The Role of Vitamins in Autism Spectrum Disorder: What Do We Know?

Abstract

Vitamin or mineral supplementation is considered to be the most commonly used medical treatment for autism spectrum disorder (ASD), in addition to other interventions such as neurological and psychological interventions. There is not much evidence of therapeutic efficacy between vitamin and mineral supplementation and improvements in ASD. However, several researchers have noted that patients with ASD have various metabolic and nutritional abnormalities including issues with sulfation, methylation, glutathione redox imbalances, oxidative stress, and mitochondrial dysfunction. There is some evidence that vitamin and mineral supplementation may support these basic physiologic processes. Recently, the nutritional status of ASD patients has been gaining focus in this particular area. Pointing out the nutritional status as a potential etiological factor for attention/communication disorders, more importance has been given to this particular point. Moreover, autistic specific considerations like the feature and behavior of ASD might be increased or at least fall in the higher risk due to the sub-optimal nutritional status.

Full text

1 23
Journal of Molecular Neuroscience
ISSN 0895-8696
J Mol Neurosci
DOI 10.1007/s12031-018-1237-5
The Role of Vitamins in Autism Spectrum
Disorder: What Do We Know?
Geir Bjørklund, Mostafa I.Waly,
Yahya Al-Farsi, Khaled Saad, Maryam
Dadar, Md.Mostafizur Rahman, Amira
Elhoufey, Salvatore Chirumbolo, et al.

1 23
Your article is protected by copyright and
all rights are held exclusively by Springer
Science+Business Media, LLC, part of
Springer Nature. This e-offprint is for personal
use only and shall not be self-archived in
electronic repositories. If you wish to self-
archive your article, please use the accepted
manuscript version for posting on your own
website. You may further deposit the accepted
manuscript version in any repository,
provided it is only made publicly available 12
months after official publication or later and
provided acknowledgement is given to the
original source of publication and a link is
inserted to the published article on Springer's
website. The link must be accompanied by
the following text: "The final publication is
available at link.springer.com”.

The Role of Vitamins in Autism Spectrum Disorder: What Do We Know?
Geir Bjørklund
1
&Mostafa I. Waly
2
&Yahya Al-Farsi
3
&Khaled Saad
4,5
&Maryam Dadar
6
&Md. Mostafizur Rahman
7,8
&
Amira Elhoufey
5,9
&Salvatore Chirumbolo
10,11
&Jagoda Jóźwik-Pruska
12,13
&Joanna Kałużna-Czaplińska
12,13
Received: 26 September 2018 /Accepted: 29 November 2018
#Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Vitamin or mineral supplementation is considered to be the most commonly used medical treatment for autism spectrum
disorder (ASD), in addition to other interventions such as neurological and psychological interventions. There is not much
evidence of therapeutic efficacy between vitamin and mineral supplementation and improvements in ASD. However,
several researchers have noted that patients with ASD have various metabolic and nutritional abnormalities including
issues with sulfation, methylation, glutathione redox imbalances, oxidative stress, and mitochondrial dysfunction. There is
some evidence that vitamin and mineral supplementation may support these basic physiologic processes. Recently, the
nutritional status of ASD patients has been gaining focus in this particular area. Pointing out the nutritional status as a
potential etiological factor for attention/communication disorders, more importance has been given to this particular point.
Moreover, autistic specific considerations like the feature and behavior of ASD might be increased or at least fall in the
higher risk due to the sub-optimal nutritional status.
Keywords Autism .Vitamins .Vitamin supplementation .Nutrition
Introduction
Autism spectrum disorder (ASD) is a complex as well as a
frequent neurodevelopmental disorder that usually begins at
or before the children are 3 years old (Kałużna-Czaplińska
et al. 2017; Kirby et al. 2017). It is observed through several
abnormalities in behavior including but not limited to lacking
in interactions, communications (verbal and nonverbal),
movements, and activities (Bjørklund et al. 2016; Elserogy
et al. 2017). It has been reported that younger children diag-
nosed at 30 months or earlier are more probably to experience
very positive outcomes than children diagnosed at 31 months
or older, indicating an earlier diagnosis of ASD symptoms
could be related with an increased likelihood for
*Geir Bjørklund
bjorklund@conem.org
1
Council for Nutritional and Environmental Medicine (CONEM),
Toften 24, 8610 Mo i Rana, Norway
2
Department of Food Science and Nutrition, College of Agricultural
and Marine Sciences, Sultan Qaboos University, Muscat, Oman
3
Department of Family Medicine and Public Health, College of
Medicine and Health Science, Sultan Qaboos University,
Muscat, Oman
4
Department of Pediatrics, Faculty of Medicine, Assiut University,
Assiut, Egypt
5
CONEM Upper Egypt Pediatric Research Group, Assiut University,
Assiut, Egypt
6
Razi Vaccine and Serum Research Institute, Agricultural Research,
Education and Extension Organization (AREEO), Karaj, Iran
7
Department of Environmental Sciences, Jahangirnagar University,
Dhaka, Bangladesh
8
Graduate School of Environmental Science, Hokkaido University,
Sapporo, Japan
9
Department of Community Health Nursing, Faculty of Nursing,
Assiut University, Assiut, Egypt
10
Department of Neurosciences, Biomedicine and Movement
Sciences, University of Verona, Verona, Italy
11
CONEM Scientific Secretary, Verona, Italy
12
Institute of General and Ecological Chemistry, Department of
Chemistry, Technical University of Lodz, Lodz, Poland
13
CONEM Poland Chemistry and Nutrition Research Group, Lodz
University of Technology, Lodz, Poland
Journal of Molecular Neuroscience
https://doi.org/10.1007/s12031-018-1237-5
Author's personal copy

overdiagnosis or better feedback to intervention efforts
(Wiggins et al. 2012). ASD more likely remains incurable
because of diagnosis lost or elderly identification of ASD
symptoms, indicating the fact that there are no medicines that
can treat the core symptoms (Helt et al. 2008;Andersonetal.
2014). There are numerous choices for ASD patients such as
behavioral treatments, physiological treatments, and some-
what inconceivable treatments that daily worry parents
(Schreck 2014).
Nonetheless, pharmaceuticals can be used to assist func-
tionality of people with ASD. For instance, pharmacotherapy
can be used to manage and control high energy levels, inabil-
ity to focus, depression, or seizures. It has been utilized to
complement other therapies while managing problematic
symptoms associated with the conditions of ASD
(Broadstock et al. 2007;GrabbandGobburu2017). In recent
years, there has been an increase in focus towards the nutri-
tional status of ASD children in the field. As one of the pro-
posed causation factor in the disorder and its pathogenesis,
nutrient deficiencies were particularly stressed in this regard.
Furthermore, the nature of the characteristics of ASD and its
behavior and autistic specific interventions may increase the
risk of sub-optimal nutrition.
For maintaining human health, vitamins, minerals, fatty
acids, and necessary amino acids are inevitable as they play
crucial role like as enzymatic cofactors in the neurotransmitter
production as well as metabolism of fatty acid (MacFabe et al.
2007; Obrenovich et al. 2015;Castroetal.2016; Gao et al.
2016; Saghazadeh et al. 2017; El-Ansary et al. 2018).
Insufficient intake of vitamins and minerals through poor food
habit has been considered as one of the main contributing
factors to numerous child health problems such as anemia,
scurvy, hypothyroidism, rickets, and so on due to lack of iron,
vitamin C, iodine, and vitamin D, respectively, in the world
(Ali et al. 2016;Kočovská et al. 2012;Cannell2017;
Kočovská et al. 2017; Adams et al. 2018). However, factors
like digestion capacity, absorption, metabolic system, and de-
mand have a significant impact on nutritional status along
with food intake. It has been focused on the interrelationship
between possible causes and effects such as metabolic imbal-
ances and developmental abnormalities that are closely related
to attention deficit disorder (Breakey 1997;Garipardicetal.
2017), learning disorders, intellectual development violence,
and other serious antisocial behavior, which probably are re-
lated to cell danger response (Carlton et al. 2000; Schoenthaler
et al. 2000; Naviaux 2014). Mitochondrial dysfunction, in-
flammation, immune dysregulation, and oxidative found in
the brain of ASD individuals indicate the biological basis for
the reported behavioral problems (Goh et al. 2014;Rossignol
and Frye 2014; Naviaux et al. 2015).
This contribution aims to evaluate the results of several
vitamin treatment studies conducted on patients with ASD
and the efficiency and safety of the nutritional interventions
in ASD and henceforth to trace a future remark about the role
of vitamin supplementation in ASD.
Food Selectivity in ASD Patients
Studieshavereportedthatcomparedtonormalchildrenfood
selectivity is higher in ASD children who in turn may restrict
the diet patterns with a significant risk of nutritional inadequa-
cy (Cornish 1998;Reynoldsetal.2012). Causes of ASD are
unknown, and associations between the nutritional status of
mother and/or their interconnections with genetic variations
have yet to be reported successfully (Schmidt et al. 2011).
Cornish (1998) who studied 17 cases of ASD patients aged
between 3 and 10 years did one of the earliest studies on the
diets of ASD children. The result of the study was as follows:
53% of the studied cases had insufficient nutrient intakes in
terms of the nutrients vitamin C, iron, vitamin D, niacin, ribo-
flavin, vitamin B
6
, calcium, and zinc. Also, the intake of food
types was extremely narrow.
Moreover, they also had very specific food preferences
such as too wet/dry, the color of food, food shape, and even
packaging type and brand. Food screening and the offering of
new foods were noticed to be the most severe challenge for
children with ASD (Cornish 1998). In those years, few studies
compared nutritional intake between ASD children and
neurotypical children. Ho et al. (1997)andCornish
(1998) made a comparison between the nutritional intake
of children with ASD and the nationally recommended
intake values. Ho et al. (1997) demonstrated that most of
the studied cases failed to meet guidelines for at least one
of their specified nutrients.
Frank Deficiencies in ASD Patients
Approximately half of the children included in Cornish’s
study had lower calcium, iron, niacin, vitamin B
6
, vitamin
C, vitamin D, and zinc, which was not reflected in their sam-
ple except in the case of vitamins. More recent studies, con-
ducted by Herndon et al. (2009), who compared the consump-
tion of macro- and micronutrients and diet pattern servings by
ASD (n= 46) and neurotypical (n= 31) children were differ-
entiated using 3-day diet records. The group with ASD con-
sumes significantly higher vitamins B
6
and E and nondairy
protein servings, less calcium, and fewer dairy serving
(Herndon et al. 2009). Similarly, Hyman et al. (2012)studied
ASD children and control groups consumed similar amounts
of nutrients from food. Only ASD children aged 4 to 8 years
consumed significantly less energy, vitamins A and C, and the
trace element zinc and those 9 to 11 years consumed less
phosphorous (Hyman et al. 2012). A larger proportion of chil-
dren with ASD met recommended levels for vitamins K and
J Mol Neurosci
Author's personal copy

