1.

Introduction
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental, biologically
based condition with an estimated prevalence of approximately 1 in 44 people [1]
that impacts all areas of child development — from behaviour, problem solving
abilities and self-care skills, to complex social communication ability, language, and
executive functioning skills. The range of symptoms and severity of Autism
Spectrum Disorder (ASD) vary greatly from child to child, and clinical
manifestations depend on the individual’s age, cognitive and language abilities, and
co-occurring conditions.

The last revision of the Diagnostic and Statistical Manual (DSM-5) defines Autism
Spectrum Disorder (ASD) as impairments in two main domains:

(1) social communication and interaction, which comprises challenges in social-

emotional reciprocity, challenges in using nonverbal strategies during social
interaction, and challenges developing, maintaining and understanding
relationships, and

(2) restricted, repetitive, and stereotyped patterns of behaviours, manifested by

unusual repetitive movements or behaviours, restricted interests, insistence on
sameness and inflexible adherence to routines, as well as sensory challenges
ranging from seeking to avoiding certain sensory stimuli [2–4].

Proposed DSM-5 Autism Spectrum Disorder (ASD) criteria include three severity
classifications: Level 1 (“Requiring support”), Level 2 (“Requiring substantial
support”), and Level 3 (“Requiring very substantial support”) [5]. Prescribers often
describe or identify level 1 as mild Autism Spectrum Disorder (ASD), level 2 as
moderate Autism Spectrum Disorder (ASD), and level 3 as the most severe form of
Autism Spectrum Disorder (ASD) [6,7].

It is a group of neurodevelopment disorders known as pervasive developmental

disorders (PDD). These disorders are characterized by three core deficits: impaired
communication, impaired reciprocal social interaction and restricted, repetitive, and
stereotyped patterns of behaviours or interests. In 1943, the American psychiatrist
Leo Kenner used the term “early infantile autism” to describe children who lacked
interest in other people.[8] In 1944, an Austrian paediatrician, Hans Asperger,
independently described another group of children with similar behaviours, but
with milder severity and higher intellectual abilities. Since then, his name has
become attached to a higher functioning form of autism, Asperger syndrome. It was
not until the 1980s that the term pervasive developmental disorders were first used
[9]. Medical comorbidities are more common in children with Autism Spectrum
Disorder (ASD) than in the general population and can include epilepsy,
macrocephaly, cerebral palsy, migraine/headaches, congenital abnormalities of the
nervous system, gastrointestinal disorders, sleep disorders, allergic disorders, and
persistent neuroinflammation [10]. According to the World Health Organisation
(WHO), approximately 1 in 100 children have Autism Spectrum Disorder (ASD);
however, these figures could be substantially higher based on results from
additional well-controlled studies and the absence of Autism Spectrum Disorder
(ASD) statistics in various low and middle-income countries [11]. In South Africa,
accurate local statistics for Autism Spectrum Disorder (ASD) are not available but it
has been estimated that between 1% and 2% of the population may be affected by
Autism Spectrum Disorder (ASD) [12].

2.Epidemiology:
Autism Spectrum Disorder (ASD) occurs more often in boys than girls, with a 4:1
male-to-female ratio. [12] The reported prevalence rates of autism and its related
disorders have been increasing worldwide over the past decades, from
approximately 4 per 10 000 to 6 per 1000 children. [13-17] Globally, autism is
estimated to affect 24.8 million people as of 2015.[18] In the 2000s, the number of
people affected was estimated at 1–2 per 1, 000 people worldwide.[19]

3.Sign and symptoms:

➢ Behavior:

 Has inexplicable tantrums

 Has unusual interests or attachments
 Has unusual motor movements such as flapping hands or spinning
 Has extreme difficulty coping with change

➢ Sensory:

 Afraid of some everyday sounds

 Uses peripheral vision to look at objects
 Fascination with moving objects
 High tolerance of temperature and pain

➢ Communication:

 Not responding to his/her name by 12 months

 Not pointing or waving by 12 months
 Loss of words previously used
 Speech absent at 18 month
  No spontaneous phrases by 24 months
 Selective hearing – responding to certain sounds but ignoring the human
voice
 Unusual language patterns (e.g. repetitive speech)

➢ Social skills:

 Looks away when you speak to him/her

 Does not return your smile
 Lack of interest in other children
 Often seems to be in his/her own world
 Does not seek to share interests with others

➢ Play:

 Prefers to play alone

 Very limited social play (e.g. “Peek-a-boo”)
 Play is limited to certain toys
 Plays with objects in unusual ways such as repetitive spinning or lining up
 Shows very strong interest in or attachment to a limited number of games or
toys[20]

4.Causes of autism:
The exact cause of Autism Spectrum Disorder (ASD) is unknown. The most current
research demonstrates that there’s no single cause. Some of the suspected risk
factors for autism include:

 having an immediate family member with autism

 genetic mutations
 fragile X syndrome and other genetic disorders
 being born to older parents
 low birth weight
 metabolic imbalances
 exposure to heavy metals and environmental toxins
 a history of viral infections
 fetal exposure to the medications valproic acid (Depakene) or thalidomide
(Thalomid)[21,22,23]

According to the National Institute of Neurological Disorders and Stroke (NINDS),

both genetics and environment may determine whether a person develops autism.

Types of Autism Spectrum Disorder (ASD):

There are three different types of Autism Spectrum Disorders:

▪ Autistic Disorder: (also called "classic" autism) This is what most people think
of when hearing the word "autism." People with autistic disorder usually have
significant language delays, social and communication challenges, and unusual
behaviors and interests. Many people with autistic disorder also have intellectual
disability.

▪ Asperger Syndrome: People with Asperger syndrome usually have some milder
symptoms of autistic disorder. They might have social challenges and unusual
behaviors and interests. However, they typically do not have problems with
language or intellectual disability.

