The obvious explanation for these
findings is that cognitively impaired
individuals do not go outdoors as often
as higher-functioning individuals and thus
have lower vitamin D levels. However,
two groups found the association after
controlling for outdoor artivities,^''"
making it likely that low vitamin D levels
per se impair cognition.
Although no birth cohort studies exist
that examined vitamin D supplementation
during pregnancy or childhood and later
development of autism, 2,000 units a day
during the first year of life was associated
with a fourfold reduction in the later
development of schizophrenia in males
(Risk ratio = 0.23), but not in females.^*
This is even more interesting when one
remembers that males are four times more
likely to develop autism than females.
In fact, estrogen and testosterone
appear to have quite different effects
on vitamin D metabolism, which may
explain the striking gender differences in
autism. The majority of studies have found
that estrogen has multiple facilitating
effects on vitamin D metabolism while
the same is not true of testosterone." For
example, Epstein and Schneider report,
"the majority of studies have found a
positive effect of estrogen on calcitriol
levels." However, after reviewing similar
studies on testosterone, they go on to
say that, "it is unlikely that testosterone
is a major controlling factor in vitamin
D metabolism" (p. 1261). If estrogen
potentiates the effect of calcitriol, but
testosterone does not, the differences in
concentrations of sex steroids during brain
development may mean that estrogen
protects developing female brains from
calcitriol deficiencies, while testosterone
exposes male ones.
Further evidence that vitamin D
may favorably affect mentation comes
from a series of randomized controlled
interventional studies evaluating the effect
of vitamin D containing multivitamins on
childhood cognition. {For a review, see
Schoenthaler et al.)*^" All 14 studies the
authors reference, including their own,
reported small (one lo two percent) to
modest (five to six percent} improvements,
most of them significant, usually in
nonverbal IQ; the first study was reported
in the Lar)cet in 1988 (Figure 3).^'* More
interestingly, most studies showed no
effect on the majority of children but very
significant effects (157o gains) in about
20% of the children, perhaps the vitamin
D-deficient subgroup.
If vitamin D has any treatment effect,
autistic children may improve with
change in latitude, sun exposure, or diets
containing large amounts of vitamin D rich
fatty fish. Consistent with the theory, not
all children diagnosed with autism retain
that diagnosis in adulthood, and some
improve, either spontaneously or after
the myriad of various treatment programs
available (Herbert et al.). Naturally,
the abundant anecdotal reports of
improvement generate skepticism that the
initial diagnosis was corred, an obvious
possibility. However, a randomized,
placebo-controlled, three-month study of
20 autistic children found multivitamins
with even low doses of vitamin D (150
units or 3.75 meg) significantly improved
sleep and gastrointestinal problems
compared to placebo."^ Furthermore,
a recent small controlled trial reported
substantial benefits for omega-3 fatty acids
in autism.*•' Such long-chain fatty acids
dissociate calcitriol from the vitamin D
binding protein, do so well within the
physiological concentrations of these
fats,*'^ and should increase the amount free
brain caicitriol.
The vitamin D theory of autism predicts
that vitamin D-rich fish consumption
during pregnancy would favorably affect
fetal development and improve the
offspring's mentation although several
factors confound such studies. Some
ocean-going fatty fish, such as salmon.
n
Jin
Fcb Mu Atn Miy lun
M
Ail| Scp Ocl Knv
DK
Jul An» Scp Oct Nov Dit
• crying
- S - hypersctiviiy
• excilabilily
- H - pounding objects
Figure 5: Ratio of days with sleep problems (top)
and ratio of days with t)Ghavioral probiems (bottom)
in each month for a 15 year-oid Japanese male
with autism, {Reprinted with permission, Biackwell
Publishing, Hayashi, 2001).
TOWNSEND LETTER ~ APRIL 2008
herring, and sardines, dre rich sources
of vitamin D, but most freshwater fish
are not. Furthermore, some fish contain
mercury, which may impair mentation.