E. Few cases in either group met the recommended intakes for
fiber, choline, calcium, vitamin D, vitamin K, and potassium.
However, different age groups reported consuming excessive
amounts of sodium, folate, manganese, zinc, vitamin A (reti-
nol), selenium, and copper. No differences were observed in
the nutritional status of children given specified diets (Hyman
et al. 2012).
Metabolic Status in ASD Patients
The participants in a study conducted by Adams et al. (2011)
were children aged 5–16 years (n= 55) compared with
nonsibling, neurotypical controls (n= 44) of similar age, gen-
der, and geographical distribution. The study measurements
included vitamins, biomarkers of vitamin status, minerals,
plasma amino acids, plasma glutathione, and biomarkers of
oxidative stress, methylation, sulfation, and energy production
(Adams et al. 2011). The study concluded that the ASD chil-
dren showed significantly different nutritional and metabolic
status, including biomarkers indicative of vitamin deficiency,
enhanced oxidative stress, and lowered capacity for energy
transport, sulfation, and detoxification (Adams et al. 2011).
Maternal Nutrient Status in ASD Patients
A population-based case-control study by Schmidt et al.
(2011) explored interconnections of genetic factors involved
in one-carbon transferred through the mother or child. The
study showed that mothers of children with ASD less often
that than those of neurotypical children took prenatal vitamins
before pregnancy. Interaction effects were prominent for
mother and child having a greater risk for ASD, while mothers
were not taking vitamins during pregnancy. However, an in-
creased risk was found for children of mothers who had dif-
ferent one-carbon gene variants related to the metabolism
pathway with no vitamins intake during pregnancy (Schmidt
et al. 2011). In their study, the maternal prenatal vitamin con-
sumption was reported 3 months before pregnancy to delivery
for 269 children (97%) with typical development and 276
children (96%) with ASD (Schmidt et al. 2011).
Children with ASD are usually selective and likely to be
nutrient deficient. Thus, the risk for the nutritional inadequacy
of children on restricted diets remains an area of scientific
interests (Kałużna-Czaplińska and Jóźwik-Pruska 2016).
Casein-free diet has been reported as a cause of lowering the
cortical bone thickness in children (Hediger et al. 2008). The
use of megavitamin intervention began in the early 1950s with
the treatment of schizophrenic patients. Pyroxidine (vitamin
B
6
) was first used with children diagnosed with Bautism
syndrome^when speech and language improvement was ob-
served in some children due to large doses of B
6
(Nye and
Brice 2005). The recent literature data show that vitamin sup-
plementation is becoming very popular in the context of au-
tism (Fig. 1). Adams et al. (2011) suggested that the oral
supplementation of vitamins and minerals for ASD children
might improve their nutritional as well as metabolic status.
Therefore, it is fundamental to assess which kind of vitamin
supplementation has reached the goal to ameliorate the neu-
ropsychological and nutritional disorders potentially related to
ASD. List of vitamins and their multiple functions in the hu-
man body and role in autism is summarized in Table 1.
BVitamins
For proper neuronal function, it is essential to have an adequate
amount of the B vitamins folic acid (vitamin B
9
), vitamin B
12
,
and vitamin B
6
. However, their deficiencies have been report-
ed to associate with an increased risk of neurodevelopmental
disorders, psychiatric disease, and dementia. Furthermore, B
vitamin absorption, metabolism, and function are attributed to
gene polymorphisms and are related to the enhanced occur-
rence of psychiatric and cognitive disorders and, in addition,
B vitamins play vital roles in methyl group donation for syn-
thesis of proteins, lipids, nucleic acids, neurotransmitters, and
hormones (Mitchell et al. 2014). An enhanced risk of behav-
ioral and mood disorders, elevated levels of serum homocys-
teine, and heart disease were recently associated with vitamin
B deficiency (Almeida et al. 2008;Fluegge2017).
Folic Acid and Folate
Folic acid and folate (the saline form) are water-soluble vita-
mins that in humans are entirely consumed through the dietary
intake (Greenblatt et al. 1994). Folic acid has a vital role dur-
ing neural development and acts as a coenzyme in the one-
carbon metabolic pathway, which is used in cell proliferation,
DNA synthesis, and immune function (Sun et al. 2016).
During pregnancy, large amounts of folic acid are required,
and thus there is a substantial risk of deficiency (Scholl and
Johnson 2000). It has been known for decades that folate
deficiency or its abuse while embryogenesis has been consid-
ered a substantial risk factor for the defects in the neural tube
in the fetus. Studies have been reporting that folate nutritional
adequacy is also essential for normal fetal growth and brain
development (Mattson et al. 2002; Wilson et al. 2007; Julvez
et al. 2009;Rozaetal.2010; Valera-Gran et al. 2017).
However, a large proportion of the women in reproductive
age usually have folate deficiency and do not use folic acid-
containing supplements or even eat fortified cereals (Scholl
and Johnson 2000). The most important food sources of folate
include orange juice, white bread, green salad, eggs, alcoholic
beverages, coffee, tea, whole milk, whole wheat, rye, other
dark bread, and spaghetti with tomato sauce (Subar et al.
J Mol Neurosci
Author's personal copy

1989; Talaulikar and Arulkumaran 2013). Representative data
from the second National Health and Nutrition Examination
Survey (NHANES II) was examined and observed no signif-
icant difference in folate intake of women surveyed (207 ±
2.9 μg/day) with the recommended dietary allowance (RDA)
for the nonpregnant state (180 μg/day), and approximately
90% of the women consumed 400 μg folate/day (the RDA
for pregnancy) and only ≈10% of the women met the preg-
nancy RDA. More black (26%) than white (18%) women had
very low folate intakes (≤100 μg/day) (Subar et al. 1989).
Suren et al. (2013) examined the association between maternal
use of prenatal folic acid supplements and subsequent risk of
ASD in children. The sample size for their study was 85,176
children who were chosen from the population-based, pro-
spective Norwegian Mother and Child Cohort Study (MoBa)
(Surén et al. 2013). In the all cases, mother consumed folic
acid from the beginning of 4 weeks before to the 8 weeks of
pregnancy. Results indicated that prenatal consumption of
folic acid as diet supplements at the time of conception was
associated with a lower risk of ASD in the MoBa cohort
(Surén et al. 2013). Roza et al. (2010) investigated the associ-
ation between folic acid use of the mother during pregnancy
and child behavioral development. Their results indicated that
due to the intake of folic acid-containing supplements,
mothers have typical developed children with fewer behavior-
al abnormalities at 18 months of age, as well as high scores on
verbal, verbal-executive function, social competence, and at-
tention measures at 4 years and reduced hyperactivity and peer
problems at 8 years (Julvez et al. 2009). Numerous defects in
the metabolism of folate have been linked to ASD
(Vahabzadeh and McDougle 2013). Studies reported the glu-
tathione abnormalities might be interrelated with ASD which
might be correlated with the polymorphism in folate-related
pathway genes and disorders in folate-related metabolism
Frye and James 2014;Fryeetal.2018). Folate is mainly
transported through the choroid plexus epithelium by using
energy-dependent endocytosis.
Cerebral folate deficiency is a disorder inwhich the concen-
trations of folate are low in the cerebrospinal fluid (CSF) but
normal in the blood. Treatment with folate has normalized the
CSF folate and improved the neurological manifestations
(Ramaekers et al. 2002; Ramaekers et al. 2005, Frye et al.
2018). Many studies have demonstrated that patients with
ASD usually had a folate deficiency, which was improved after
treatment with folinic acid (Moretti et al., 2005;Ramaekers
et al. 2005; Ramaekers et al. 2007; Moretti et al. 2008; Frye
and Rossignol 2014). However, a study revealed no evidence
for an association between early folic acid supplements for
reduced risk of ASD in offspring of women compared with
women with no supplement use in the same period (Virk et al.
2016). The most recent randomized, double-blind placebo-
controlled trial (Frye et al. 2018) on patients with nonsyndrom-
ic ASD treatment with high-dose folinic acid for 3 months
resulted in improvement in verbal communication as com-
pared with placebo (Frye et al. 2018). Another study revealed
that folate receptor α(FRα) autoantibodies (FRAAs) are com-
mon in ASD patients. The binding of FRAAs to the FRαcould
disrupt transport of folate across the blood-brain barrier (Frye
et al. 2017). On the other hand, the overexpression of FRαin
the early fetal thyroid indicates that maternal FRAAs during
fetal and neonatal exposure could affect thyroid development
and may contribute to the ASD pathology (Frye et al. 2017).
In conclusion, various studies showed some evidence on
the treatment with folinic acid might improve the autistic
symptoms and the effect of the periconceptional use of prena-
tal vitamins. Maternal folic acid consumption may reduce the
risk of having children with ASD, especially for genetically
susceptible mothers (Schmidt et al. 2011; Schmidt et al. 2012;
Faucher 2013). However, one of the veryfew studies (Tamura
et al. 2005) found no differences in neuropsychological test
scores between children exposed to low and high folate in
pregnancy. The results of Tamura et al. (2005) may be ex-
plained by their small sample number of mothers with low
plasma folate and the follow-up of a nonpopulation-based
Fig. 1 The frequency of reports
concerning ASD and vitamins
(2007–2017). The literature
review was based on PubMed
sources for the following phrases:
ASD or autistic or autism and (A)
vitamins; (B) vitamin B
9
or B
9
or
folate or folic acid; (C) vitamin
B
12
; (D) vitamin B
6
or pyridox-
ine; (E) vitamin B
1
; (F) vitamin C
or ascorbic acid; (G) vitamin D;
and (H) vitamin E
J Mol Neurosci
Author's personal copy

Table 1 The different types of vitamins used in ASD with information about the treatment efficiency
Vitamin Role in the human body Probable consequences of improper level Treatment efficiency in ASD
patients (Adams 2013)
References
B
9
(folate) Participates in the synthesis of nucleic acids;
essential for the proper functioning of the
nervous system; helps to deal with stress;
in the fetal period, folic acid regulates the
development of nerve cells
Affective disorders (depression, anger) Worse 5% Sun et al. (2016), Mattson et al. (2002), Wilson
et al. (2007), Julvez et al. (2009), Roza et al.
(2010), Valera-Gran et al. (2017), Reynolds
et al. (1984), Abou-Saleh and Coppen
(1989), Fava et al. (1997), Fafouti et al.
(2002), Fraguas et al. (2006), Fava and
Mischoulon (2009)
No change 50%
Improvement in 45%
B
12
Essential cofactor in methionine
transmethylation/transsulfuration
metabolism
Anemia, cognitive impairment, affective
disorders (depression, anger)
Wor se 6% Mo rri s et al . ( 2007), Selhub et al. (2009),
Hendren et al. (2016), Reynolds et al.
(1984), Abou-Saleh and Coppen (1989),
Fava et al. (1997), Fafouti et al. (2002),
Fraguas et al. (2006), Fava and Mischoulon
(2009)
No change 22%
Improvement in 72%
B
6
Involved in neurotransmitter synthesis, gene
expression; cofactor in many reactions
(e.g., transamination, decarboxylation);
important role in brain development
Anemia associated with depression; impaired
immune function; may be associated with
convulsive seizures
Alone Worse 8% Hvas et al. (2004), Almeida et al. (2016),
Spinneker et al. (2007)No change 63%
Improvement in 30%
With magnesium Worse 4%
No change 46%
Improvement in 49%
B
1
Essential for the proper functioning of
the nervous system; participate in the
metabolism of carbohydrates
CNS diseases; Wernicke-Korsakoff syndrome,
beriberi; may cause language deficiency;
strong association with ASD
No data available Obrenovich et al. (2015)
C Antioxidant properties; essential for proper
functioning of the body; participates in
enzymatic reactions
Scurvy, impaired immune function Worse 2% Arrigoni and De Tullio (2002)
No change 52%
Improvement in 46%
A Improvement of gut microbiota; increased
plasma retinol, CD38, and RORA mRNA
Impairment of central nervous system
development; a decrease of CARS score;
increased serum 5-hydroxytryptamine
(5-HT) levels
No data available Liu et al. (2017)
Guo et al. (2018)
D Play a role in brain development and
function, mood regulation; e.g.,
neuronal differentiation, axonal
connectivity, dopamine ontogeny,
immunological modulation;
transcriptional control over a large
number of genes
Deficiency may contribute to the pathogenesis
of certain psychiatric disorders, e.g.,
depression; strong association with ASD
No data available Berk et al. (2007), Fernell et al. (2015)
J Mol Neurosci
Author's personal copy