▪ Pervasive Developmental Disorder: Not Otherwise Specified (PDD-NOS; also

called "atypical autism") People who meet some of the criteria for autistic disorder
or Asperger syndrome, but not all, may be diagnosed with PDD-NOS. People with
PDD-NOS usually have fewer and milder symptoms than those with autistic
disorder. The symptoms might cause only social and communication challenges.
[24,25,26]

5.DIAGNOSIS:
Diagnosis is based on behavior, not cause or mechanism.[27,28] Under the DSM-5,
autism is characterized by persistent deficits in social communication and
interaction across multiple contexts, as well as restricted, repetitive patterns of
behavior, interests, or activities. These deficits are present in early childhood,
typically before age three, and lead to clinically significant functional impairment.
[29] Sample symptoms include lack of social or emotional reciprocity, stereotyped
and repetitive use of language or idiosyncratic language, and persistent
preoccupation with unusual objects. Several diagnostic instruments are available.
Two are commonly used in autism research: the Autism Diagnostic Interview-
Revised (ADI-R) is a semi structured parent interview, and the Autism Diagnostic
Observation Schedule (ADOS)[30] uses observation and interaction with the child.
The Childhood Autism Rating Scale (CARS) is used widely in clinical environments
to assess severity of autism based on observation of children. [31] The Diagnostic
interview for social and communication disorders (DISCO) may also be used. [32]
Although the symptoms of autism and Autism Spectrum Disorder (ASD) begin early
in childhood, they are sometimes missed; years later, adults may seek diagnoses to
help them or their friends and family understand themselves, to help their
employers make adjustments, or in some locations to claim disability living
allowances or other benefits. Girls are often diagnosed later than boys. [33]
6.Pathophysiology:
➢ Autism mechanism can be divided into two areas: the pathophysiology of brain
structures and processes associated with autism, and the neuropsychological
linkages between brain structures and behaviours.[34] The behaviours appear to
have multiple pathophysiologies.[35] How autism occurs is not well understood.

➢ A 2015 review proposed that immune dysregulation, gastrointestinal

inflammation, malfunction of the autonomic nervous system, gut flora alterations,
and food metabolites may cause brain neuroinflammation and dysfunction.[36] A
2016 review concludes that enteric nervous system abnormalities might play a role
in neurological disorders such as autism. Neural connections and the immune
system are a pathway that may allow diseases originated in the intestine to spread
to the brain.[37] Several lines of evidence point to synaptic dysfunction as a cause of
autism. Some rare mutations may lead to autism by disrupting some synaptic
pathways, such as those involved with cell adhesion. [38]

➢ All known teratogens (agents that cause birth defects) related to the risk of
autism appear to act during the first eight weeks from conception, and though this
does not exclude the possibility that autism can be initiated or affected later, there is
strong evidence that autism arises very early in development. [39]

➢ Autism affects the amygdala, cerebellum, and many other parts of the brain.[40]

7.STRATEGIES FOR Autism Spectrum Disorder (ASD) TREATMENT

Therapeutic interventions for a complex disorder like Autism Spectrum
Disorder (ASD) need to be multi-directional. Available treatment strategies were
divided based on the species and the stage of research: humans (clinical research
and practice) and rodents (basic and translational research) (Fig. 1). No single
strategy claims to be a multifaceted solution to the diverse symptomatology of
Autism Spectrum Disorder (ASD). As such, each one is used for single-target
modifications in standalone issues recognized in Autism Spectrum Disorder (ASD)
pathogenesis.

It is suggested to divide treatment strategies in humans into three groups:

current, promising, and perspective (Table 1). Current/basic: These therapies were
studied and continue to be verified through expanding research efforts. Most of the
strategies in this group are safe and recommended for current clinical use.
Promising: Strategies in this group still need to be approved for clinical use but
show good signs for the near future after ample research evidence is published and
verified. Perspective: Strategies here are considered the cutting-edge of current
scientific research. As such, they have a tempting quality to be regarded as complete
treatment strategies. However, as studies need to support their safety and viability
in clinical practice, they cannot be included in the current recommendations.
Research on treatment strategies that potentially improve the quality of life for
people with Autism Spectrum Disorder (ASD) is ongoing. Newer, safer, and potential
aches are still under development. Treatment must be initiated as soon as possible,
and specific therapies must be chosen for each case. Herein, treatment strategies
undergoing rigorous testing and research are presented. Some are still being tested
in animal models to establish their safety levels; others are approved for testing in
human cohorts worldwide.

Table 1. Classification of suggested Autism Spectrum Disorder (ASD)

treatment strategies in humans.

Improvement of E/I Imbalance

Risperidone
Glutamate modulators
NMDA-receptor modulators
GABA-receptor agonists
rTMS
Oxytocin
Improvement of Mitochondrial Dysfunction
Antioxidants
L-Carnosine
L-Carnitine
Butyrate
Resveratrol
Rapamycin
Regulation of Methylation
B12, B9
GI Regulation /Restoring Gut Microbiota
Current/basic strategies Microbiota Transfer Therapy (MTT)
Probiotics / Prebiotics
PPA Corrections through Biofilm Treatment
Dietary Corrections (GFCFD, KD)
Chelation Therapy
DMSA
Anti-Inflammatory Treatment
NSAIDS
Vitamin D
HBOT
Vitamin and Mineral Supplementation
Zinc and Copper
Selenium
Magnesium and Calcium
 Vitamin A, C, D, E, B1, B6, B9 and B12
Tryptophan and supplementation
Promising strategies Immunotherapy
IVIg
Treatment with cannabinoids
Prospective strategies Cellular therapy

8.Improvement of excitation and inhibition imbalances

Key Mechanisms of Excitation-Inhibition (E/I) Imbalance in Autism Spectrum
Disorder (Autism Spectrum Disorder (ASD))

1. Genetic Mutations: Mutations in scaffolding proteins like SHANK-3 and

synaptic cell adhesion molecules such as NLGN3, NLGN4, and NRXN1 disrupt
synaptic function, contributing to E/I imbalance in Autism Spectrum
Disorder (ASD) [41].
2. Disruptions in Neural Signalling Pathways: Impaired function of
Parvalbumin (PV)-positive inhibitory neurons reduces cortical plasticity and
disrupts gamma oscillations in the neocortex and hippocampus, further
exacerbating imbalance [42].
3. Alterations in Neuronal Network Development: Disturbances in the
GABAergic pathway, critical for synaptic tuning and proper neuronal wiring,
result in abnormal neuronal network construction [43].
4. GABAergic and Glutamatergic Dysfunction: Evidence suggests a link
between Autism Spectrum Disorder (ASD) and disruptions in both
GABAergic and glutamatergic receptors, which play key roles in maintaining
neuronal balance [44].

Strategies for Addressing E/I Imbalance

1. Direct Interventions: Utilizing agents that directly target GABA and

glutamate systems to restore balance.
2. Indirect Interventions: Approaches that address secondary issues such as:
 Mitochondrial dysfunction
 Impaired methylation
 Gut microbiota dysregulation

Zinc (Zn) and Copper (Cu) in Modulating E/I Balance

1. Zinc:
 Approximately 10% of total brain Zn resides in synaptic vesicles of
glutamatergic neurons.
  Zinc plays a role in regulating GABAergic inhibition, reducing seizure
susceptibility, and maintaining anxiolytic effects.
 Zn deficiency has been shown to impair GABAergic function [45].