Fatty fish, fish liver oils, and fish body
oils also all contain omega-3 fats, which
favorably affect mentation. As mentioned
above, fish oils dissociate vitamin D from
its binding protein, raising free calcitriol
levels. Finally, fish liver oils, but not fish
or fish body oils, contains substantial,
variable, but potentially toxic, amounts of
vitamin A, which antagonizes the action
of vitamin D.''""'
Consistent with the vitamin D theory of
autism, the group of women who received
advice to consume sea fish during
pregnancy produced infants with higher
birth weights and had fewer preterm
births than control women.""^ Higher
fish consumption during pregnancy was
associated with better infant cognition
with the greatest effect for infants whose
mothers consumed the most fish.^''
Very recently, low maternal seafood
consumption was associated with infants
with an increased risk of lower verbal IQs
and suboptimal outcomes for prosocial
behaviors and fine motor, communication,
and social development,*"^ outcomes eerily
similar to autism.
In reviewing studies of fish and fish
oi I on pregnancy outcomes, Rogers
et al. found fish consumption has a
positive effect on fetal growth, but fish
oil consumption has little or no effect on
fetal growth.*"" The authors concluded, "It
may be that some constituent of fish other
than omega-3 fatty acids is responsible for
the association of fish intake with birth
weight" (p. 490). Consistent with that
constituent being vitamin D are studies
finding low maternal vitamin D intakes
are associated with low birth weights and
intrauterine growth retardation.''^^''
I know of no latitudinal studies of
autism that would support or refute the
theory that matemal vitamin D deficiency contributes to neurodevelopmental
disorders. That is, if vitamin D played a
role in autism, the disorder should be less
common at more equatorial latitudes, at
least before modern sun avoidance. Recent
CDC prevalence data from 14 states show
no obvious latitudinal variations although
the state with the highest prevalence. New
Jersey, was the second most northern;
Alabama, with the lowest prevalence,
was the most southern of the 14 states
surveyed.''' Studies on season-of-birth
and autism are contradictory, as would
be expected if calcitriol deficiencies can
impair brain development during either
TOWNSEND LETTER - APRIL 2008
gestation or in early childhood. However,
several studies show excessive autism
births in the winter, especially March
(Figure 4), when vitamin D levels are at
their lowest.^'
If vitamin D was useful in the treatment
of autism, then symptoms should improve
in the summer, when vitamin D levels
are the highest. Again, to the best of my
knowledge, no such studies of seasonality
exist. However, a case study reported
dramatic improvements in both sleep and
behavioral problems in the summer (Figure
5)." Furthermore, Hung and Thelander
reported significant improvements in
autistic behaviors during a summer camp
program that included swimming, hiking,
boating, and other activities that would
increase brain levels of calcitriol."
If maternal or postnatal vitamin D
deficiency caused autism, then parents
who rigorously complied with sun
avoidance advice would be more likely
to have children with autism. Parents
from higher socioeconomic strata are
more likely to apply sunscreen to their
children,''' as are parents with a higher
education.'^ Although numerous studies,
especially early ones, linked higher social
class with autism, ascertainment bias
confounds such associations.
