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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.
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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
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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 Cornishs
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
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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 516 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.
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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
(20072017). 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
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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
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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
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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
qucLương and Nguyn2013). 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 315 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 510 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
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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 38) and compared the two groups according to the
mothers 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 (712 years) with the dietary ref-
erence intake (DRI). Forty-seven parents or caretaker sub-
jects were included: 22 boys (78 years) and 25 of the
subjects of aged 912. 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
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(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
childreninaged318 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-
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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.
PublishersNote Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations.
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... These effects have been attributed to an increase in vitamin D receptor level (Taniura et al. 2006) and a reduction in Ca 2+ channel levels (Brewer et al. 2001). Many studies have established a low level of vitamin D in children with ASD relative to their counterparts (Bjørklund et al. 2019). Administration of vitamin D could decrease the high level of serotonin and gastrointestinal inflammation in patients with ASD (Patrick and Ames 2014). ...
... Another research revealed that around 80% of autistic children are vitamin A deficient (Guo et al. 2018). It was also demonstrated that vitamin A supplementation could be a potential agent for ASD patients to aid in the maintenance of numerous biochemical responses in autistic children (Bjørklund et al. 2019). ...
... Vitamin B1 deficiency may be implicated in ASD through several mechanisms such as apoptosis, oxidative stress, and mitochondrial dysfunction (Bjørklund et al. 2019). Interestingly, a patented device used as therapy for ASD provides patients with a thiamine derivative (Lonsdale and Frackelton 2002). ...
Chapter
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Nutrition is vital for normal brain functions. Psychiatric disorders constitute a major percentage of disability worldwide and impose economic, social, and health burdens. Current treatments are focused on pharmacotherapy and psychotherapy. Nevertheless, such therapies prevent only about 50% of the disease’s impact, revealing that new approaches are required to prohibit and cure psychiatric diseases. Appropriate dietary nutrition helps in the prevention and treatment of psychiatric disorders. This chapter aims to discuss the effects of dietary nutrients on oxidative stress, neuroinflammation, mitochondrial dysfunction, and kynurenine pathway, which are significant mechanisms relevant to nutrients’ effects on brain health and disease. Furthermore, this chapter emphasizes the relevance of multiple possible pathways such as metabolic regulation, nutrigenomics, and gut-brain axis of nutrition to psychiatric diseases and therapeutic potential. Also, it provides insights into the effects of macronutrients such as AAs and fatty acids, and micronutrients, including vitamins and minerals, on psychiatric disorders like autism spectrum disorder, anxiety, attention deficit hyperactivity disorder, obsessive-compulsive disorder, depression, and bipolar depression. Particular attention will be given to the nexus between nutrients and schizophrenia. Taken together, dietary interventions may be repositioned as burgeoning, cost-effective therapeutic approaches in psychiatric disorders.KeywordsNutritionVitaminsGut-brain axisNutrigenomicsAutismDepressionSchizophreniaAttention deficit hyperactivity disorderObsessive-compulsive disorder
... In recent years, increasing attention has been paid to the nutritional status of children with ASD. The complex psychopathological picture that includes restricted interests or repetitive behaviour, disability in social reciprocity and abnormal communication that are characteristic of ASD strongly influences children's eating behaviour [11][12][13][14]. Epidemiological studies reported that 46-89% of children with ASD exhibit feeding difficulties (five times more common among children with ASD than typically developing children) [13]. ...
... Partly for this reason, children may not have a sufficient number of vitamins, minerals or essential amino acids, which can cause an imbalance in the whole body. Chronic diarrhea, constipation or gastroenteritis can also be the reason why they do not get enough nutrients [11,12]. Nutrients are essential for the proper development of children. ...
... Among them, vitamin B6 is widely used to manage the symptoms observed in children with ASD. Vitamin B plays a critical role in methyl group donation for the synthesis of nucleic acids, lipids, proteins, hormones and neurotransmitters [11]. Deficiencies of vitamin B can lead to disorders of the nervous system, heart disease, deterioration of well-being, increased risk of behavioural and mood disorders, as well as disorders of cholesterol and homocysteine levels in body fluids. ...