2. Copper:
 Copper is a strong inhibitor of GABA-evoked responses, particularly affecting
Purkinje cells.
 By interacting with Zn and the GABAA receptor complex, copper modulates
synaptic transmission [45].

Relevance for Autism Spectrum Disorder (ASD) Treatment: Due to their

regulatory roles in the GABAergic and glutamatergic systems, maintaining
appropriate levels of Zn and Cu is crucial. Balancing these metals may enhance
synaptic function, improve neuronal communication, and contribute to addressing
E/I imbalances in Autism Spectrum Disorder (ASD) [45].

8.1. Dopamine and Serotonin Receptor Antagonist - Risperidone

The pharmacological management of autism spectrum disorder (Autism Spectrum

Disorder (ASD)) has primarily aimed at addressing behavioural symptoms such as
aggression, self-injury, and hyperactivity. Although typical antipsychotics are
effective in alleviating repetitive behaviours, tantrums, and hyperactivity while
improving social interactions, their use is often limited due to the presence of
unwanted extrapyramidal effects (UEE). Atypical antipsychotics, however, show
similar efficacy in managing these symptoms while presenting a lower risk of UEEs
[46]. Additionally, the evaluation of medications in Autism Spectrum Disorder (ASD)
is complicated by movement disorders, which may be intrinsic to the condition or
arise because of treatment, making it difficult to assess the effectiveness of therapies
on unusual stereotypic behaviours [46].

Risperidone (Risperdal) is an FDA-approved atypical antipsychotic with significant

potential for behavioural management in Autism Spectrum Disorder (ASD). It has
demonstrated a high safety profile in conditions such as bipolar I disorder,
psychosis, depression with psychotic features, and acute or chronic schizophrenia,
as well as in autistic disorder [47]. Its chemical structure includes a
tetrahydropyrido[1,2-a]pyrimidin-4-one scaffold connected via a piperidine moiety
to a benzisoxazole nucleus. This design enables risperidone to act as a combined
antagonist of dopamine D2 and serotonin 5-HT2A receptors [48].

Risperidone is among the few FDA-approved medications specifically indicated for

managing irritability in children with Autism Spectrum Disorder (ASD) aged 5 to 16
[49]. The dosage is weight-dependent, typically beginning with a lower starting dose
that is gradually increased to the target dose before tapering off after the prescribed
course of therapy [49-51]. Some studies recommend an additional four-week
extension for patients showing continued improvement and willing to proceed with
treatment [52,53].

Clinical studies on risperidone have employed various Autism Spectrum Disorder

(ASD) assessment tools, including the Aberrant Behaviour Checklist (ABC), Clinical
Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-
I), and Children’s Global Assessment Scale (C-GAS). On average, risperidone has
performed well across these parameters, with experimental groups demonstrating
noticeable and consistent improvements in behaviours and mannerisms associated
with Autism Spectrum Disorder (ASD). However, dropout rates in both
experimental and placebo groups were observed across studies, which may
contribute to the ongoing difficulty in reaching a consensus on an optimal
pharmacological treatment for Autism Spectrum Disorder (ASD)-related
behavioural symptoms [46, 49-53].

8.2. Glutamate Modulating Medications

Emerging treatments targeting glutamatergic neurotransmission are gaining

attention as research increasingly suggests a critical role of glutamatergic
dysfunction in autism spectrum disorder (Autism Spectrum Disorder (ASD)).
Evidence from peripheral biomarkers, neuroimaging, protein expression studies,
genetics, and animal models supports the connection between glutamate
dysregulation and Autism Spectrum Disorder (ASD). Medications that modulate
glutamate, originally developed for other disorders, are now being repurposed for
Autism Spectrum Disorder (ASD). For example, the valproic acid (VPA) animal
model of Autism Spectrum Disorder (ASD) demonstrates excitatory/inhibitory (E/I)
imbalances caused by increased differentiation of glutamatergic neurons and
reduced GABAergic neuron populations [54].

Agmatine, an endogenous polyamine synthesized from arginine, is a promising

candidate for repurposing in Autism Spectrum Disorder (ASD) treatment. It has
been implicated in the pathophysiology of several disorders, including anxiety,
depression, and schizophrenia [55, 56]. Agmatine exhibits various therapeutic
properties, including anticonvulsant, neuroprotective, antiapoptotic, antioxidant,
anxiolytic, and antidepressant effects [57]. It also inhibits the nitric oxide synthase
enzyme and acts as an antagonist at NMDA alpha-2 and imidazoline receptors [57].
Experimental studies suggest that agmatine can alleviate Autism Spectrum Disorder
(ASD)-like symptoms by addressing E/I imbalances. In the VPA animal model, a
single regimen of agmatine treatment improved impaired social behaviours and
reduced hyperactivity and repetitive behaviours [57]. Notably, patients with Autism
Spectrum Disorder (ASD) have significantly lower levels of agmatine, suggesting
that its deficiency may contribute to Autism Spectrum Disorder (ASD) pathogenesis
and highlighting its potential as a therapeutic target [55, 57].Another approach to
reducing excitatory neurotransmission involves inhibiting metabotropic glutamate
5 (mGlu5) receptors using negative allosteric modulators. For instance, the mGlu5
receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has been studied
in the BTBR mouse model of Autism Spectrum Disorder (ASD). Acute treatment with
MPEP in this model successfully decreased repetitive behaviours in BTBR mice,
demonstrating its potential as a therapeutic strategy (Silverman et al. 2012) [58].

8.3. NMDA Receptor Modulators

The N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor, plays
a vital role in synaptic plasticity and is essential for learning and memory. Research
suggests that disruptions in NMDA receptor signaling may be involved in the
development of Autism Spectrum Disorder (ASD) (autism spectrum disorder) [59].

Memantine, an NMDA receptor modulator, has been explored as a potential

treatment for Autism Spectrum Disorder (ASD). It functions by inhibiting excessive
NMDA receptor activity, potentially helping to restore the balance between
excitatory and inhibitory signals in the brain. Clinical trials assessing memantine's
efficacy in treating Autism Spectrum Disorder (ASD) have yielded mixed outcomes
[60–62].

Additionally, other NMDA receptor modulators are under investigation for their
therapeutic potential in Autism Spectrum Disorder (ASD). For instance, d-
cycloserine, a partial agonist of NMDA receptors, has demonstrated improvements
in social interactions and reductions in repetitive behaviors in animal models of
Autism Spectrum Disorder (ASD) [63–65]. However, further studies are necessary
to confirm whether these effects translate to human populations.