sample of educationally and environmentally deprived wom-
en in their study (Tamura et al. 2005).
Vitamin B
12
Vitamin B
12
is an essential cofactor in methionine
transmethylation/transsulfuration metabolism. Severe deficiency
of vitamin B
12
, regardless of serum folate, was associated with a
significantly increased prevalence of both anemia and cognitive
impairment (Morris et al. 2007; Selhub et al. 2009; Hendren
et al. 2016). Research indicates that affective disorders such as
depression and anger may be linked to vitamin B
12
and/or folic
acid deficiency (Fava et al. 1997;Fafoutietal.2002;Fraguas
et al. 2006; Fava and Mischoulon 2009). Supplementation with
B
12
has the potential to improve methylation capacity (S-
adenosylmethionine/S-adenosyl-l-homocysteine) and the
Bredox status^in ASD children (Hendren et al. 2016). A 3-
month open-label trial study of 48 ASD children involved the
use of injectable methyl B
12
combined with folinic acid.
Children with ASD showed improved antioxidant capacity with
significant increases in cysteine and glutathione (GSH) while
oxidized glutathione improved to near-normal levels.
However, the treatment did not improve the metabolism of me-
thionine or methylation capacity. Patients showed improve-
ments in behavior, but the details were not reported in the study
by James et al. (2009). Bertoglio et al. (2010) investigated the
impact of methyl B
12
treatment in the improvement of behavior
in ASD children in 30 subjects who completed a 12-week,
double-blind study and 22 subjects completed a 6-month exten-
sion study. Results showed no statistically significant mean dif-
ferences in behavior tests or glutathione status were identified
between active and placebo groups (Bertoglio et al. 2010). A
studyfromOmanfoundasignificant difference in vitamin B
12
between 40 children with ASD and 40 neurotypical controls
(Al-Farsi et al. 2013). The study demonstrates how important
it is to ensure sufficient intakes of essential nutrients by ASD
children to alleviate any effect due to nutrient deficiencies.
Numerous studies proposed that some children with ASD have
changed the metabolism of B vitamin and decreased methyla-
tion capacity (Main et al. 2010). Limited research has identified
independent relevance between the functional gene variants
within the methionine, B vitamin-dependent folate, and
transmethylation process and ASD. These variants include
dihydrofolate reductase (DHFR), solute carrier family 19, mem-
ber 1 (SLC19A1, RFC1), 5,10-methylenetetrahydrofolate re-
ductase (MTHFR), transcobalamin II (TCN2), 5-
methyltetrahydrofolate-homocysteine methyltransferase
(MTRR), and catechol-O-methyltransferase (COMT) (Rodier
et al. 1996; James et al. 2006;Adamsetal.2007; James et al.
2010). Hendren et al. (2016) conducted a large RCTwith inject-
able methyl B12 in ASD children compared with placebo. The
Clinical Global Impressions-Improvement (CGI-I) score was
statistically significantly improved in patients receiving methyl
B
12
than in the placebo group. However, no improvements were
reported in the parent-rated Aberrant Behavior Checklist or
Social Responsiveness Scale (Hendren et al. 2016). Clinical
improvement among the treatment group was positively associ-
ated with an increase in the levels of methionine, decrease in S-
adenosyl-l-homocysteine (SAH), and improvements in the S-
adenosylmethionine/S-adenosyl-l-homocysteine ratio, demon-
strating an enhancement in the cellular methylation capacity in
children with ASD (Hendren et al. 2016). Also, the important
role of vitamin B
12
in brain development and ASD has been
revealed. Vitamin B
12
exists in different forms, including
methylcobalamin and adenosylcobalamin, which in the
cytoplasm serve as cofactors for methionine synthase. Zhang
et al. (2016) analyzed the levels of vitamin B
12
in postmortem
frontal cortex from children with ASD (< 10 years) and com-
pared the results with the levels in control subjects (< 13 years).
In the study, the average total levels of vitamin B
12
,
methylcobalamin, and adenosylcobalamin were lower in the
ASD children than in the controls (Zhang et al. 2016). Boston
Birth Cohort, an ongoing longitudinal prospective birth cohort
study, showed that high levels of maternal vitamin B
12
(600 pmol/L) in pregnancy were also related to elevated risk
of ASD in offspring. Also, the ASD risk was greater if the
mothers had both high prenatal levels of vitamin B
12
and folate
(Raghavan et al. 2016). Excessive levels of both vitamin B
12
and
folate may occur in pregnant women on a diet rich in natural
dietary folates who also take supplements containing folic acid
(Raghavan et al. 2018).
Pyridoxine (Vitamin B
6
)
Vitamin B
6
(pyridoxine) is a water-soluble vitamin that acts as
an important coenzyme in several reactions involved in lipid,
carbohydrates, and amino acid metabolism. High-dose sup-
plementation of vitamin B
6
with magnesium has been studied
in many double-blind, placebo-controlled studies, with nearly
all reported improvement in behavioral manifestations.
However, the studies had many limitations including small
sample size and using scales of inadequate validity, but in
general, the studies recommended the beneficial effect for
ASD patients (Marti 2014;Adams2015). A study addressed
the biochemical basis of vitamin B
6
therapy in patients with
ASD by evaluating of total vitamin B
6
level in the plasma of
those ASD individuals who are not taking supplements com-
pared to controls, which are taking supplements. It has been
reported that 77% of the ASD children had high levels of B
6
rather than controls (Adams et al. 2006). Moreover, past stud-
ies by Rimland et al. reported positive results of high-dose
vitamin B
6
and magnesium in treating ASD (Rimland et al.
1998). Furthermore, another study revealed that vitamin B
6
has important roles in brain development, and its maternal
deficiency induces alterations in the expression of genes
J Mol Neurosci
Author's personal copy

related to the gamma-aminobutyric acid (GABA) ergic sys-
tems in the offspring (Almeida et al. 2016).
Thiamine (Vitamin B
1
)
Thiamine (B
1
) is a vital water-soluble vitamin. It has been im-
plicated in many CNS diseases, including ASD. Thiamine de-
ficiency resulted in many neurological diseases, e.g., Wernicke-
Korsakoff syndrome and beriberi. Animal studies showed that
the developing brain is affected by thiamine deficiency
(Obrenovich et al. 2015). The connection between the level of
thiamine and the onset of ASD has been strongly established in
several studies. Thiamine may be involved in ASD through
several factors including apoptosis (transcription factor p53,
Bcl-2, and caspase-3), neurotransmission (serotonin, acetylcho-
line, and glutamate), and oxidative stress (prostaglandins,
cyclooxygenase-2, reactive oxygen species, nitric oxide
synthase, the reduced form of nicotinamide adenine
dinucleotide phosphate, and mitochondrial dysfunction) (vinh
quốcLương and Nguyễn2013). Inadequate intake of thiamine
has been identified as a risk factor for ASD. In a small pilot
study, Lonsdale et al. (2002) investigated the clinical and bio-
chemical effects of thiamine tetrahydrofurfuryl disulfide
(TTFD) on ten ASD children. Thiamine deficiency was ob-
served in three out of the ten patients, and after administration
of TTFD, eight of ten children improved clinically (Lonsdale
et al. 2002). Also, patented technical device suggested a method
for therapy of ASD with an effective amount of a lipid-soluble
thiamine derivative such as TTFD (Lonsdale and Frackelton
2003). A case study indicated that a woman who consumed
herbal remedies containing thiaminase, an enzyme that causes
thiamine deficiency, during pregnancy gave birth to a girl with
ASD (García et al. 2011). Also, an 11-year-old male with ASD
revealed deficiencies of vitamin B in a critically ASD child with
a restricted diet (Baird and Ravindranath 2015). Another study
showed that children with ASD had normal urinary and plasma
thiamine concentrations, while thiamine pyrophosphate was
declined 24% in ASD children (Anwar et al. 2016).
Moreover, language delay, which is often known in children
with ASD, could develop because of infantile thiamine defi-
ciency (Fattal-Valevski et al. 2009).
Vitamin C
Vitamin C (ascorbic acid (AA)) is very popular because of its
antioxidant properties (Arrigoni and De Tullio 2002). For the
human health concerns, AA is considered as one of the most
important and essential water-soluble vitamins as many phys-
iological functions in the human body require it. It is consumed
from fresh fruits, vegetables, and synthetic tablet supplement.
However, several factors are responsible such as stress,
smoking, infections, and burns for the depletion of AA in the
body, which demand higher additional intake through ascorbic
acid supplementation (Naidu 2003). Vitamin C also acts as an
antioxidant, protecting the body against damage from free rad-
icals (Iqbal et al. 2004;Naidu2003).
Al-Gadani (2009) measured oxidative stress and
antioxidant-related parameters in 30 Saudi children with ASD
(22 males and 8 females) aged 3–15 years and in 30 healthy as a
control group. Oxidative stress markers such as lipid peroxida-
tion were found significantly higher in ASD children as well as
antioxidant factors such as vitamin E and vitamin C (nonsig-
nificant), and glutathione was lower compared to the controls
(Al-Gadani et al. 2009). Furthermore, the enzymatic antioxi-
dants glutathione peroxidase (GPx) and superoxide dismutase
(SOD) were found significantly higher in the ASD group com-
pared to the control group. The authors suggested that the Saudi
children with ASD were under H
2
O
2
stress due to GSH deple-
tion and overexpression of SOD together with the unchanged
catalase enzyme. The results of the previous study have report-
ed the insufficient endogenous antioxidant while exogenous
counterpart may play a critical role in preventing oxidative
stress in ASD (Al-Gadani et al. 2009; Krajcovicova-
Kudlackova et al. 2009). Dolske et al. (1993) assessed the ef-
fectiveness of AA (8 g/70 kg/day) as a supplement in a double-
blind, placebo-controlled trial or a supplemental pharmacolog-
ical treatment for ASD children,for30weeksinthetrial(N=
18). The results indicated that use of vitamin C caused signif-
icant improvements in sensorimotor behaviors and reduction in
autism severity behavior when compared to the use of placebo
(Dolske et al. 1993). The authors stated that the improvements
seen with vitamin C (ascorbic acid) treatment are likely due to
the dopaminergic effects of vitamin C. A pilot scale study con-
ducted by Krajcovicova-Kudlackova et al. (2009) measured
plasma concentrations of vitamin C, vitamin E, vitamin A,
beta-carotene, and lycopene in 51 subjects with ASD aged 5–
18 years (27 children aged 5–10 years, 24 subjects aged 11–
18 years). The results revealed that older ASD subjects com-
pared to neurotypical controls had a significantly higher content
of vitamin C and beta-carotene plasma values with 92 and 71%
vs. 54 and 13% of optimal over-threshold values, respectively.
In younger vs. older children with ASD, almost similar plasma
concentrations of vitamins were found. Vitamin E and A status
in plasma level of ASD children showed below a threshold
value, but very little percentage showed over-threshold al-
though there is the nonsignificant difference between ASD
and control (Krajcovicova-Kudlackova et al. 2009). However,
research suggests that plasma concentrations of exogenous an-
tioxidants, vitamin E and vitamin A, and lycopene in ASD
subjects are insufficient. Some studies indicate that there is
evidence that vitamin C brings about significant improvement
in people with ASD (Dolske et al. 1993; Al-Gadani et al. 2009;
El-Ansary et al. 2017).
Recent studies have outlined that vitamin C deficiency in
pediatric cohorts of subjects is relatively frequent and occurs
J Mol Neurosci
Author's personal copy