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Autism Spectrum Disorders (ASD) are characterized by numerous comorbidities, including various metabolic and nutritional abnormalities. In many children with ASD, problems with proper nutrition can often lead to inadequate nutrient intake and some disturbances in metabolic profiles, which subsequently correlate with impaired neurobehavioural function. The purpose of this study was to investigate and compare the relationship between supplementation, levels of homovanillic acid (HVA) and vanillylmandelic acid (VMA) and the behaviour of children with ASD using quantitative urinary acid determination and questionnaires provided by parents/caregivers. The study was carried out on 129 children between 3 and 18 years of age. HVA and VMA were extracted and derivatized from urinary samples and simultaneously analyzed by gas chromatography-mass spectrometry (GC-MS). In addition, parents/caregivers of children with ASD were asked to complete questionnaires containing information about their diet and intake/non-intake of supplements. The application of the Mann–Whitney U test showed a statistically significant difference between the level of HVA and vitamin B supplementation (p = 1.64 x 10-2) and also omega-6 fatty acids supplementation and the levels of HVA (p = 1.50 x 10--3) and VMA (p = 2.50 x 10-3). In some children, a reduction in the severity of autistic symptoms (better response to own name or better reaction to change) was also observed. These results suggest that supplementation affects the levels of HVA and VMA and might also affect the children’s behaviour. Further research on these metabolites and the effects of supplementation on their levels, as well as the effects on the behaviour and physical symptoms among children with ASD is needed.
... Language deficits, which are common in children with autism, could occur as a consequence of infantile vitamin B3 shortage (FATTAL-VALEVSKI et al. 2009). In addition, neuropsychiatric disorders named Korsakoff's psychosis, beriberi, and Wernicke's encephalopathy are among serious CNS complications of thiamine deficiency (E et al. 2012;Bjørklund et al. 2019). Vitamin B3 converts tryptophan to serotonin and melatonin. ...
... Vitamin B9 deficiency has been related to an elevated level of neuroinflammation and oxidative stress (Bordeleau et al. 2021). B vitamin supplementation may have neuroprotective effects in many psychiatric disorders, including anxiety, MDD, and autism spectrum disorder (ASD) (Bjørklund et al. 2019; Calderón-Ospina and Nava-Mesa 2020). Vitamin B12 (cobalamin) is a coenzyme in various biochemical processes that are vital for a healthy CNS. ...
Chapter
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Adequate food consumption of dietary nutrients is vital for normal brain functions. There is considerable proof that dietary nutrition helps in the cure and prevention of many psychiatric and neurological disorders. This chapter aims to highlight the effects of macronutrients, including fatty acids and amino acids, and micronutrients, including vitamins and minerals, on different brain functions such as neuronal functions, synaptic plasticity, memory, neuroinflammation, and neuronal signaling network. Furthermore, this chapter discusses the underpinning neuroprotective mechanisms of dietary nutrients, including antioxidant and anti-inflammatory effects, modulation of hypothalamic-pituitary-adrenal (HPA) axis, regulation of neurotransmitter synthesis, and neurotrophic functions. The highlighted relationships of dietary nutrients on brain functions in health and psychiatric diseases have revealed some of the critical mechanisms underpinning diet’s effect on brain health and will aid to control how best to utilize dietary nutrients to boost neuronal resistance to injuries and promote mental health.KeywordsNutritionBrain functionsAmino acidsMineralsVitaminsFatty acidsPUFA
... Prevotella sp. is one of the producers of vitamin B1 (thiamine) [73]. Vitamin B1 deficiency has been previously detected in autistic children and identified as a risk factor for autism spectrum disorder [74]. Thus, the lack of these bacteria in autism patients could be associated with the development of their symptoms. ...
Article
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The ketogenic diet (KD) has been important in treating epilepsy since the 1920s. The benefits of KD further expanded to other neurological diseases, including Alzheimer’s diseases, autism spectrum disorder, and nutritional disorder (obesity). Although the therapeutic efficacy of KD has been generally accepted, there is limited knowledge about its underlying mechanism of action, particularly its effect on our gut microbiome. Gut dysbiosis has been proposed to be involved in those diseases, and KD can promote gut microbiota remodeling that may assist in recovery. This review explores the therapeutic applications of KD, the roles of the gut microbiome in neurological diseases and obesity, as well as the effect of KD on the gut microbiome. The present information suggests that KD has significant roles in altering the gut microbiome to improve disease symptoms, mainly by incrementing Bacteroidetes to Firmicutes (B/F) ratio and reducing Proteobacteria in certain cases. However, current gaps call for continued research to understand better the gut microbiota profile altered by KD.