The exploration of NMDA receptor modulators as a treatment option for Autism

Spectrum Disorder (ASD) remains ongoing. More comprehensive research is
required to fully assess their efficacy and safety in individuals with Autism
Spectrum Disorder (ASD).

8.4. GABA Receptor Agonists

GABA receptor agonists are being studied as potential treatments for Autism
Spectrum Disorder (ASD) [66]. Research using Fragile X mouse models (Fmr1-
knockout) has revealed a reduction in GABAergic input across various brain regions,
leading to diminished GABAergic activity.
The selective GABA-B receptor agonist R-baclofen has been shown to reverse social
deficits and reduce repetitive behaviors in a mouse model of Fragile X syndrome
[67]. To further evaluate R-baclofen in a broader range of Autism Spectrum
Disorder (ASD) mouse models, the enantiomer was tested in two inbred mouse
strains exhibiting low sociability and/or pronounced repetitive or stereotyped
behaviors [68]. In BTBR mice, R-baclofen treatment reduced repetitive self-
grooming and high marble-burying scores. At non-sedating doses, it also decreased
stereotypical jumping behavior in C58/J (C58) mice [68].

Moreover, a randomized, double-blind, placebo-controlled study investigated the

efficacy of baclofen as an adjuvant to risperidone over a ten-week period [69].
Participants were assessed three times, and the findings indicated that those in the
baclofen adjuvant group experienced greater improvements on the ABC-C scale
compared to those receiving a placebo with risperidone. The targeted Autism
Spectrum Disorder (ASD)-related behaviors that improved included irritability,
lethargy, stereotypic behaviors, hyperactivity, and inappropriate speech. Overall,
this clinical trial supports the use of baclofen as an effective and safe adjuvant to
risperidone for managing Autism Spectrum Disorder (ASD)-associated symptoms
[69].

8.5. Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method that
modulates brain excitability and synaptic plasticity. Studies using animal models
with autistic-like behaviors induced by neonatal isolation showed that a two-week
low-frequency rTMS treatment significantly improved these behaviors in young
adult rats. Additionally, rTMS restored the excitation/inhibition (E/I) balance at the
synaptic level by regulating GABA transmission in synaptosomes [70].

In clinical practice, rTMS is increasingly utilized to enhance inhibitory mechanisms,

resulting in notable reductions in core Autism Spectrum Disorder (ASD) symptoms
[71]. Protocols for multicenter randomized controlled trials have been established,
highlighting the growing importance of this therapeutic approach [72].

8.6. Treatment with Oxytocin (OXT)

A central deficit in oxytocin (OXT) is considered a significant contributing factor to
Autism Spectrum Disorder (ASD), potentially underlying impairments in social
behavior [73]. To investigate this hypothesis, studies using valproate (VPA) and
fragile X rodent models of autism disrupted the neuroprotective, oxytocin-driven
shift in GABA signaling from excitatory to inhibitory during delivery [73]. Recent
research on the central OXT system in VPA-induced rat models of autism further
explores this connection. Research supports the hypothesis that oxytocin (OXT)
deficits contribute to Autism Spectrum Disorder (ASD). Lower OXT levels were
observed in the hypothalamic mRNA of adolescent valproate (VPA) rats and the
supraoptic nucleus (SON) of neonatal VPA rats, both of which exhibited autistic-like
behaviors [74]. Intranasal OXT administration restored social preference in
adolescent VPA rats, while early postnatal OXT treatment showed long-term
therapeutic effects on autistic-like behaviors in these models [74].

Findings in animal studies align with human research, showing that oxytocin is well-
tolerated and can significantly improve social behaviors in children with Autism
Spectrum Disorder (ASD) [75]. A double-blind, randomized, placebo-controlled trial
involving intranasal OXT administered over four weeks to 40 adult Autism
Spectrum Disorder (ASD) patients showed no treatment-specific improvements but
suggested positive trends in secondary outcomes like repetitive behaviors and
avoidance. This study recommended further research on multi-dose regimens to
evaluate long-term efficacy [76].

Another study aimed to clarify the mechanisms of intranasal oxytocin (IN-OXT) in

38 adult Autism Spectrum Disorder (ASD) patients, addressing the
recommendations of previous trials [77]. Oxytocin, a neuropeptide, modulates social
behavior by influencing cooperation, attachment, and bonding. Anatomical effects
were assessed using imaging of the amygdala and posterior superior temporal sulci
(pSTS). Reduced bilateral amygdala activity correlated with improved social
behavior, while increased pSTS activity was linked to enhanced social engagement
[77].

A single dose of IN-OXT showed variable effects on amygdala activity depending on

emotional states. It attenuated activity in happy states but increased it in angry
states. In contrast, multiple doses of IN-OXT reduced bilateral amygdala activity
across both emotional states compared to placebo, suggesting sustained
improvement in social behavior through consistent amygdala attenuation.
Additionally, a single dose of IN-OXT significantly improved social behavior by
amplifying pSTS activity, regardless of hemisphere or emotional state [77].
However, a generalized negative trend was observed with multiple-dose regimens.
Notably, the right pSTS demonstrated a stronger overall response to multiple-dose
IN-OXT therapy compared to the left pSTS.

Based on these findings, the study suggests exploring extended multiple-dose IN-
OXT treatment regimens to promote neural changes in Autism Spectrum Disorder
(ASD) patients that persist beyond those achieved with four-week treatments [77].

9. Mitochondrial Dysfunction Improvement

9.1. Antioxidant Therapy
Recent research on the pathophysiology of Autism Spectrum Disorder (ASD) has
identified oxidative stress and inflammation as contributing factors to its
development [78,79]. Studies have reported decreased levels of endogenous
antioxidant enzymes and elevated oxidative stress biomarkers in individuals with
Autism Spectrum Disorder (ASD). Consequently, antioxidant compounds have been
proposed as potential therapeutic agents to reduce or prevent the effects of free
radical damage in Autism Spectrum Disorder (ASD) patients [80,81].

Sulforaphane, an antioxidant found in vegetables such as broccoli, cauliflower, and

cabbage, has been extensively studied in individuals with Autism Spectrum Disorder
(ASD). Results from double-blind, randomized, placebo-controlled clinical trials
indicate that sulforaphane significantly improves core behavioral and cognitive
symptoms in patients with Autism Spectrum Disorder (ASD) [82].