mainly in at-risk populations having iron overload and neuro-
logic disorders (Golriz et al. 2017). This concern is particularly
stressed for ASD individuals, as children with ASD fail in
meeting recommended nutritional levels of micronutrients
and vitamins, though they are even used in dietary cereal prod-
ucts; they meet insufficient levels of thiamine, calcium, ascor-
bate, and riboflavin (Marí-Bauset et al. 2017). Attempts to
address ascorbate (vitamin C) deficiency by a therapeutic in-
tervention were approached in many further cases of neurolog-
ical disorders, also with fragile X syndrome, although the re-
sults were not encouraging (de Diego-Otero et al. 2014;Frye
and Rossignol 2014).
Vitamin D
Vitamin D has been considered recently as a research interest
in the area of psychiatry. The brain contains vitamin D recep-
tors, which may regulate mood and depressive disorders dur-
ing the insufficiency of vitamin D (Berk et al. 2007). Animal
studieshave confirmed that severe vitamin D deficiency during
pregnancy dysregulates many proteins that are highly critical
for brain development and leads to rat pups with pathological
changes such as increased brain size and enlarged ventricles,
abnormalities similar to those present in children with ASD
(Eyles et al. 2013). Recent studies have demonstrated that the
level of vitamin D in ASD children is significantly lower than
in their counterparts (Ehlayel et al. 2011; Bener et al. 2014;
Cannell 2017;Kočovská et al. 2017; Vinkhuyzen et al. 2017).
Several medical conditions including gastrointestinal prob-
lems, asthma, and allergies have been associated with ASD,
and multiple risk factors, both genetic and environmental, have
been proposed (Pioggia et al. 2014). Among them, vitamin D
deficiency has been suggested to play a crucial role in ASD
(Kočovská et al. 2012; Pioggia et al. 2014;Uğur and Gürkan
2014). Vitamin D plays an important physiological role in bone
growth and development, so a deficiency of vitamin D can
contribute to decreased bone cortical thickness (BCT).
Studies showed children with ASD are reported to have re-
duced BCT (Molloy et al. 2010). Uğur and Gürkan (2014)
measured the serum levels of vitamin D (25-OH-D) and folate
in 54 young children with ASD and 54 neurotypical subjects
(aged 3–8) and compared the two groups according to the
mother’s vitamin D, multivitamin and calcium intake, as well
as the associations with the level of mental development, se-
verity of autism symptoms, and problematic behaviors. Their
results showed no difference in these measures between chil-
dren with ASD and controls. Also, there were no significant
associations between autism severity, problematic behaviors,
mental/developmental levels of ASD children, and serum
values. Many studies investigated plasma levels of vitamin D
directly in individuals with ASD (Uğur and Gürkan 2014).
Meguid et al. (2010) investigated the potential role of vitamin
D in ASD via serum level determination, in a case-controlled
cross-sectional study in 70 Egyptian ASD children. Children
with ASD had a significantly lower level of both calcidiol
25(OH)D (28.5 ng/ml) and calcitriol 1,25(OH)(2)D
(27.1 ng/ml) as well as lower calcium serum values compared
to healthy controls (Meguid et al. 2010). Furthermore, it was
also found that there is no significant influence of birth season
in relation to either vitamin D or ASD compared to controls
(Meguid et al. 2017). Molloy et al. (2010) compared the actual
plasma 25-hydroxyvitamin D (25(OH)D) concentration in a
cohort study of Caucasian males with ASD (n=49;4to8years
old) and a group of age-matched neurotypical boys (n= 40).
No significant group differences were observed (Molloy et al.
2010). However, 54 (61%) of the children in the entire cohort
study had a plasma 25(OH)D concentration of less than
20 ng/ml. Humble et al. (2010) tested vitamin D levels in adult
outpatients with a range of psychiatric disorders and found that
those with a diagnosis of ASD or schizophrenia had signifi-
cantly lower 25-OHD levels than other groups. Also, a consid-
erable improvement in several cases of some of their psychiat-
ric symptoms is that significant improvement of psychosis or
depression was obtained through vitamin D deficiency treat-
ment. However, there are some limitations to the study by
Humble et al. (2010). There may have been a selection bias.
Also, there was very little information on details of the treat-
ment of subjects, and there was no control group. Although
these results of vitamin D status in children and adults with
ASD seems contradicting, of the three studies, two are subject
to significant methodological problems. The study by Molloy
et al. (2010) suffered from the fact that the control children
were likely to have had some degree of inflammation, which
could have affected the vitamin D levels. The study by Humble
et al. (2010) did not have a control group and investigated a
range of disorders, not only ASD. By contrast, in the study by
Meguid et al. (2010), vitamin D was measured appropriately,
and the recruitment of cases and controls minimized the
bias. Taking these studies together, they are suggestive
that there may be a link between low vitamin D and
ASD and this will be an important direction for future
research (Humble et al. 2010;Meguidetal.2010;
Molloy et al. 2010). In a cross section, Williams-Hooker
et al. (2013) compared the calcium and vitamin D intake
of boys with ASD ages (7–12 years) with the dietary ref-
erence intake (DRI). Forty-seven parents or caretaker sub-
jects were included: 22 boys (7–8 years) and 25 of the
subjects of aged 9–12. The results showed that 77.27%
(17 out of 22 males) of ages 7 to 8 consumed significantly
less calcium (P= .0085) and vitamin D (P=.0085) than
the age-appropriate DRI. Ninety-two percent (23 out of
25 boys) aged 9 to 12 consumed significantly less calcium
than the DRI levels (P= .0001). Similarly, 84% (21 out of
25males)aged9to12alsoconsumedsignificantlyless
vitamin D compared with the age-appropriate DRI levels
J Mol Neurosci
Author's personal copy

(P= .0045). Concluding boys with ASD (7 to 12 years)
may be at higher risk for calcium and vitamin D deficien-
cies (Williams-Hooker et al. 2013).
Wang et al. (2016) collected all studies including both se-
rum vitamin D in ASD children and healthy controls and then
meta-analyzed the information, accounting for 870 patients
with ASD and 782 neurotypical controls. Results from this
meta-analysis have shown that levels of serum 25(OH)D in
ASD individuals were significantly lower than controls, attrib-
uting that may be the lower level of vitamin D is a risk factor
for ASD (Wang et al. 2016). Due to the fact of vitamin D
deficiency in ASD, vitamin D supplementation for ASD chil-
dren with insufficient vitamin D is necessary. Jia et al. (2015)
reported a 32-month-old ASD child with vitamin D deficiency
whose autistic manifestations markedly improved after vitamin
D therapy (Jia et al. 2015). Saad et al. (2015)performeda
cohort study of vitamin D supplementation in children with
ASD. Eighty-three ASD children completed a 3-month open-
label trial with the daily oral administration of vitamin D3 at
the dose of 300 IU/kg/day not to exceed 5000 IU/day. Sixty-
seven of the tested children had significantly recovered in core
symptoms, such as behavior, stereotypy, eye contact, and at-
tention span, assessed by autism behavior checklist and
Childhood Autism Rating Scale (CARS) at the end of the trial.
All children with a final serum 25(OH)D levels below
30 ng/ml had no improvements in clinical symptoms, and 31
children of the 45 patients with final serum 25-OHD levels
above 30 ng/ml had improved autism symptoms (Saad et al.
2018; Saad et al. 2015). Another study showed that ASD
scores were significantly reduced on the autism behavior
checklist and CARS in ASD children after a trial of 3 months
with intramuscular injection and oral administration of vitamin
D. The study revealed that treatment effects assessed by the
reduction of total autism behavior checklist scores and total
CARS scores were more evident in younger children with
ASD (Feng et al. 2017). Also, in a study with a total of 79
childreninaged3–18 years with attention deficit hyperactivity
disorder (ADHD) or ASD in the Van region of Turkey reported
that deficiency of vitamin D might induce an increased risk of
ASD (Garipardic et al. 2017). Saad et al. (2016) conducted the
first double-blind RCT with 109 ASD children. The daily dose
used in the therapy group was 300 IU vitamin D
3
/kg/day, not to
exceed 5000 IU/day. After the 4-month study duration, the total
scores assessed respectively by Autism Behavior Checklist
scores, total CARS scores, Social Responsiveness Scale, and
Autism Treatment Evaluation Checklist showed a significant
improvement in the vitamin D treatment group compared with
the placebo group (Saad et al. 2016). Their study is a first but
single center randomized clinical trial with a relatively small
sample size of patients and a great deal of additional wide-scale
studies is needed to validate the efficacy of vitamin D in ASD
critically. Also, child and paternal vitamin D metabolism could
reveal a significant effect in the etiology of ASD (Schmidt et al.
2015;Chirumboloetal.2017).
Vitamin E
Vitamin E, also known as tocopherol, is a fat-soluble vitamin
that plays a significant role as an antioxidant in human health.
Few studies showed some evidence for reduced plasma levels
of vitamin E in children with ASD (Gumpricht and Rockway
2014). Frustaci et al. (2012) reviewed the published studies
about vitamin E and ASD. They found three studies where
vitamin E levels were measured; all the data reported lower
vitamin E levels in children with ASD (Frustaci et al. 2012).
The previous study in combination with decreased glutathione
levels in ASD individuals suggests that the antioxidant de-
fense mechanisms in neuronal oxidative stress are affected
by ASD (Chauhan et al. 2012; Gumpricht and Rockway
2014). Therefore, the combination of reduced vitamin E levels
and raised oxidative stress in ASD patients powerfully pro-
poses an urgent need for a clinical trial of vitamin E therapeu-
tic intervention in ASD.
Vitamin A
It has been reported that vitamin A is capable of increasing the
level of oxytocin via the CD38 process pathway in ASD pa-
tients (Riebold et al. 2011), and therefore, brain activity and
social abilities significantly may beincreased through the oxy-
tocin in the autism patients (Gordon et al. 2013).
Some studies have reported that 77.9% of ASD children
were suffering from vitamin A deficiency (Guo et al. 2018),
which known asthe most important deficiency rate among the
nutrients (Liu et al. 2016). Guo etal. (2018) also demonstrated
that vitamin A deficiency exacerbates ASD symptoms in pa-
tients because it plays an important role in numerous biolog-
ical pathways such as differentiation, proliferation, and devel-
opment of the vertebrate central nervous system. Also, Sun
et al. (2013) reported that ASD patients did not intake the
dietary reference for vitamin A, and due to their specific eating
patterns, their vitamin A level in the serum was lower com-
pared with the control children. Vitamin A deficiency leads to
a decrease in learning and memory functions (Jiang et al.
2012; Hou et al. 2015). More recently, a study of 64 ASD
children with aged 1 to 8 years old that completed a follow-
up of 6-month with vitamin A intervention showed the poten-
tial role of vitamin A in the changes of ASD biomarkers (Liu
et al. 2017). Also, it revealed that supplementation with vita-
min A could be an acceptable therapy for ASD patients to help
to the maintenance of various cellular biochemical reactions in
children with autism. Therefore, the above data indicate sup-
J Mol Neurosci
Author's personal copy