... Vitamin A, a fat-soluble vitamin, has been indicated as an adjuvant therapy for infectious diseases (Mawson et al., 2013; and has a potential adjunct therapeutic effect on children with autism spectrum of disorders (ASD) (Bjørklund et al., 2019), possibly by altering gut microbiota. A recent study demonstrated that vitamin A supplementation in the form of retinoic acid (that is a physiologically active metabolite of vitamin A) in a murine model could inhibit murine norovirus replication (Lee et al., 2017). ...
Thesis
The human intestinal microbiota is composed of several types of microorganisms, including bacteria, archaea, fungi, unicellular eukaryotes and viruses. Among them, bacteria are the most diverse and abundant with a gene catalog 150 times larger than the genes present in the human genome, which represents a tremendous metabolic potential. These bacteria actively participate in the maintenance of intestinal homeostasis. Dysbiosis of the gut microbiota could be observed at course of many human pathologies, particularly inflammatory diseases intestinal chronic diseases (IBD), such as Crohn's disease (CD) or Ulcerative colitis (UC). These dysbiosis could contribute to the onset and progression of diseases. For example, gut microbiota transplantation experiments in murine model have allowed to show that a dysbiotic microbiota is sufficient to induce chronic inflammation in the colon and thus lead to the development of a metabolic syndrome or colitis. Different intervention strategies, including fecal transplantation, administration of probiotics or even special nutritional diets have been developed to act on the microbial communities of the digestive tract and to restore homeostasis of host tissues. The success of some interventions like Fecal transplantation represent a proof of concept in humans that acting on the composition of the intestinal microbiota is a strong lever to resolve certain physio pathological situations associated with gut microbiota dysbiosis. Diet is another important method for modulating the gut microbiota since it is the most important factor influencing its composition. In fact, the nutrients ingested can act directly on the composition of the microbiota by serving as substrates for microorganisms and indirectly by modulating intestinal homeostasis and components of the immune system associated, themselves contributing to regulate the composition microbiota. It is expected that ingestion of these beneficial microorga nisms can stimulate the immune system, promote intestinal homeostasis and to some extent contribute to the balance of the microbiota intestinal. The use of probiotic microorganisms is found to be very effective in some studies to treat different physiopathological situations (colitis, metabolic syndrome) in laboratory model organisms (rats, mice), however the use of these same probiotics in humans have given relatively disappointing clinical results, with poorly reproducible results across cohorts of patients. Except for the treatment of antibiotic-associated diarrhea. These discrepancies in results between pre-clinical models and clinical trials encourage better characterization of the molecular mechanisms used by probiotics to exert their beneficial effects and especially better understand the relationship of these probiotic microorganisms with the resident microbiota and diet.Among the different rising intervention strategies practiced nowadays in the purpose to shape the microbiota, a growing interest is given to other dietary interventions, like caloric restriction (CR) which has demonstrated several beneficial effects on various physiological systems, including the gastro-intestinal system, by modulating the innate and adaptative immune responses. In fact, emerging evidence suggests that the immune system function might be heavily influenced by the sensing of nutrient, reinforcing the idea that diet can deeply influence the inflammatory responses.
... Food intervention in children with ASD could help to modify the intestinal microbiota in such a way as to improve clinical, gastrointestinal and immune status (Ristori et al., 2019;Tomova et al., 2020). Other authors have suggested that children with ASD have a greater need for certain antioxidant vitamins than children with typical development (TD) since oxidative stress biomarkers and other metabolic abnormalities were found to be higher in children with ASD (Bjørklund et al., 2019;Geraghty et al., 2010;Leader et al., 2020). ...
Article
Lay abstract: Children with autism spectrum disorder (ASD) have a fivefold elevated risk of developing eating problems, which predisposes them to nutritional deficiencies. This study assesses nutritional intake and adequacy in children with ASD, subdiagnostic autistic symptoms and typically developing (TD) children. Preschool children with ASD and subdiagnostic symptoms had slightly lower intake of monounsaturated fatty acids (MUFA), vitamin D and vitamin B12. Primary school children with ASD and subdiagnostic symptoms had slightly higher intake of protein, cholesterol, thiamine and niacin, and a higher percentage of obesity than children with TD. All children had a high intake in sugars, fats and saturated fatty acids; a very highly inadequate intake of vitamins (vitamins D and E), fibre, b-carotene, calcium and magnesium; and a moderately inadequate intake of vitamin C, folate and iron. However, although all children need nutrition advice, children with ASD and subdiagnostic autistic symptoms had a poorer quality diet than those with TD.