9.2. L-Carnosine Supplementation

A meta-analysis of four double-blind, placebo-controlled randomized controlled
trials (RCTs) and one open-label trial evaluated the neuroprotective, antioxidant,
and anti-convulsive properties of L-carnosine. However, the findings were
inconclusive due to the lack of well-designed RCTs with larger sample sizes [83].

One study examined the effectiveness of L-carnosine as an adjunct to risperidone in

70 children with Autism Spectrum Disorder (ASD) [84]. While the treatment did not
significantly affect irritability subscale scores, it did lead to improvements in the
hyperactivity/noncompliance subscales of the Aberrant Behavior Checklist-
Community (ABC-C) in these patients [84].

Additionally, a meta-analysis of three studies found no significant differences

between the L-carnosine-supplemented groups and placebo-controlled groups on
the Gilliam Autism Rating Scale [83].

9.3. L-Carnitine Supplementation

Carnitine plays a key role in transporting long-chain fatty acids into mitochondria
for oxidation and energy production. Some treatments for mitochondrial diseases
have shown improvements in core and associated Autism Spectrum Disorder (ASD)
symptoms. Around 10%-20% of Autism Spectrum Disorder (ASD) patients
experience disorders in L-carnitine synthesis, making supplementation the
treatment of choice for them [85].

In one study, 30 children with Autism Spectrum Disorder (ASD) were divided into
experimental (L-carnitine-supplemented) and placebo-controlled groups. The
experimental group showed significant improvements in CARS scores, with notable
differences in both free and total carnitine levels, though no direct link between
these changes was established. The study suggests a six-month L-carnitine
supplementation regimen to improve autism severity but calls for further research
to support this recommendation [86].

Systemic Primary Carnitine Deficiency (PCD) is associated with numerous clinical

issues, including hepatomegaly, muscle weakness, elevated transaminase levels,
hyperammonemia, and gastrointestinal motility changes [87]. Although
neurodevelopmental disorders like Autism Spectrum Disorder (ASD) have not been
reliably linked to PCD, a case report described a 7-year-old girl with Autism
Spectrum Disorder (ASD) caused by systemic PCD. The report suggested that early
PCD screening could detect carnitine deficiencies and allow for early
supplementation, potentially preventing brain carnitine deficiencies that lead to
functional brain changes later on. In this case, a delayed diagnosis and
supplementation resulted in only mild to moderate responses to treatment, with no
observed improvements in Autism Spectrum Disorder (ASD) features [87]. Thus,
further studies are needed to explore the potential connection between
undiagnosed, worsening PCD and functional brain changes linked to Autism
Spectrum Disorder (ASD).

Additionally, recent studies have explored the benefits of combined therapies. A

randomized, double-blind, placebo-controlled clinical trial showed that adding L-
carnitine to risperidone treatment in children and adolescents with Autism
Spectrum Disorder (ASD) improved symptoms, including social isolation,
stereotypic behavior, and inappropriate speech [88].

9.4. Butyrate Treatment

Butyrate is a major metabolite produced by anaerobic microbes like Clostridium
clusters IV and XIVa in the gut microbiome [89], though Lactobacilli contribute
indirectly by supporting clostridia growth [90]. Butyrate plays several important
regulatory roles, including improving mitochondrial function during oxidative
stress, maintaining gut barrier integrity, modulating the microbiome-gut-brain axis,
enhancing mucosal immunity with its anti-inflammatory effects, and promoting the
expression of genes linked to cognition and behavior (such as CREB1 and
CamKinase II) [91].

Studies have shown that butyrate treatment can improve Autism Spectrum Disorder
(ASD)-related behaviors, including regulating social behavior in autistic mice [92],
acting on transporters and receptors to correct gut-brain axis abnormalities [95],
and suppressing Histone Deacetylase activity to improve immune response [91].

9.5. Resveratrol Treatment

Resveratrol (RSV) is an antioxidant and anti-inflammatory compound that enhances
mitochondrial function and helps prevent social impairments in the VPA animal
model of autism [94]. Prenatal exposure to VPA in animals leads to sensory behavior
changes, altered localization of GABAergic parvalbumin (PV+) neurons in sensory
brain regions, and modifications in excitatory and inhibitory synapse protein
expression. RSV treatment prevents these pathological changes in the brains of
experimental animals [95]. Additionally, the role of RSV in regulating mitochondrial
fatty acid oxidation (mt-FAO) and energy homeostasis is being explored as a
potential strategy for treating Autism Spectrum Disorder (ASD) [94].

9.6. Rapamycin Therapy

The mTOR signaling pathway plays a crucial role in regulating cell growth and
metabolism and is closely linked to intracellular oxidative stress when
overactivated [96,97]. In mice with tuberous sclerosis complex (TSC), treatment
with rapamycin, a specific mTOR inhibitor, resulted in recovery from social
interaction deficits [98]. Therefore, regulating mitochondrial dysfunction with
antioxidants could improve Autism Spectrum Disorder (ASD) behavior by
modulating the mTOR pathway.

10. Regulation of Methylation: Administration of Vitamins B12 and

B9
Some key metabolic pathways involved in redox regulation are disrupted in
individuals diagnosed with Autism Spectrum Disorder (ASD). Glutathione (GSH), a
primary redox buffer in all cells, is significantly influenced by methylation processes
(linked to vitamin B12) and folate metabolism (linked to vitamin B9) [99].

Research has shown that individuals with Autism Spectrum Disorder (ASD) often
have vitamin B12 deficiency [100-102]. Low B12 levels result in elevated
homocysteine and reduced levels of S-Adenosylmethionine (SAM), a critical co-
substrate involved in methyl group transfers, which affects DNA and histone
methylation throughout the body, including in the brain. Depletion of SAM leads to a
decrease in GSH production, impairing the antioxidant defense system.

A clinical trial demonstrated that methyl B12 supplementation improved symptoms

and reduced oxidative stress in children with autism [103]. Further studies explored
the relationship between low cobalamin levels and the decreased GSH seen in both
Autism Spectrum Disorder (ASD) and schizophrenia. Specifically, both total
cobalamin (vitamin B12) and methyl-cobalamin (active B12) levels were found to
be low in GCLM-KO mice, which exhibited reduced GSH levels [104].

Folinic acid (vitamin B9), a folate analog, can pass through the blood-brain barrier
even in the presence of folate receptor (FRα) autoantibodies, which are commonly
found in children with Autism Spectrum Disorder (ASD) and their mothers
[104,105]. These autoantibodies block folate activity, and folinic acid has been
shown to prevent behavioral deficits in rats. In humans, folate supplementation
during preconception and gestational periods may help prevent Autism Spectrum
Disorder (ASD) by enabling the methylation of B12, activating the methionine cycle,
and producing GSH.