If postnatal vitamin D deficiency
caused autism, then rachitic children
would be at greater risk for the disease. To
the best of my knowledge, no studies have
looked at the neuropsychological profiles
of children with vitamin D-deficient
rickets, although such children are more
likely to be hypotonie, display decreased
activity, and have developmental motor
delay." Hypotonia is common in children
with autism,'" as is decreased activity,"
and developmental motor delays are the
rule.«"
Vitamin D deficiency in childhood
is associated with an increased risk of
respiratory infections."' The vitamin D
theory of autism predicts autistic children
would be more prone to respiratory
infections in early life, but a recent study
found no such association.«^ However,
a Japanese study found a strong positive
correlation
(r-0.92)
between
the
prevalence of infantile autism in oneyear birth cohorts and the number of
children hospitalized for pneumonia and
bronchiolitis during their birth year.^'
Finally, if postnatal - and not just
prenatal - vitamin D deficiency causes
autism, then the disease should be rare
before weaning in formula-fed babies
(as infant formula contains significant
amounts of vitamin D when calculated
Autism & Vitamin D
on a per pound basis), and rare in breastfed babies who are supplemented with
vitamin D. However, the disease should
rapidly progress after weaning, unless
the child takes vitamin D supplements
or drinks significant amounts of vil.imin
D fortified milk. Although, to the best
of my knowledge, such infant dietary
studies do not exist, a recent prospective
longitudinal study of 87 infants, some at
high risk for autism and others not, found
no statistically significant neurocognitive
differences between the two groups
at six months."'' That is, the children
who later developed autism appeared
normal at six months. However, around
the age of weaning, the babies who
developed autism first showed impaired
neurocognitive development with rapid
additional impairments occurring between
14 and 24 months, the age many children
begin consuming sodas and juice drinks
instead of vitamin D-enriched formula or
Vitamin D and Skin Color
Vitamin D deficiency discriminates
based on race, or more precisely, skin
color, as melanin in the skin is an effective
and ever-present sunscreen. The vitamin D
theory predicts that neurodevelopmental
disorders would be more common in
children born to darker-skinned mothers.
Such studies are difficult as they raise
sensitive social issues, although three
of four recent US studies found a higher
incidence of autism in black children,
sometimes
appreciably
higher.***""^
Furthermore, at least three studies outside
the US indicate autism rates are higher in
children with immigrant parents and such
immigrants are often dark-skinned. (See
Newschaffer et al. for a review of autism's
epidemiology.**)
Several studies indicate black mothers
are more likely to give birth to infants who
weigh less and die shortly after birth,'" ''^'"
and low birth weight is a clear risk factor
for autism.^'' Black babies also have lower
Apgar scores.'''^ In fact, low Apgar scores
are associated with poor prenatal vitamin
D intake^*" and with autism as welL^' The
CDC and others report black children
have significantly higher rates of mild
mental retardation than white children,
and the difference cannot be explained by
socioeconomic factors.^"'^'MFor a review of
such studies, see Yeargln-Allsopp et al.)
Autism & Vitamin D
Bodnar et al. recently reported that the
incidence of preeclampsia significantly
decreases in white women during the
summer months, but not in black women,
suggesting vitamin D has an effect in such
disorders, as long as skin color is light
enough to rapidly generate vitamin D from
incidental sun exposure.'"" Furthermore,
multivitamins containing vitamin D
reduces the risk of preterm and low birth
weight infants.""'"-- "" Twelve hundred
units (30 meg) per day of vitamin D in the
third trimester significantly increased birth
weights while 600,000 units (15 mg) given
in both the seventh and eighth month of
pregnancy increased birth weights even
more."**
of black women in the northern United
States were vitamin D-sufficient in early
gestation (four to 21 weeks).'"^ That is,
96% of pregnant black women and 63%
of pregnant white women did not have
adequate 25(OH)D blood levels. Their
infants faired little better and showed the
same racial inequity. Furthermore, 45% of
the pregnant black women, but only two
percent of the pregnant white women,
were severely deficient (Figure 6), Prenatal
vitamins containing vitamin D (400 units
or 10 meg) offered linle protective effect
for mother or infant; 90% of the women in
the study reported taking them.