portive data for the important role of vitamin A in the ASD
pathogenesis.
Vitamins and Micronutrient Deficiency
in ASD: How We Can Address the Issue?
Besides the already mentioned cases of vitamin deficiency, a
further intriguing suggestion in neuropathology is that high
doses of vitamins B
1
,B
2
,B
3
,B
5
,B
6
,B
12
, biotin, folate, C, D,
and K are critical for ASD individuals (Adams 2015). Also, it is
suggested that vitamin B
2
and B
6
supplementation is applicable
in decreasing of dicarboxylic acids level in the urine of children
with ASD (Kałużna-Czaplińska et al. 2011). In a case of a
severely ASD child with limp, tachypnea, cough, hypoxia,
and tachycardia induce pulmonary hypertension because of un-
detectable vitamin C level as well as inadequate levels of vita-
min B
1
, vitamin B
6
, vitamin B
12
, and vitamin D (Duvall et al.
2013). Furthermore, recent studies have reported the supportive
role of vitamin K in neural development (DeSoto 2016). On the
other hand, research indicates that vitamin K deficiency may be
more frequent in ASD children than in neurotypical individuals
(Johnson et al. 2008). Therefore, a high percentage of ASD
children met recommendations for vitamin K (Hyman et al.
2012). Biotin is another B vitamin with antioxidant activity that
has typically low levels in the blood of ASD children relative to
controls (Adams et al. 2011).Accordingtoaurinarymarker,
some of the children with ASD in a Greek cohort were reported
for biotin deficiency (Spilioti et al. 2013). Based on the same
study, providing biotin to the children results in the improve-
ment of functional behavior. Also, a study with 28 autism Saudi
male patients revealed that inadequate contents of vitamin D
play an important role in the ASD etiology and severity (El-
Ansary et al. 2018). These data suggest that ASD children may
have dysregulations in vitamin and micronutrient availability
due to the many reasons associated with dietary behaviors and
metabolic imbalance. Also, parents of individuals with ASD
noted that the essential fatty acids, mineral/vitamin supple-
ments, and healthy gluten-free, casein-free, and soy-free diet
were the most effective at improving nonverbal IQ, nutritional
status, and ASD symptoms (Adams et al. 2018).
Concluding Remarks
Many pivotal studies in the field of autism research failed in
elucidating a thorough and clear overview of the different nu-
tritional interventions in ASD, due to the many factors associ-
ated with nutrient biochemistry, pharmacokinetics, and bio-
availability. ASD is a neurodevelopmental disorder recognized
through the presence of disability in social reciprocity, restrict-
ed interests or repetitive behavior, abnormal communication,
and with obvious symptoms by 3 years of age. This complex
psychopathological picture strongly affects also the nutritional
behavior. Furthermore, prenatal vitamins with
periconceptional use could reduce the risk of ASD in children,
principally for genetically susceptible children and mothers.
However, according to a recent study, vitamin supplements
are among the most generally recommended medical interven-
tions, which are approved by 49% of physicians for children
with ASD. A primary diagnosis of metabolic impairments and
nutrition deficiency in ASD patients and appropriate therapeu-
tic approaches in some children with ASD remarkably recover
behavioral deficiencies as well as cognitive abilities. Some
studies proposed that development of nutrient intake against
nutritional and metabolic problems could alleviate the comor-
bidities and symptoms of ASD. Therefore, it is recommended
that all diagnosed adults and children with ASD evaluate for 2–
3 months with a vitamin/mineral supplement. It could start
with a low dose and continue with increasing it, resulting in
minimal risk of adverse effects for many children and adults
with ASD. Expanded studies have reported specific risk factors
related to certain vitamins such as vitamin D and folic acid in
both utero and early life that are possibly related to an elevated
risk of ASD. This would mean that oral vitamin supplementa-
tion is effective in ameliorating the metabolic and nutritional
status of ASD children such as alleviation of glutathione, meth-
ylation, sulfation, oxidative stress, NADH, ATP, and NADPH.
The vitamin groups revealed significantly high improvements,
suggesting a vitamin supplement is an acceptable adjunct ther-
apy to evaluate for most children with ASD and adults. There
is a need for further research to highlight this complex topic.
Compliance with Ethical Standards
Conflict of Interest All authors have read the manuscript and declared
no conflict of interests.
Publisher’sNote Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations.
References
Adams J (2015) Vitamin/mineral supplements for children and adults
with autism. Vitam Miner 3:2376. https://doi.org/10.4172/2376-
1318.1000127
Adams JB, George F, Audhya T (2006) Abnormally high plasma levels of
vitamin B6 in children with autism not taking supplements com-
pared to controls not taking supplements. J Altern Complement
Med 12:59–63. https://doi.org/10.1089/acm.2006.12.59
Adams M, Lucock M, Stuart J, Fardell S, Baker K, Ng X (2007)
Preliminary evidence for involvement of the folate gene polymor-
phism 19 bp deletion-DHFR in occurrence of autism. Neurosci Lett
422:24–29. https://doi.org/10.1016/j.neulet.2007.05.025
Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E,
Gehn E, LorestoM, Mitchell J, Atwood S (2011) Effect of a vitamin/
mineral supplement on children and adults with autism. BMC
Pediatr 11:111. https://doi.org/10.1186/1471-2431-11-111
J Mol Neurosci
Author's personal copy

Adams JB, Audhya T, Geis E, Gehn E, Fimbres V, Pollard EL, Mitchell J,
Ingram J, Hellmers R, Laake D (2018) Comprehensive nutritional
and dietary intervention for autism spectrum disorder—a random-
ized, controlled 12-month trial. Nutrients 10:369. https://doi.org/10.
3390/nu10030369
Al-Farsi YM, Waly MI, Deth RC, Al-Sharbati MM, Al-Shafaee M, Al-
Farsi O, Al-Khaduri MM, Gupta I, Ali A, Al-Khalili M (2013) Low
folate and vitamin B12 nourishment is common in Omani children
with newly diagnosed autism. Nutrition 29:537–541. https://doi.org/
10.1016/j.nut.2012.09.014
Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L (2009) Metabolic bio-
markers related to oxidative stress and antioxidant status in Saudi
autistic children. Clin Biochem 42:1032–1040. https://doi.org/10.
1016/j.clinbiochem.2009.03.011
Ali A, Cui X, Eyles D (2016) Developmental vitamin D deficiency and
autism: putative pathogenic mechanisms. J Steroid Biochem Mol
Biol 175:108–118. https://doi.org/10.1016/j.jsbmb.2016.12.018
Almeida OP, McCaul K, Hankey GJ, Norman P, Jamrozik K, Flicker L
(2008) Homocysteine and depression in later life. Arch Gen
Psychiatry 65:1286–1294. https://doi.org/10.1001/archpsyc.65.11.
1286
Almeida MR, Mabasa L, Crane C, Park CS, Venâncio VP, Bianchi MLP,
Antunes LMG (2016) Maternal vitamin B6 deficient or supplement-
ed diets on expression of genes related to GABAergic, serotonergic,
or glutamatergic pathways in hippocampus of rat dams and their
offspring. Mol Nutr Food Res 60:1615–1624. https://doi.org/10.
1002/mnfr.201500950
Anderson DK, Liang JW, Lord C (2014) Predicting young adult outcome
among more and less cognitively able individuals with autism spec-
trum disorders. J Child Psychol Psychiatry 55:485–494. https://doi.
org/10.1111/jcpp.12178
Anwar A, Marini M, Abruzzo PM, Bolotta A, Ghezzo A, Visconti P,
Thornalley PJ, Rabbani N (2016) Quantitation of plasma thiamine,
related metabolites and plasma protein oxidative damage markers in
children with autism spectrum disorder and healthy controls. Free
Radic Res 50:S85–S90. https://doi.org/10.1080/10715762.2016.
1239821
Arrigoni O, De Tullio MC (2002) Ascorbic acid: much more than just an
antioxidant. Biochim Biophys Acta 1569:1–9. https://doi.org/10.
1016/S0304-4165(01)00235-5
Baird JS, Ravindranath TM (2015) Vitamin B deficiencies in a critically
ill autistic child with a restricted diet. Nutr Clin Pract 30:100–103.
https://doi.org/10.1177/0884533614541483
Bener A, Khattab AO, Al-Dabbagh MM (2014) Is high prevalence of
vitamin D deficiency evidence for autism disorder?: in a highly
endogamous population. J Pediatr Neurosci 9:227–233. https://doi.
org/10.4103/1817-1745.147574
Berk M, Sanders KM, Pasco JA, Jacka FN, Williams LJ, Hayles AL,
Dodd S (2007) Vitamin D deficiency may play a role in depression.
Med Hypotheses 69:1316–1319. https://doi.org/10.1016/j.mehy.
2007.04.001
Bertoglio K, Jill James S, Deprey L, Brule N, Hendren RL (2010) Pilot
study of the effect of methyl B12 treatment on behavioral and bio-
marker measures in children with autism. J Altern Complement Med
16:555–560. https://doi.org/10.1089/acm.2009.0177
Bjørklund G, Saad K, Chirumbolo S, Kern JK, Geier DA, Geier MR,
Urbina MA (2016) Immune dysfunction and neuroinflammation in
autism spectrum disorder. Acta Neurobiol Exp (Wars) 76:257–268
Breakey J (1997) The role of diet and behaviour in childhood. J Paediatr
Child Health 33:190–194. https://doi.org/10.1111/j.1440-1754.
1997.tb01578.x
Broadstock M, Doughty C, Eggleston M (2007) Systematic review of the
effectiveness of pharmacological treatments for adolescents and
adults with autism spectrum disorder. Autism 11:335–348. https://
doi.org/10.1177/1362361307078132
Cannell JJ (2017) Vitamin D and autism, what’snew? Rev Endocr Metab
Disord 18:183–193. https://doi.org/10.1007/s11154-017-9409-0
Carlton RM, Ente G, Blum L, Heyman N (2000) Rational dosages of
nutrients have a prolonged effect on learning disabilities. Altern
Ther Health Med 6:85
Castro K, Klein LS, Baronio D, Gottfried C, Riesgo R, Perry IS (2016)
Folic acid and autism: what do we know? Nutr Neurosci 19:310–
317. https://doi.org/10.1179/1476830514Y.0000000142
Chauhan A, Audhya T, Chauhan V (2012) Brain region-specific glutathi-
one redox imbalance in autism. Neurochem Res 37:1681–1689.
https://doi.org/10.1007/s11064-012-0775-4
Chirumbolo S, Bjørklund G, Sboarina A, Vella A (2017) The role of
vitamin D in the immune system as a pro-survival molecule. Clin
Ther 39:894–916. https://doi.org/10.1016/j.clinthera.2017.03.021
Cornish E (1998) A balanced approach towards healthy eating in autism.
J Hum Nutr Diet 11:501–509. https://doi.org/10.1046/j.1365-277X.
1998.00132.x
de Diego-Otero Y, Calvo-Medina R, Quintero-Navarro C, Sánchez-
Salido L, García-Guirado F, del Arco-Herrera I, Fernández-
Carvajal I, Ferrando-Lucas T, Caballero-Andaluz R, Pérez-
Costillas L (2014) A combination of ascorbic acid and α-
tocopherol to test the effectiveness and safety in the fragile X syn-
drome: study protocol for a phase II, randomized, placebo-
controlled trial. Trials 15:345. https://doi.org/10.1186/1745-6215-
15-345
DeSoto M (2016) Speculations on vitamin K, VKORC1 genotype and
autism. Med Hypotheses 96:30–33. https://doi.org/10.1016/j.mehy.
2016.09.013
Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L (1993) A
preliminary trial of ascorbic acid as supplemental therapy for autism.
Prog Neuro-Psychopharmacol Biol Psychiatry 17:765–774. https://
doi.org/10.1016/0278-5846(93)90058-Z
Duvall MG, Pikman Y, Kantor DB, Ariagno K, Summers L, Sectish TC,
Mullen MP (2013) Pulmonary hypertension associated with scurvy
and vitamin deficiencies in an autistic child. Pediatrics 2012-3054.
https://doi.org/10.1542/peds.2012-3054
Ehlayel M, Bener A, Sabbah A (2011) Is high prevalence of vitamin D
deficiency evidence for asthma and allergy risks? Eur Ann Allergy
Clin Immunol 43:81
El-Ansary A, Bjørklund G, Chirumbolo S, Alnakhli OM (2017) Predictive
value of selected biomarkers related to metabolism and oxidative
stress in children with autism spectrum disorder. Metab Brain Dis
32:1209–1221. https://doi.org/10.1007/s11011-017-0029-x
El-Ansary A, Cannell JJ, Bjørklund G, Bhat RS, Al Dbass AM, Alfawaz
HA, Chirumbolo S, Al-Ayadhi L (2018) In the search for reliable
biomarkers for the early diagnosis of autism spectrum disorder: the
role of vitamin D. Metab Brain Dis 33:917–931. https://doi.org/10.
1007/s11011-018-0199-1
Elserogy YM, Saad K, Al-Atram AA, Othman HA, El-Baseer KAA,
Ahmed AE (2017) Chromosomal aberrations in children with au-
tism spectrum disorders in Upper Egypt. Anadolu Psikiyatri Dergisi
18:243
Eyles DW, Burne TH, McGrath JJ (2013) Vitamin D, effects on brain
development, adult brain function and the links between low levels
of vitamin D and neuropsychiatric disease. Front Neuroendocrinol
34:47–64. https://doi.org/10.1016/j.yfrne.2012.07.001
Fafouti M, Paparrigopoulos T, Liappas J, Mantouvalos V, Typaldou R,
Christodoulou G (2002) Mood disorder with mixed features due to
vitamin B12 and folate deficiency. Gen Hosp Psychiatry 24:106–
109. https://doi.org/10.1016/S0163-8343(01)00181-5
Fattal-Valevski A, Azouri-Fattal I, Greenstein YJ, Guindy M, Blau A,
Zelnik N (2009) Delayed language development due to infantile
thiamine deficiency. Dev Med Child Neurol 51:629–634. https://
doi.org/10.1111/j.1469-8749.2008.03161.x
J Mol Neurosci
Author's personal copy