Studies have suggested that administering low-dose folic acid orally alongside
subcutaneously injected methyl-cobalamin can increase blood plasma levels of
glutathione, which may enhance antioxidant capacity and reduce oxidative stress in
a subset of children with autism [103,106].

A two-part study in China found that folic acid supplementation increased

homocysteine levels, supporting its potential role in improving Autism Spectrum
Disorder (ASD)-related behaviors. Regulation of Glutathione Metabolism and Folate
Supplementation Recent studies suggest that supplementation with folic acid can
improve biochemical pathways related to glutathione metabolism, leading to
enhanced sociability, verbal and non-verbal communication, and overall social
interaction in children with autism compared to a control group [107,108].
However, a review analyzing the impact of folic acid supplementation during
pregnancy on the risk of Autism Spectrum Disorder (ASD) in offspring found
conflicting results, mainly due to differences in study designs. As a result, the review
could not conclusively confirm that folic acid supplementation during pregnancy
increases the likelihood of Autism Spectrum Disorder (ASD) in unborn children
[109].

11. Restoring Gut Microbiota in Autism Spectrum Disorder (ASD)

Alterations in gut microbiota have been proposed as potential pathways for the
development of Autism Spectrum Disorder (ASD). Research has increasingly
focused on characterizing the "fragile gut" in children with autism, which is marked
by low digestive enzyme activity and impaired gut barrier integrity. This supports
the hypothesis that dietary peptides and metabolites from microbial activity in the
gut entering the bloodstream might trigger an abnormal immune response [110-
112]. Interventions aimed at regulating the "fragile gut" through microbiota transfer
therapy, pre/probiotic treatment, fatty acid supplementation, and specific diets (e.g.,
gluten-free/casein-free or ketogenic) have generally shown improvements in
gastrointestinal (GI) and behavioral symptoms.

11.1. Microbiota Transfer Therapy (MTT)

An open-label clinical trial examining the effects of Microbiota Transfer Therapy
(MTT) on gut microbiota composition, GI symptoms, and Autism Spectrum Disorder
(ASD) behaviors found that GI symptoms decreased by nearly 80% by the end of the
study, with improvements persisting for eight weeks. Behavioral improvements in
Autism Spectrum Disorder (ASD) symptoms were also observed during and after
treatment. Analysis of bacterial and phage deep sequencing showed successful
partial engraftment of donor microbiota and beneficial changes in the gut
environment, indicating that MTT could be an effective method for improving both
Autism Spectrum Disorder (ASD) and comorbid GI symptoms by modifying the gut
microbiome [110]. Thus, targeting the gut microbiome through pre/probiotics, fecal
microbiota transplantation, and biofilm eradication could be promising treatments
for Autism Spectrum Disorder (ASD) [113-115].

11.2. Probiotics and Prebiotics

Probiotics, beneficial microorganisms in the gut, support metabolism, immunity,
and health, influencing neuro-intestinal processes through the gut-brain axis.
Prebiotics, non-digestible carbohydrates that serve as food for probiotics, work
synergistically with probiotics. In individuals with Autism Spectrum Disorder (ASD),
altered gut microbiota has been observed, with a decrease in beneficial strains like
Alistipes and Parabacteroides, and an increase in others like Corynebacterium and
Lactobacillus [117]. This imbalance leads to common GI symptoms such as
constipation, abdominal pain, diarrhea, and flatulence. Animal studies have shown
that probiotics may have a lasting effect on neuroactive compounds like GABA and
serotonin [116,118]. For example, a study involving golden Syrian hamsters
demonstrated that probiotics containing Bifidobacteria and Lactobacilli restored gut
microbiota, reduced glutamate, and increased GABA and Mg2+ levels, suggesting
their potential as a safe treatment for glutamate excitotoxicity [119]. Additionally,
probiotics have been shown to reduce the activity of the HPA axis in depression
cases [120].

Given these positive findings, several studies have examined whether restoring gut
microbiota in Autism Spectrum Disorder (ASD) patients could improve
neurobehavioral symptoms. A 12-week randomized, double-blind, controlled trial
showed some improvements in GI symptoms but no changes in adaptive or
repetitive behaviors [121]. A second randomized, double-blind, placebo-controlled
study reported contrasting results when testing prebiotic monotherapy and
combination therapy. Monotherapy showed no GI improvements, while
combination therapy, along with gluten and casein-free diets, resulted in reduced
anti-sociability scores [122]. Another study with 40 Egyptian children with Autism
Spectrum Disorder (ASD) (aged 2-5) found that after three months of daily probiotic
supplementation, Bifidobacterium and Lactobacillus levels in stool samples
significantly increased. Additionally, 80% of the children exhibited reduced anxiety
and improved sleep patterns [123].
A crossover-design pilot study investigated the effects of bovine colostrum product
(BCP) supplementation in children with Autism Spectrum Disorder (ASD) and
chronic GI symptoms, using both BCP alone and a combination of BCP and
Bifidobacterium (B.). The study included a washout period between the different
regimens [124,125]. The researchers observed significant improvements in GI
symptoms and stool quality, along with notable reductions in aberrant behaviors.
However, due to several limitations of the study, such as the lack of a control group,
the short study duration, and the continuation of concurrent Autism Spectrum
Disorder (ASD) treatments, the authors suggest that further, more rigorous studies
are necessary to verify the reliability of these findings.

11.3. Propionic Acid (PPA) Adjustments through Biofilm Treatment

Propionic acid (PPA), along with other short-chain fatty acids produced in the gut, is
found in elevated amounts in individuals with autism, and it is associated with
behavioral impairments due to its ability to easily cross the blood-brain barrier
[126]. In rats, PPA administration causes abnormal neural cell organization and
induces several electrophysiological, behavioral, and neuropathological changes
characteristic of Autism Spectrum Disorder (ASD) [127]. The harmful effects of PPA
are primarily linked to its concentration in the body. PPA is produced by gut
bacteria, particularly Clostridia, which generate PPA and exotoxins [128].
Interestingly, children with Autism Spectrum Disorder (ASD) exhibit differences in
gut microbiota compared to neurotypical individuals, with a decrease in
Bacteroidetes and an increase in Candida [117, 129, 130]. This imbalance disrupts
the cycle of PPA production and degradation, leading to elevated PPA levels that
contribute to behavioral deficits.