... Since the restricted dietary behavior of autistic children could augment their nutritional inadequacy due to various reasons like bowel irritation or incommodious food intake, as autistic individuals have issues with food texture, there comes a need to explore the role of essential nutrients and vitamin supplements. The most common vitamin deficiency noticed among ASD children includes vitamin C, vitamin D, niacin, and riboflavin (Bjørklund et al., 2019). Vitamin D3(cholecalciferol), which is converted into hydroxyvitamin D3 in the liver is crucial for brain development. ...
Article
Full-text available
Recent advances in gut microbiota researches are establishing the association between food, gut microbiota, and brain health. Previously unknown communication networks between inhabiting microbes within the gut linings and the brain are being uncovered. The nature of the interaction between gut microbiota and the brain is a new frontier of research exploration. Diet plays an important role in modulating microbiota-gut-brain axis and exerts a profound influence on brain functioning. This review focuses on the effect of plant food bioactives or phytochemicals in modulating gut microbiota profile in Autistic individuals, for improving brain health and functioning. Autism Spectrum Disorder (ASD) is a neurodevelopmental disease marked by issues with speech, memory, and social behavior. Currently, an alarming rise in ASD cases among the children across the globe is being recorded. ASD has no known cure or causes; genetic or environmental factor possibly plays an important role in the development of ASD. Since dietary intervention is one of the most important solutions that might bring a positive change in the overall brain functioning of the ASD individuals. In this review, important plant food bioactives and gut microbes associated with better brain health and functioning in ASD individuals with its mode of action have been explained. Specifically plant food bioactives having influence over brain functions like memory, behavior, and cognition through balancing beneficial gut microbiota to reduce the symptoms associated with ASD are presented.
... Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by social interaction deficits and stereotyped and repetitive patterns of behavior, interests, and activities, as well as communication impairment [1]. ASD usually begins at or before the age of 3 [2,3], and in the United States, approximately 1 in 59 children is diagnosed with ASD by the age of 8 [4]. ...
Article
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Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder. Over the past few decades, many studies have investigated the effects of VA supplementation in ASD patients and the relationship between vitamin A (VA) levels and ASD. VA is an essential micronutrient that plays an important role in various systems and biological processes in the form of retinoic acid (RA). Recent studies have shown that serum VA concentration is negatively correlated with the severity of ASD. The lack of VA during pregnancy or early fetal development can affect brain development and lead to long-term or even permanent impairment in the learning process, memory formation, and cognitive function. In addition, VA deficiency has been reported to have a major impact on the gastrointestinal function of children with ASD, while VA supplementation has been shown to improve the symptoms of ASD to a certain extent. This paper provides a comprehensive review of the relationship between VA and ASD.
Article
Autism spectrum disorder (ASD) is a neuropsychiatric disease, characterized by deficits in social communication, presence of restricted interests and repetitive behaviors. This review aims to address the different nutrients that can be included in the diet of patients with ASD in order to reduce the different signs and symptoms present in this disorder. Different bibliographic sources were reviewed, such as PubMed, MEDLINE, ScienceDirect, Embase, and SciELO, using the keywords "Probiotics", "Vitamin B", Vitamin C", "Gluten", “Omega-3" and “Autism Spectrum Disorder”. It was found that probiotics and gluten improve gastrointestinal symptoms and, in addition, like vitamins B6, B9, B12 and C, as well as omega 3, help improve neurobehavioral symptoms, language and social behavior of children with ASD.
Article
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This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3–58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. −0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.