Faucher MA (2013) Folic acid supplementation before and in early preg-
nancy may decrease risk for autism. J Midwifery Womens Health
58:471–472. https://doi.org/10.1111/jmwh.12081_1
Fava M, Mischoulon D (2009) Folate in depression: efficacy, safety,
differences in formulations, and clinical issues. J Clin Psychiatry
70:12–17. https://doi.org/10.4088/JCP.8157su1c.03
Fava M, BorusJS, AlpertJE, Nierenberg AA (1997) Folate, vitamin B12,
and homocysteine in major depressive disorder. Am J Psychiatry
154:426–428. https://doi.org/10.1176/ajp.154.3.426
Feng J, Shan L,Du L, Wang B, Li H, Wang W, Wang T, Dong H, YueX,
Xu Z (2017) Clinical improvement following vitamin D3 supple-
mentation in autism spectrum disorder. Nutr Neurosci 20:284–290.
https://doi.org/10.1080/1028415X.2015.1123847
Fluegge K (2017) Propionic acid metabolism, ASD, and vitamin B12: is
there a role for environmental nitrous oxide? Int J Dev Neurosci 57:
21–23. https://doi.org/10.1016/j.ijdevneu.2016.12.007
Fraguas R Jr, Papakostas GI, Mischoulon D, Bottiglieri T, Alpert J, Fava
M (2006) Anger attacks in major depressive disorder and serum
levels of homocysteine. Biol Psychiatry 60:270–274. https://doi.
org/10.1016/j.biopsych.2005.08.026
Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina
B, Bonassi S (2012) Oxidative stress-related biomarkers in autism:
systematic review and meta-analyses. Free Radic Biol Med 52:
2128–2141. https://doi.org/10.1016/j.freeradbiomed.2012.03.011
Frye RE, James SJ (2014) Metabolic pathology of autism in relation to
redox metabolism. Biomark Med 8:321–330
Frye RE, Rossignol DA (2014) Treatments for biomedical abnormalities
associated with autism spectrum disorder. Frontiers in pediatrics 2:
66. https://doi.org/10.3389/fped.2014.00066
Frye R, Wynne R, Rose S, Slattery J, Delhey L, Tippett M, Kahler S,
Bennuri S, Melnyk S, Sequeira J (2017) Thyroid dysfunction in
children with autism spectrum disorder is associated with folate
receptor αautoimmune disorder. J Neuroendocrinol 29. https://doi.
org/10.1111/jne.12461
Frye R, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey
A, Wynne R, Rose S, Melnyk S (2018) Folinic acid improves verbal
communication in children with autism and language impairment: a
randomized double-blind placebo-controlled trial. Mol Psychiatry
23:247–256. https://doi.org/10.1038/mp.2016.168
Gao Y, Sheng C, Xie RH, Sun W, Asztalos E, Moddemann D,
Zwaigenbaum L, Walker M, Wen SW (2016) New perspective on
impact of folic acid supplementation during pregnancy on
neurodevelopment/autism in the offspring children—asystematic
review. PLoS One 11:e0165626. https://doi.org/10.1371/journal.
pone.0165626
García JAO, Angulo MG, Sobrino-Najul EJ, Soldin OP, Mira AP,
Martínez-Salcedo E, Claudio L (2011) Prenatal exposure of a girl
with autism spectrum disorder to 'horsetail' (Equisetum arvense)
herbal remedy and alcohol: a case report. J Med Case Rep 5:129.
https://doi.org/10.1186/1752-1947-5-129
Garipardic M, Doğan M, Bala KA, Mutluer T, Kaba S, Aslan O, Üstyol L
(2017) Association of attention deficit hyperactivity disorder and
autism spectrum disorders with mean platelet volume and vitamin
D. Med Sci Monit 23:1378–1384. https://doi.org/10.12659/MSM.
899976
Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS (2014) Mitochondrial
dysfunction as a neurobiological subtype of autism spectrum disor-
der: evidence from brain imaging. JAMA psychiatry 71:665–671.
https://doi.org/10.1001/jamapsychiatry.2014.179
Golriz F, Donnelly LF, Devaraj S, Krishnamurthy R (2017) Modern
American scurvy—experience with vitamin C deficiency at a large
children’s hospital. Pediatr Radiol 47:214–220. https://doi.org/10.
1007/s00247-016-3726-4
Gordon I, Vander Wyk BC, Bennett RH, Cordeaux C, Lucas MV, Eilbott
JA, Zagoory-Sharon O, Leckman JF, Feldman R, Pelphrey KA
(2013) Oxytocin enhances brain function in children with autism.
Proc Natl Acad Sci 110:20953–20958. https://doi.org/10.1073/pnas.
1312857110
Grabb MC, Gobburu JV (2017) Challenges in developing drugs for pe-
diatric CNS disorders: a focus on psychopharmacology. Prog
Neurobiol 152:38–57. https://doi.org/10.1016/j.pneurobio.2016.05.
003
Greenblatt JM, Huffman LC, Reiss AL (1994) Folic acid in
neurodevelopment and child psychiatry. Prog Neuro-
Psychopharmacol Biol Psychiatry 18:647–660. https://doi.org/10.
1016/0278-5846(94)90074-4
Gumpricht E, Rockway S (2014) Can ω-3 fatty acids and tocotrienol-rich
vitamin E reduce symptoms of neurodevelopmental disorders?
Nutrition 30:733–738. https://doi.org/10.1016/j.nut.2013.11.001
Guo M, Zhu J, Yang T, Lai X, Liu X, Liu J, Chen J, Li T (2018) Vitamin
A improves the symptoms of autism spectrum disorders and de-
creases 5-hydroxytryptamine (5-HT): a pilot study. Brain Res Bull
137:35–40. https://doi.org/10.1016/j.brainresbull.2017.11.001
Hediger ML, England LJ, Molloy CA, Kai FY, Manning-Courtney P,
Mills JL (2008) Reduced bone cortical thickness in boys with autism
or autism spectrum disorder. J Autism Dev Disord 38:848–856.
https://doi.org/10.1007/s10803-007-0453-6
Helt M, Kelley E, Kinsbourne M, Pandey J, Boorstein H, Herbert M, Fein
D (2008) Can children with autism recover? If so, how?
Neuropsychol Rev 18:339–366. https://doi.org/10.1007/s11065-
008-9075-9
Hendren RL, James SJ, Widjaja F, Lawton B, Rosenblatt A, Bent S
(2016) Randomized, placebo-controlled trial of methyl B12 for chil-
dren with autism. J Child Adolesc Psychopharmacol 26:774–783.
https://doi.org/10.1089/cap.2015.0159
Herndon AC, DiGuiseppi C, Johnson SL, Leiferman J, Reynolds A (2009)
Does nutritional intake differ between children with autism spectrum
disorders and children with typical development? J Autism Dev
Disord 39:212–222. https://doi.org/10.1007/s10803-008-0606-2
Ho HH, Eaves LC, Peabody D (1997) Nutrient intake and obesity in
children with autism. Focus Autism Other Dev Disabl 12:187–
192. https://doi.org/10.1177/108835769701200308
Hou N, Ren L, GongM, Bi Y, Gu Y, Dong Z, Liu Y, Chen J, Li T (2015)
Vitamin A deficiency impairs spatial learning and memory: the
mechanism of abnormal CBP-dependent histone acetylation regu-
lated by retinoic acid receptor alpha. Mol Neurobiol 51:633–647.
https://doi.org/10.1007/s12035-014-8741-6
Humble MB, Gustafsson S, Bejerot S (2010) Low serum levels of 25-
hydroxyvitamin D (25-OHD) among psychiatric out-patients in
Sweden: relations with season, age, ethnic origin and psychiatric
diagnosis. J Steroid Biochem Mol Biol 121:467–470. https://doi.
org/10.1016/j.jsbmb.2010.03.013
Hyman SL, Stewart PA, Schmidt B, Lemcke N, Foley JT, Peck R,
Clemons T, Reynolds A, Johnson C, Handen B (2012) Nutrient
intake from food in children with autism. Pediatrics 130:S145–
S153. https://doi.org/10.1542/peds.2012-0900L
Iqbal K, Khan A, Khattak MMAK (2004) Biological significance of
ascorbic acid (vitamin C) in human health—a review. Pak J Nutr
3:5–13. https://doi.org/10.3923/pjn.2004.5.13
James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH,
Cutler P, Bock K, Boris M, Bradstreet JJ (2006) Metabolic
endophenotype and related genotypes are associated with oxidative
stress in children with autism. Am J Med Genet B Neuropsychiatr
Genet 141:947–956. https://doi.org/10.1002/ajmg.b.30366
James SJ, Melnyk S, Fuchs G, Reid T, Jernigan S, Pavliv O, Hubanks A,
Gaylor DW (2009) Efficacy of methylcobalamin and folinic acid
treatment on glutathione redox status in children with autism. Am
JClinNutr89:425–430. https://doi.org/10.3945/ajcn.2008.26615
James SJ, Melnyk S, Jernigan S, Pavliv O, Trusty T, Lehman S, Seidel L,
Gaylor DW, Cleves MA (2010) A functional polymorphism in the
reduced folate carrier gene and DNA hypomethylation in mothers of
J Mol Neurosci
Author's personal copy