Unless infants are supplemented
after birth via direct supplementation or
via vitamin D-enriched formula, infant
vitamin D levels are remarkably low
with African American infants at highest
risk; 78% of unsupplemented breast-fed
Iowa infants had levels less than 11 ng/ml
Recent studies of vitamin D deficiency
during winter."^ (For those who wonder
during pregnancy show striking raeial
how vitamin D could be important for
inequities in maternal vitamin D levels.
brain development, given its very low
Bodnar et al, recently found that only 37%
levels in breast milk, Hollis and Wagner
of white women and only four percent
discovered that breast milk is always
a rich source of vitamin D - enough
A
White women
Black women
D 23(OH)D 15-3Zng/mL • i;<OH)D >32ng/mL
to maintain healthy levels in infants
n-39
n-50
TI=53
n=57
n=43
n=68
0,')
0.8
Ü.7
aci
0.5
0,4
0,3
0,2
O.I
0
Winler
Spnng
n=50
n=49
0,9
0,8
0.7
0,6
0,5
0,4
0.3
0,2
0,1
0
I
Winler Spnng
C
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
n=50 n=48
Summer Fall
n=47
n=53
Summer Fall
n=45 n=52
Winter
Spring
n
Summer Fall
n=50 n=37 n=
Wjnier
Spring
n=42
n=32
n=35
ii=53
Summer Fall
n=27
n=70
Discussion
Wimei
Spring
Summer Fall
Winler
Spring
Summer Fall
Figure 6: Prevalence of vitamin D deficiency [25{OH)D<15
ng/ml], insufficiency [25(OH)D 15-32 ng/ml], and sufficiency
[25(OH)D>32 ng/ml] among 200 white and 200 black women at
4-21 week gestation (A): at term (B): and in their neonates (C),
{Reproduced with permission. American Society of Nutrition,
Bodnar et al,, 2007),
96
- as long as the mothers took 4,000
units [100 meg] per day.)'"'
In 2002, Nesby-O'Dell et al.
found almost 50% of young black
women of childbearing age had
vitamin D levels lower than 15 ng/
ml and 12% had levels less than
10 ng/ml, compared to one-half of
one percent of white women.'"*
While it is unknown if such levels
approach those seen in the animal
studies reviewed above, it may be
that white children have a huge
developmental
advantage over
black children, an advantage that
begins immediately after conception
- one that has nothing to do with
innate ability and everything to do
with environment.
The
theory
that
vitamin
D
deficiency
contributes
to
neurodevelopmental disorders, in
utero, in infancy, or in childhood, is
of medieal and soeial consequence,
has a tenable mechanism of action,
subsumes several other theories,
implies simple prevention, and is
easily disprovable - all components
of a useful theory. A genetic lesion
in some component of the vitamin
D system would explain its high
monozygotic twin concordance
rate, while decreased neural levels of
calcitriol during later life would explain its
varying phenotypic expression, increased
prevalence in African Americans, and rapid
increase in incidence. Discrepant effects of
sex steroids on ealeitriol metabolism may
explain its male preponderance. Several
types of studies eould easily address the
theory.
For example, is there an association
between sun exposure during pregnancy
or childhood and autism? Are parents of
autistic children more likely to practice
sun avoidance for their children than
controis? Is dietary vitamin D intake
associated with autism? Do rachitic
children show symptoms of autism?
Do autistic symptoms improve in the
summer? Are 25(OH)D levels of mothers
who had autistic children - available
from stored sera - different from controls?
Are there latitudinal variations in autism?
(Latitudinal studies would require similar
and strict diagnostic criteria be used at
different sites, an effort currently under
way by the CDC)
Do autistic symptoms improve when
vitamin D deficiency is treated? Does
ultraviolet irradiation, either natural or
artificial, improve autistic symptoms? Is the
severity of autistic symptoms associated
with 25(OH)D levels? What 25(OH)D
levels, if any, are associated with maximal
mental functioning? Do adequate doses
of vitamin D reduce markers of oxidative
stress? Do they correct immunological
markers? Do they restore normal
glutathione metabolism? Do they promote
heavy metal excretion? Obviously, many
studies await.
The question is, what to do while we
wait for such studies? If we do nothing,
we are in effect continuing an unplanned
naturalistic experiment on those pregnant
women, their unborn children, and
autistic individuals who are currently
vitamin D-deficient due to sun avoidance.