Several clinicians using biofilm eradication protocols have been successful in

balancing PPA concentrations. This approach involves a stepwise, nutrition-based
method aimed at restoring gut microbiome integrity. Initially, proteolytic enzymes
such as nattokinase, streptokinase, and other mucolytics break down the biofilm,
exposing the underlying microbial colonies [131,132]. Next, antimicrobial therapies
(antibiotics and antifungals) target these dense populations. Then, binders like
EDTA, chitosan, and citrus pectin are used to remove the remnants [133]. Finally,
probiotics and prebiotics are introduced to restore a normal physiological
environment [134].

12. Proposed Dietary Corrections

12.1. Gluten-Free and/or Casein-Free (GFCF) Diet in Children with Autism
Spectrum Disorder (ASD)
In 1979, Panksepp suggested that autism might be caused by endogenous
overactivity in the brain's opioid system, proposing what is known as the "opioid
excess theory" of autism. He hypothesized that proteins like gluten from wheat and
casein from milk could be potential contributors to Autism Spectrum Disorder
(ASD) development. These proteins are broken down into peptides
(gluteomorphine from gluten and casomorphins from casein), which can bind to
opiate receptors in the central nervous system (CNS), mimicking the effects of
opioids and potentially leading to symptoms associated with autism [135-138].

The updated version of this theory suggests that children with Autism Spectrum
Disorder (ASD), often having a "leaky gut," may metabolize gluten and casein
incompletely. This allows these peptides to pass through a compromised intestinal
barrier, enter the bloodstream, and penetrate the blood-brain barrier, affecting
brain function and neurotransmission [139]. The benefits of a GFCF diet are thus
thought to stem from both the "opioid excess theory" and its updated version.

Children with celiac disease, who are sensitive to gluten, exhibit an immune
response where their intestinal T cells react to gluten, producing interferon-γ,
which impairs gluten digestion and damages the intestinal lining [140,141]. Both
gluten and casein are also common allergens, triggering immune responses that
produce IgA and IgG antibodies [142].

The GFCF diet as an Autism Spectrum Disorder (ASD) treatment option has been
debated. Some studies report improvements in Autism Spectrum Disorder (ASD)
behaviors in children with comorbid gastrointestinal (GI) symptoms when following
the GFCF diet, as observed by their parents. However, other studies find no
statistically significant differences between experimental and control groups [143-
145]. Some researchers criticize the GFCF diet findings as methodologically flawed,
recommending its use only if gluten or casein intolerance or allergy is diagnosed
[146].

12.2. Ketogenic Diet (KD)

Behavioral assessments of the ketogenic diet (KD) in Autism Spectrum Disorder

(ASD) models have shown positive changes in social behaviors, including higher
sociability and increased social novelty scores [147,148]. Recent studies suggest
that a low-carbohydrate, moderate-protein, high-fat diet can significantly improve
core autism features in both animals and humans, with these effects lasting over
extended periods [149-152].

In one case-control study, participants were divided into three groups [150]. The
first group followed a modified version of the ketogenic diet called the Modified
Atkins Diet (MAD), which is less restrictive than the standard KD. The second group
adhered to the gluten-free/casein-free (GFCF) diet, and the third group served as
the control. All participants were assessed using the Childhood Autism Rating Scale
(CARS) and the Autism Treatment Evaluation Checklist (ATEC). The study found
that both MAD and GFCF diets led to a reduction in CARS and ATEC scores,
indicating improvements in autism-related behaviors. Notably, MAD participants
showed significant improvements in speech, social interaction, and cognition as
measured by the ATEC. The study concluded that both diets showed beneficial
effects, although these improvements were more pronounced in different
behavioral areas depending on the diet [150].

A six-month pilot study with 30 participants aged 4 to 10 years used the John
Radcliffe keto diet [151]. Of the 18 participants who completed the study, varying
levels of psychosomatic improvements were observed. The researchers
hypothesized that autistic children have impaired glucose oxidation and that ketone
bodies could serve as an alternative energy source for their brains. The study
acknowledged several limitations, including the heterogeneity of the participants'
biochemical responses, difficulties for some children (especially those with severe
Autism Spectrum Disorder (ASD)) in adhering to the diet, and uncertainty about the
optimal duration and method of applying the diet.

13. Chelation Therapy

Chelation therapy is a medical treatment that uses chelating agents to remove toxic
metals from the body [153-155]. Its application in children with Autism Spectrum
Disorder (ASD) remains controversial due to mixed results from various studies.
The choice of chelating agent depends on the type and severity of metal toxicity and
the patient's overall health. One clinical study found that meso-2,3-
dimercaptosuccinic acid (DMSA) was effective in reducing lead and mercury levels
and improving autistic symptoms in children with high levels of these metals [156].

Metallothioneins (MTs) are proteins that bind to metals to prevent their harmful
effects, but toxic metals like mercury (Hg) can displace zinc (Zn) and copper (Cu)
from MTs, potentially causing negative health effects. Chelation therapy increases
the excretion of essential trace elements like Cu and Zn, which can lead to
deficiencies, so monitoring these levels is critical. Excess Cu in the body can
interfere with Zn absorption, affecting MT gene transcription and the elimination of
toxic metals, emphasizing the importance of careful monitoring of metal toxicity and
the patient's health status [155].
Chelation therapy should only be conducted under medical supervision, after
assessing the potential risks and benefits. A review of available data identified
serious adverse events associated with chelation therapy in Autism Spectrum
Disorder (ASD), including hypocalcemia, renal impairment, and even deaths, leading
to the conclusion that the risks currently outweigh any proven benefits [157].

14. ANTI-INFLAMMATORIES
14.1. Non-steroidal Anti-inflammatories (NSAIDs)

Non-steroidal anti-inflammatory drugs (NSAIDs), such as Ibuprofen (a non-selective

COX-1 and COX-2 inhibitor) and Acetaminophen (a COX-3 inhibitor), have been
investigated for their potential anti-inflammatory effects during fever in children
with Autism Spectrum Disorder (ASD). Studies found that Ibuprofen was less
associated with the development of Autism Spectrum Disorder (ASD) in children
compared to Acetaminophen. Additionally, the use of Acetaminophen in children
aged 12 to 18 months was associated with an eightfold increased risk of developing
Autism Spectrum Disorder (ASD) compared to control children [158].