children with autism. Am J Med Genet B Neuropsychiatr Genet
153:1209–1220. https://doi.org/10.1002/ajmg.b.31094
Jia F, Wang B, Shan L, Xu Z, Staal WG, Du L (2015) Core symptoms of
autism improved after vitamin D supplementation. Pediatrics 135:
e196–e198. https://doi.org/10.1542/peds.2014-2121
Jiang W, Yu Q, Gong M, Chen L, Wen EY, Bi Y, Zhang Y, Shi Y, Qu P,
Liu YX (2012) Vitamin A deficiency impairs postnatal cognitive
function via inhibition of neuronal calciumexcitability in hippocam-
pus. J Neurochem 121:932–943. https://doi.org/10.1111/j.1471-
4159.2012.07697.x
Johnson CR, Handen BL, Mayer-Costa M, Sacco K (2008) Eating habits
and dietary status in young children with autism. J Dev Phys Disabil
20:437–448. https://doi.org/10.1007/s10882-008-9111-y
Julvez J, Fortuny J, Mendez M, TorrentM, Ribas-Fitó N, Sunyer J (2009)
Maternal use of folic acid supplements during pregnancy and four-
year-old neurodevelopment in a population-based birth cohort.
Paediatr Perinat Epidemiol 23:199–206. https://doi.org/10.1111/j.
1365-3016.2009.01032.x
Kałużna-Czaplińska J, Jóźwik-Pruska J (2016) Nutritional strategies and
personalized diet in autism—choice or necessity? Trends Food Sci
Technol 49:45–50. https://doi.org/10.1016/j.tifs.2016.01.005
Kałużna-Czaplińska J, Socha E, Rynkowski J (2011) B vitamin supple-
mentation reduces excretion of urinary dicarboxylic acids in autistic
children. Nutr Res 31:497–502. https://doi.org/10.1016/j.nutres.
2011.03.009
Kałużna-Czaplińska J, Jóźwik-Pruska J, Chirumbolo S, Bjørklund G
(2017) Tryptophan status in autism spectrum disorder and the influ-
ence of supplementation on its level. Metab Brain Dis 32:1585–
1593. https://doi.org/10.1007/s11011-017-0045-x
Kirby AV, Boyd BA, Williams KL, Faldowski RA, Baranek GT (2017)
Sensory and repetitive behaviors among children with autism spec-
trum disorder at home. Autism 21:142–154. https://doi.org/10.1177/
1362361316632710
Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C (2012) Vitamin
D and autism: clinical review. Res Dev Disabil 33:1541–1550.
https://doi.org/10.1016/j.ridd.2012.02.015
Kočovská E, Gaughran F, Krivoy A, Meier U-C (2017) Vitamin-D defi-
ciency as a potential environmental risk factor in multiple sclerosis,
schizophrenia, and autism. Front Psychiatry 8:47. https://doi.org/10.
3389/fpsyt.2017.00047
Krajcovicova-Kudlackova M, Valachovicova M, Mislanova C,
Hudecova Z, Sustrova M, Ostatnikova D (2009) Plasma concentra-
tions of selected antioxidants in autistic children and adolescents.
Bratisl Lek Listy 110:247–250
Liu X, Liu J, Xiong X, Yang T, Hou N, Liang X, Chen J, Cheng Q, Li T
(2016) Correlation between nutrition and symptoms: nutritional sur-
vey of children with autism spectrum disorder in Chongqing, China.
Nutrients 8:294. https://doi.org/10.3390/nu8050294
Liu J, Liu X, Xiong X-Q, Yang T, Cui T, Hou N-L, Lai X, Liu S, Guo M,
Liang X-H (2017) Effect of vitamin A supplementation on gut mi-
crobiota in children with autism spectrum disorders—a pilot study.
BMC Microbiol 17:204. https://doi.org/10.1186/s12866-017-1096-
1
Lonsdale D, Frackelton JP (2003) Lipid-soluble thiamine derivatives in
the treatment of autism. Google Patents 6:585–996
Lonsdale D, Shamberger RJ, Audhya T (2002) Treatment of autism spec-
trum children with thiamine tetrahydrofurfuryl disulfide: a pilot
study. Neuro Endocrinol Lett 23:303–308
MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE,
Boon F, Taylor AR, Kavaliers M, Ossenkopp K-P (2007)
Neurobiological effects of intraventricular propionic acid in rats:
possible role of short chain fatty acids on the pathogenesis and
characteristics of autism spectrum disorders. Behav Brain Res 176:
149–169. https://doi.org/10.1016/j.bbr.2006.07.025
Marí-Bauset S, Llopis-González A, Zazpe I, Marí-Sanchis A, Morales
Suárez-Varela M (2017) Comparison of nutritional status between
children with autism spectrum disorder and typically developing
children in the Mediterranean Region (Valencia, Spain). Autism
21:310–322. https://doi.org/10.1177/1362361316636976
Marti LF (2014) Dietary interventions in children with autism spec-
trum disorders—an updated review of the research evidence.
Curr Clin Pharmacol 9:335–349. https://doi.org/10.2174/
15748847113086660074
Mattson MP, Kruman II, Duan W (2002) Dietary folate, B vitamins and
the brain: the homocysteine connection. In: Mattson MP (ed) Diet–
brain connections. Springer, Boston, pp 105–124
Meguid NA, Hashish AF, Anwar M, Sidhom G (2010) Reduced serum
levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian
children with autism. J Altern Complement Med 16:641–645.
https://doi.org/10.1089/acm.2009.0349
Meguid NA, Anwar M, Bjørklund G, Hashish A, Chirumbolo S,Hemimi
M, Sultan E (2017) Dietary adequacy of Egyptian children with
autism spectrum disorder compared to healthy developing children.
Metab Brain Dis 32:607–615. https://doi.org/10.1007/s11011-016-
9948-1
Mitchell ES, Conus N, Kaput J (2014) B vitamin polymorphisms and
behavior: evidence of associations with neurodevelopment, depres-
sion, schizophrenia,bipolar disorder and cognitive decline. Neurosci
Biobehav Rev 47:307–320. https://doi.org/10.1016/j.neubiorev.
2014.08.006
Molloy CA, Kalkwarf HJ, Manning-Courtney P, Mills JL, Hediger ML
(2010) Plasma 25(OH)D concentration in children with autism spec-
trum disorder. Dev Med Child Neurol 52:969–971. https://doi.org/
10.1111/j.1469-8749.2010.03704.x
Moretti P, Sahoo T, Hyland K, Bottiglieri T, Peters S, Del Gaudio D, Roa
B, Curry S, Zhu H, Finnell R (2005) Cerebral folate deficiency with
developmental delay, autism, and response to folinic acid.
Neurology 64:1088–1090. https://doi.org/10.1212/01.WNL.
0000154641.08211.B7
Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T,
Hopkin RJ, Peach E, Min SH, Goldman D (2008) Brief report:
autistic symptoms, developmental regression, mental retardation,
epilepsy, and dyskinesias in CNS folate deficiency. J Autism Dev
Disord 38:1170–1177. https://doi.org/10.1007/s10803-007-0492-z
Morris MS, Jacques PF, Rosenberg IH, Selhub J (2007) Folate and vita-
min B-12 status in relation to anemia, macrocytosis, and cognitive
impairment in older Americans in the age of folic acid fortification.
Am J Clin Nutr 85:193–200. https://doi.org/10.1093/ajcn/85.1.193
Naidu KA (2003) Vitamin C in human health and disease is still a mystery?
An overview. Nutr J 2:7. https://doi.org/10.1186/1475-2891-2-7
Naviaux RK (2014) Metabolic features of the cell danger response.
Mitochondrion 16:7–17.https://doi.org/10.1016/j.mito.2013.08.006
Naviaux JC, Wang L, Li K, Bright AT, Alaynick WA, Williams KR,
Powell SB, Naviaux RK (2015) Antipurinergic therapy corrects
the autism-like features in the Fragile X (Fmr1 knockout) mouse
model. Mol Autism 6:1. https://doi.org/10.1186/2040-2392-6-1
Nye C, Brice A (2005) Combined vitamin B6-magnesium treatment in
autism spectrum disorder. Cochrane Database Syst Rev 4:
CD003497 http://www.thecochranelibrary.com
Obrenovich ME, Shola D, Schroedel K, Agrahari A, Lonsdale D (2015)
The role of trace elements, thiamin(e) in autism and autistic spec-
trum disorder. Front Biosci 7:263–277. https://doi.org/10.2741/730
Pioggia G, Tonacci A, Tartarisco G, Billeci L, Muratori F, Ruta L,
Gangemi S (2014) Autism and lack of D3 vitamin: a systematic
review. Res Autism Spectr Disord 8:1685–1698. https://doi.org/10.
1016/j.rasd.2014.09.003
Raghavan R, Fallin MD, Wang X (2016) Maternal plasma folate, vitamin
B12 levels and multivitamin supplementation during pregnancy and
risk of autism spectrum disorder in the Boston Birth Cohort. The
FASEB J 30:151–156
Raghavan R,Riley AW, Volk H, Caruso D, Hironaka L, Sices L, Hong X,
Wang G, Ji Y, Brucato M, Wahl A, Stivers T, Pearson C, Zuckerman
J Mol Neurosci
Author's personal copy