That is, the abrupt change in sun exposure
over the last several decades has almost
certainly had the unforeseen consequence
of lowering brain levels of calcitriol in
many of us. The choice is either doing
nothing while we wait for more studies,
or diagnosing and treating vitamin D
deficiency while we wait for more studies.
A risk/benefit analysis tells us that the risk
of doing nothing is potentially great, while
the risk of treating vitamin D deficiency is
minimal and simply good medicine.
Therefore, while we wait for additional
studies, pregnant women and autistic
children should be assessed for vitamin
D deficiency and promptly treated if
TOWNSEND LETTER - APRIL 2008
found. As the hypothesis that vitamin D
may ameliorate autistic symptoms is only
theoretical, doses that may ameliorate
symptoms are unknown. However, the
window of opportunity to affect brain
development is limited, so time may be
of the essence to detect and treat vitamin
D deficiency in pregnancy and early
childhood.
The critical question of "What is
an ideal 25-hydroxy-vitamin D level?"
must be answered, "In regard to what?"
Levels needed to prevent rickets and
osteomalacia (10 ng/ml) are lower
than those that dramatically suppress
parathyroid hormone levels (20 -30 ng/
ml)."^ In turn, those levels are lower
than levels needed to optimize intestinal
calcium absorption (34 ng/ml)."" In
turn, Lappe et al. recently found levels
of around 40 ng/ml effectively reduced
the incidence of internal cancers.'"
Finally, neuromuscular performance in
4100 older patients steadily improved as
25(OFH)D levels increased, and maximum
performance was associated with levels
around 50 ng/ml."'' Levels for optimal
brain development and functioning are
unknown.
Given what we do know, adequate
25(OFH)D levels are now thought to be
somewhere above 40 and probably closer
to 50 ng/ml."' Ideal 25(OH)D levels are
unknown but they are probably close to
levels the human genome evolved on.
Natural levels, that is, levels found in
humans who live or work in the sun, are
around 50 - 70 ng/ml - levels obtained
by only a small fraction of modern
humans."*
Conclusions
The current "epidemic of autism" may
be iatrogenic, brought on by medical
organizations that advised sun avoidance
without making provisions to compensate
for the predictable consequent "epidemic
of vitamin D deficiency.""'' The theory
should be tested by a variety of properly
conducted epidemiological, genetic, and
interventional trials. FHowever, physicians
caring for pregnant women and autistic
individuals should take immediate steps
to restore adequate vitamin D levels in
deficient patients. In the complete absence
ofsun exposure, humans requiresubstantial
doses of vitamin D to compensate for lack
of sun exposure. The goal of treatment of
vitamin D deficiency is to restore 25(OFH}
D levels to normal summertime levels,
40-70 ng/ml. Those who care for afflicted
individuals should target blood levels
towards the higher reference range in the
TOWNSEND LETTER - APRIL 2008
hope that vitamin D's anti-inflammatory,
immunomodulatory,
and
nootropic
properties will modify autism's clinical
course.
Acknowledgements
1 wish to thank Professor Cedric Garland of
the University of California at 5an Diego,
San Diego, California, Dr. Alan Kaluev of the
National Institutes of Mental Health, Bethe&da,
Maryland, Dr. Coleen Boyle, Centers for
Disease Control, Atlanta, Georgia, and Dr.
Hjördis Adadottir of the University of Aarhus,
Denmark for reviewing the manuscript and
making many useful suggestions.
A shortened version of this article appeared in
Medical Hypotheses.
Declarations of Interest
Dr. Cannell heads Ihe non-profit educational
group, "The Vitamin D Council."
John Cannell, MD
Department of Psychiatry
Atascadero State Hospital
10333 El Camino Rea
Atascadero, CA 93422
805 468-2061;
[email protected]
Notes
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TOWNSEND LETTER - APRIL 2008