Article
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Autism spectrum disorder (ASD) affects about 1% of the world’s population. Vitamin D is thought to be essential for normal brain development and modulation of the immune system. Worldwide about 1 billion people are affected by vitamin D deficiency. High-sensitivity C-reactive protein (hs-CRP), cytochrome P450 2E1 (CYP2E1) and 8hydroxy-2′-deoxyguanosine (8-OH-dG) are biomarkers related to inflammation and oxidative stress. In the present study, these biomarkers were together with serum 25-hydroxyvitamin D (25(OH)D3) analyzed in 28 (mean age seven years) Saudi male patients with ASD. The study was conducted to determine if there is any relationship between vitamin D levels, the tested biomarkers and the presence and severity of ASD. The hope was to identify if these biomarkers may be useful for early ASD diagnosis. The Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRS) were used to measure autism severity. The results of the ASD children were compared with 27 age and gender-matched neurotypical controls. The data indicated that Saudi patients with ASD have significantly lower plasma levels of 25(OH)D3 than neurotypical controls (38 ng/ml compared to 56 ng/ml, respectively; [P=0.001]). Surprisingly, the levels of CYP2E1 were lower in the children with ASD than the neurotypical controls (0.48±0.08 vs. 69±0.07 ng/ml, respectively; P=0.001). The ASD children also had significantly higher levels of hs-CRP (0.79± 0.09 vs. 0.59 ± 0.09 ng/ml, respectively; P=0.001) and 8-OH-dG (8.17±1.04 vs. 4.13± 1.01 ng/ml, respectively; P=0.001, compared to neurotypical age and gender-matched controls. The values for hsCRP and 8-OH-dG did not correlate [P<0.001] with autism severity. There was found a relationship between autism severity on the CARS scale and the levels of 25(OH)D 3 and CYP1B1. But this was not found for SRS. All four biomarkers seemed to have good sensitivity and specificity, but the sample size of the present study was too small to determine clinical usefulness. The findings also indicate that inadequate levels of vitamin D play a role in the etiology and severity of autism. Furthermore, the results of the present study suggest the possibility of using 25(OH)D3, CYP1B1, hs-CRP and 8-OH-dG, preferably in combination, as biomarkers for the early diagnosis of ASD. However, further research is needed to evaluate this hypothesis.
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Background: Dysbiosis of gut microbiota are commonly reported in autism spectrum disorder (ASD) and may contribute to behavioral impairment. Vitamin A (VA) plays a role in regulation of gut microbiota. This study was performed to investigate the role of VA in the changes of gut microbiota and changes of autism functions in children with ASD. Results: Sixty four, aged 1 to 8 years old children with ASD completed a 6-month follow-up study with VA intervention. High-performance liquid chromatography was used to assess plasma retinol levels. The Autism Behaviour Checklist (ABC), Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS) were used to assess autism symptoms. CD38 and acid-related orphan receptor alpha (RORA) mRNA levels were used to assess autism-related biochemical indicators' changes. Evaluations of plasma retinol, ABC, CARS, SRS, CD38 and RORA mRNA levels were performed before and after 6 months of intervention in the 64 children. Illumina MiSeq for 16S rRNA genes was used to compare the differences in gut microbiota before and after 6 months of treatment in the subset 20 of the 64 children. After 6 months of intervention, plasma retinol, CD38 and RORA mRNA levels significantly increased (all P < 0.05); the scores of ABC, CARS and SRS scales showed no significant differences (all P > 0.05) in the 64 children. Meanwhile, the proportion of Bacteroidetes/Bacteroidales significantly increased and the proportion of Bifidobacterium significantly decreased in the subgroup of 20 (all false discovery rate (FDR) q < 0.05). Conclusions: Bacteroidetes/Bacteroidales were the key taxa related to VA. Moreover, VA played a role in the changes in autism biomarkers. It remains unclear whether the VA concentration is associated with autism symptoms. Trial registration: The study protocol was peer reviewed and approved by the institutional review board of Children's Hospital, Chongqing Medical University in 2013 and retrospectively registered in Chinese Clinical Trial Registry (ChiCTR) on November 6, 2014 (TRN: ChiCTR-ROC-14005442 ).
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Background: The benefits of the use of folic acid supplements (FASs) during the periconception period to prevent neural tube defects and to ensure normal brain development in offspring are well known. There is concern, however, about the long-term effects of the maternal use of high dosages of FASs that exceed the Tolerable Upper Intake Level (UL) (≥1000 μg/d) on child neurocognitive outcomes.Objective: The objective of the study was to examine the association between the use of high dosages of FASs during pregnancy and child neuropsychological development at ages 4-5 y.Design: The multicenter prospective mother-child cohort study, the Infancia y Medio Ambiente (INMA) Project, was conducted in 4 regions of Spain: Asturias, Sabadell, Gipuzkoa, and Valencia. Pregnant women were recruited between 2003 and 2008. Data on 1682 mother-child pairs were included in the final analyses. The pregnant women completed an interviewer-administered questionnaire that was validated to estimate typical dietary folate intake and the use of FASs at 10-13 and 28-32 wk of gestation. Neuropsychological development scores at 4-5 y of age were estimated with the use of the McCarthy Scales of Children's Abilities. Multiple linear regression and meta-analysis were used to obtain combined-effect estimates.Results: During the periconception period, one-third of the women (n = 502) took FAS dosages ≥1000 μg/d. The use of FAS dosages ≥1000 μg/d in this period was negatively associated with severa