B, Stuart EA, Landa R, Fallin MD, Wang X (2018) Maternal mul-
tivitamin intake, plasma folate and vitamin B12 levels and autism
spectrum disorder risk in offspring. Paediatr Perinat Epidemiol 32:
100–111. https://doi.org/10.1111/ppe
Ramaekers V, Häusler M, Opladen T, Heimann G, Blau N (2002)
Psychomotor retardation, spastic paraplegia, cerebellar ataxia and
dyskinesia associated with low 5-methyltetrahydrofolate in cerebro-
spinal fluid: a novel neurometabolic condition responding to folinic
acid substitution. Neuropediatrics 33:301–308. https://doi.org/10.
1055/s-2002-37082
Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N,
Quadros EV, Selhub J (2005) Autoantibodies to folate receptors in
the cerebral folate deficiency syndrome. N Engl J Med 352:1985–
1991. https://doi.org/10.1056/NEJMoa043160
Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV (2007)
Folate receptor autoimmunity and cerebral folate deficiency in low-
functioning autism with neurological deficits. Neuropediatrics 38:
276–281
Reynolds A, Krebs NF, Stewart PA, Austin H, Johnson SL, Withrow N,
Molloy C, James SJ, Johnson C, Clemons T (2012) Iron status in
children with autism spectrum disorder. Pediatrics 130:S154–S159.
https://doi.org/10.1542/peds.2012-0900M
Riebold M, Mankuta D, Lerer E, Israel S, Zhong S, Nemanov L,
Monakhov MV, Levi S, Yirmiya N, Yaari M (2011) All-trans
retinoic acid upregulates reduced CD38 transcription in
lymphoblastoid cell lines from autism spectrum disorder. Mol Med
17:799–806. https://doi.org/10.2119/molmed.2011.00080
Rimland B, Findling R, Maxwell K, Witnitzer M (1998) High dose vita-
min B6 and magnesium in treating autism: response to study by
Findling et al. J Autism Dev Disord 28:581–582. https://doi.org/
10.1023/A:1026000901515
Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996)
Embryological origin for autism: developmental anomalies of the
cranial nerve motor nuclei. J Comp Neurol 370:247–261. https://doi.
org/10.1002/(SICI)1096-9861(19960624)370:2<247::AID-
CNE8>3.0.CO;2-2
Rossignol DA, Frye RE (2014) Evidence linking oxidative stress, mito-
chondrial dysfunction, and inflammation in the brain of individuals
with autism. Front Physiol 5:150. https://doi.org/10.3389/fphys.
2014.00150
Roza SJ, van Batenburg-Eddes T, Steegers EA, Jaddoe VW, Mackenbach
JP, Hofman A, Verhulst FC, Tiemeier H (2010) Maternal folic acid
supplement use in early pregnancy and child behavioural problems:
the Generation R Study. Br J Nutr 103:445–452. https://doi.org/10.
1017/S0007114509991954
Saad K, Eltayeb AA, Mohamad IL, Al-Atram AA, Elserogy Y, Bjørklund
G, El-Houfey AA, Nicholson B (2015) A randomized, placebo-
controlled trial of digestive enzymes in children with autism spec-
trum disorders. Clin Psychopharmacol Neurosci 13:188–193.
https://doi.org/10.9758/cpn.2015.13.2.188
Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, Cannell JJ,
Bjørklund G, Abdel-Reheim MK, Othman HA, El-Houfey AA, Abd
El-Aziz NH (2016) Vitamin D status in autism spectrum disorders
and the efficacy of vitamin D supplementation in autistic children.
Nutr Neurosci 19:346–351. https://doi.org/10.1179/1476830515Y.
0000000019
Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey
AA, Othman HA-K, Bjørklund G, Jia F, Urbina MA, Abo-Elela
MGM (2018) Randomized controlled trial of vitamin D supplemen-
tation in children with autism spectrum disorder. J Child Psychol
Psychiatry 59:20–29. https://doi.org/10.1111/jcpp.12788
Saghazadeh A, Mahmoudi M, Ashkezari AD, Rezaie NO, Rezaei N
(2017) Systematic review and meta-analysis shows a specific mi-
cronutrient profile in people with Down syndrome: lower blood
calcium, selenium and zinc, higher red blood cell copper and zinc,
and higher salivary calcium and sodium. PLoS One 12:e0175437.
https://doi.org/10.1371/journal.pone.0175437
Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ,
Tassone F, Hertz-Picciotto I (2011) Prenatal vitamins, one-carbon
metabolism gene variants, and risk for autism. Epidemiology
(Cambridge, Mass) 22:476–485. https://doi.org/10.1097/EDE.
0b013e31821d0e30
Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H,
Schmidt LC, Tassone F, Hertz-Picciotto I (2012) Maternal
periconceptional folic acid intake and risk of autism spectrum dis-
orders and developmental delay in the CHARGE (CHildhood
Autism Risks from Genetics and Environment) case-control study.
Am J Clin Nutr 96:80–89.https://doi.org/10.3945/ajcn.110.004416
Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Sconberg JL, Schmidt
LC, Volk HE, Tassone F (2015) Selected vitamin D metabolic gene
variants and risk for autism spectrum disorder in the CHARGE
Study. Early Hum Dev 91:483–489. https://doi.org/10.1016/j.
earlhumdev.2015.05.008
Schoenthaler SJ, Bier ID, Young K, Nichols D, Jansenns S (2000) The
effect of vitamin-mineral supplementation on the intelligence of
American schoolchildren: a randomized, double-blind placebo-con-
trolled trial. J Altern Complement Med 6:19–29. https://doi.org/10.
1089/acm.2000.6.7
Scholl TO, Johnson WG (2000) Folic acid: influence on the outcome of
pregnancy. Am J Clin Nutr 71:1295S–1303S. https://doi.org/10.
1093/ajcn/71.5.1295s
Schreck KA (2014) Autism, parents, and treatments for their children. In:
Patel V, Preedy V, Martin C (eds) Comprehensive guide to autism.
Springer, New York, pp 2283–2296
Selhub J, Morris MS, Jacques PF, Rosenberg IH (2009) Folate–vitamin
B-12 interaction in relation to cognitive impairment, anemia, and
biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr
89:702S–706S. https://doi.org/10.3945/ajcn.2008.26947C
Spilioti M, Evangeliou A, Tramma D, Theodoridou Z, Metaxas S,
Michailidi E, Bonti E, Frysira H, Haidopoulou K, Asprangathou D
(2013) Evidence for treatable inborn errors of metabolism in a co-
hort of 187 Greek patients with autism spectrum disorder (ASD).
Front Hum Neurosci 7:858. https://doi.org/10.3389/fnhum.2013.
00858
Subar A, Block G, James L (1989) Folate intake and food sources in the
US population. Am J Clin Nutr 50:508–516. https://doi.org/10.
1093/ajcn/50.3.508
Sun C, Xia W, Zhao Y, Li N, Zhao D, Wu L (2013) Nutritional status
survey of children with autism and typically developing children
aged 4–6 years in Heilongjiang Province. J Nutr Sci 2:e16. https://
doi.org/10.1017/jns.2013.9
Sun C, Zou M, Zhao D, Xia W, Wu L (2016) Efficacy of folic acid
supplementation in autistic children participating in structured teach-
ing: an open-label trial. Nutrients 8:337. https://doi.org/10.3390/
nu8060337
Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK,
Lipkin WI, Magnus P, Reichborn-Kjennerud T (2013) Association
between maternal use of folic acid supplements and risk of autism
spectrum disorders in children. JAMA 309:570–577. https://doi.org/
10.1001/jama.2013.4879
Talaulikar V, Arulkumaran S (2013) Folic acid in pregnancy. Obstetrics,
Gynaecology & Reproductive Medicine 23:286–288. https://doi.
org/10.1016/j.ogrm.2013.06.007
Tamura T, Goldenberg RL, Chapman VR, Johnston KE, Ramey SL,
Nelson KG (2005) Folate status of mothers during pregnancy and
mental and psychomotor development of their children at five years
of age. Pediatrics 116:703–708. https://doi.org/10.1542/peds.2004-
2189
Uğur Ç, Gürkan CK (2014) Serum vitamin D and folate levels in children
with autism spectrum disorders. Res Autism Spectr Disord 8:1641–
1647. https://doi.org/10.1016/j.rasd.2014.09.002
J Mol Neurosci
Author's personal copy

Vahabzadeh A, McDougle CJ (2013) Maternal folic acid supplementation
and risk of autism. JAMA 309:2208–2208. https://doi.org/10.1001/
jama.2013.4879
Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, Fernández-
Somoano A, Tardón A, Ibarluzea J, Balluerka N, Murcia M,
González-Safont L, Romaguera D (2017) Effect of maternal high
dosages of folic acid supplements on neurocognitive development in
children at 4–5 y of age: the prospective birth cohort Infancia y
Medio Ambiente (INMA) study. Am J Clin Nutr 106:878–887.
https://doi.org/10.3945/ajcn.117.152769
vinh quốcLương K, Nguyễn LTH (2013) The role of thiamine in autism.
American Journal of Psychiatry and Neuroscience 1:22–37
Vinkhuyzen AA, Eyles DW, Burne TH, Blanken LM, Kruithof CJ,
Verhulst F, White T, Jaddoe VW, Tiemeier H, McGrath JJ (2017)
Gestational vitamin D deficiency and autism spectrum disorder.
BJPsych open 3:85–90. https://doi.org/10.1192/bjpo.bp.116.004077
Virk J, Liew Z, Olsen J, Nohr EA, Catov JM, Ritz B (2016)
Preconceptional and prenatal supplementary folic acid and multivi-
tamin intake and autism spectrum disorders. Autism 20:710–718.
https://doi.org/10.1177/1362361315604076
Wang T, Shan L, Du L, Feng J, Xu Z, Staal WG, Jia F (2016) Serum
concentration of 25-hydroxyvitamin D in autism spectrum disorder:
a systematic review and meta-analysis. Eur Child Adolesc
Psychiatry 25:341–350. https://doi.org/10.1007/s00787-015-0786-1
Wiggins LD, Baio J, Schieve L, Lee L-C, Nicholas J, Rice CE (2012)
Retention of autism spectrum diagnoses by community profes-
sionals: findings from the autism and developmental disabilities
monitoring network, 2000 and 2006. J Dev Behav Pediatr 33:387–
395. https://doi.org/10.1097/DBP.0b013e3182560b2f
Williams-Hooker R, George EO, Levy M, Morgan C, Smith TL, Bittle JB
(2013) Calcium and vitamin D intake of boys who have autism.
ICAN: Infant Child Adolesc Nutr 5:113–117. https://doi.org/10.
1177/1941406413478167
Wilson RD, Désilets V, Wyatt P, Langlois S, Gagnon A, Allen V, Blight
C, Johnson J-A, Audibert F, Brock J-A (2007) Pre-conceptional
vitamin/folic acid supplementation 2007: the use of folic acid in
combination with a multivitamin supplement for the prevention of
neural tube defects and other congenital anomalies. J Obstet
Gynaecol Can 29:1003–1013. https://doi.org/10.1016/S1701-
2163(16)32685-8
Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M,
Cuenod M, Do KQ, Deth RC (2016) Decreased brain levels of
vitamin B12 in aging, autism and schizophrenia. PLoS One 11:
e0146797. https://doi.org/10.1371/journal.pone.0146797
J Mol Neurosci
Author's personal copy