14.2. Vitamin D Supplementation

Among all the vitamins linked to Autism Spectrum Disorder (ASD) pathology,
Vitamin D has the strongest and most extensively researched correlation. Several
studies have found a connection between Vitamin D deficiency in pregnant mothers
and an increased likelihood of their children developing Autism Spectrum Disorder
(ASD) [159, 160]. This led to research exploring how low Vitamin D levels might
contribute to Autism Spectrum Disorder (ASD) and how supplementation might
alleviate related symptoms. Vitamin D's anti-inflammatory effects are seen in its
ability to counteract inflammation induced by Lipopolysaccharide (LPS) by
inhibiting MAPK pathways and the production of inflammatory molecules [161].
Additionally, Vitamin D has a synergistic effect with serotonin. Calcitriol activates
Tryptophan Hydroxylase 2 and suppresses Tryptophan Hydroxylase 1 transcription,
which increases serotonin in the brain, leading to prosocial behaviors. However, this
effect is absent in children with autism who exhibit antisocial behaviors [162]. A
randomized controlled trial demonstrated that Vitamin D supplementation led to
better retention of its precursor, 25(OH)D, and resulted in significantly improved
scores across various behavioral assessments after four months of supplementation
[163].

14.3. Hyperbaric Chamber Therapy

Hyperbaric oxygen therapy (HBOT) is an emerging treatment for Autism Spectrum
Disorder (ASD) that may improve inflammatory responses in children with cerebral
hypoperfusion. HBOT involves placing patients in a chamber with 100% oxygen at
pressures greater than one atmosphere, promoting tissue recovery and improved
physiological function due to increased oxygen availability. Neuroimaging studies
have shown cerebral hypoperfusion in children with Autism Spectrum Disorder
(ASD) [164]. HBOT has been suggested to counteract this condition, and while it is
effective for treating conditions like carbon monoxide poisoning, there is still
limited evidence supporting its use in Autism Spectrum Disorder (ASD). A single
randomized controlled trial reported positive changes in Aberrant Behavior
Checklist-Community (ABC), Autism Treatment Evaluation Checklist (ATEC), and
Clinical Global Impression-Improvement (CGI) scores [165], but another study
found no significant differences between HBOT and placebo groups in terms of
social reciprocity, communication, or repetitive behaviors [166]. These results have
not been consistently replicated, and researchers emphasize the need for further
large-scale studies to clarify HBOT's effectiveness in treating Autism Spectrum
Disorder (ASD) symptoms. The FDA has not endorsed the use of HBOT for children
with Autism Spectrum Disorder (ASD) due to insufficient evidence.

15. Mineral Imbalances

15.1. Zinc and Copper

Zinc is an essential trace element critical for maintaining optimal brain function
[167, 168]. A deficiency in zinc can lead to neuropsychological changes such as
emotional instability, irritability, and depression [169, 170]. Zinc is also vital for
cognitive performance and plays a role in glutamatergic transmission, influencing
both short-term and long-term mental effects [45]. Zinc acts by blocking NMDA
receptors and serving as a signal factor in various cellular processes, and its
deficiency may impair neurotransmission [171]. Moreover, zinc acts as a co-
transmitter with glutamate, helping to prevent excitotoxicity and providing
essential nutrients for enzymes involved in synaptic functions related to learning
and memory processes [45].

Copper toxicity can have a significant impact on the brain, leading to symptoms such
as depression, irritability, anxiety, nervousness, as well as learning and behavioral
issues [45, 170]. Copper serves as a cofactor for dopamine-β-hydroxylase (DBH), an
enzyme that converts dopamine into norepinephrine [172]. Excess copper can
elevate norepinephrine levels, which have been observed in individuals with Autism
Spectrum Disorder (ASD). Additionally, excess copper inhibits the enzyme
hydroxytryptophan decarboxylase, which results in reduced serotonin production.
Hypercupremia, or copper excess, may be linked to depression. Furthermore, an
overabundance of Cu/Zn-dependent superoxide dismutase can heighten oxidative
stress, causing redox imbalances through reactions with hydrogen peroxide (H₂O₂)
and peroxynitrite [45]

Zinc (Zn) and copper (Cu) are essential trace elements with an inverse relationship,
and their levels in the body are crucial for various biological processes. Cytokines
play a role in regulating this balance by facilitating Zn uptake and the production of
ceruloplasmin in the liver. In neurotypical individuals, the normal Zn-to-Cu ratio is
approximately 1:1 [45]. The plasma zinc/serum copper ratio can be used to quickly
assess the functional state of metallothioneins (MTs). Studies have shown that
children with Autism Spectrum Disorder (ASD) tend to have lower Zn/Cu ratios
compared to neurotypical children, suggesting either a deficiency in Zn or an
accumulation of toxic metals that antagonize Zn [45, 169, 170]. Mercury toxicity, in
particular, may significantly disrupt MT function in children with Autism Spectrum
Disorder (ASD), potentially reflected in the altered Zn/Cu ratio [45].

Toxic metals such as cadmium (Cd) and mercury (Hg) can have opposing effects on
Zn and Cu metabolism. MT induction in the liver may influence Cu excretion more
significantly than its mobilization into the bloodstream, while Zn's mobilization to
the blood is more affected. Increased MT induction due to oxidative stress may also
lead to the retention of toxic metals like Cd and Hg in organs such as the liver and
kidneys, explaining the higher levels of these metals found in Autism Spectrum
Disorder (ASD) patients. Once accumulated, these metals may further impair Zn
metabolism, worsening the patient's condition [45].

Patients with Autism Spectrum Disorder (ASD) may have a reduced tolerance to
toxic metal exposure. Enhanced MT induction due to oxidative stress may also
disrupt Cu excretion through the bile, leading to Cu accumulation in the liver and
potential toxicity. This buildup could interfere with Zn metabolism and reduce
tolerance to additional toxic metal exposure. The opposing effects of MT induction
on Cu and Zn metabolism may worsen both Zn deficiency and Cu toxicity
simultaneously in Autism Spectrum Disorder (ASD) patients [45].

15.2. Selenium

Research suggests that disruptions in selenium (Se) metabolism may play a role in
the development of Autism Spectrum Disorder (ASD) [173, 174]. Oxidative stress,
which is commonly observed in Autism Spectrum Disorder (ASD), is linked to
mitochondrial dysfunction, immune dysfunction, and inflammation [78, 79, 174].
Selenium has been shown to help alleviate these conditions, prompting several
studies to explore its potential role in managing Autism Spectrum Disorder (ASD)
[175, 176]. However, the exact mechanisms remain unclear, as numerous peer-
reviewed studies have reported altered selenoprotein expression in Autism
Spectrum Disorder (ASD), while others have found no significant changes [175].

Selenium may offer protection against the harmful effects of mercury [177, 178] and
may also protect against heavy metal toxicity, which has been hypothesized as a
contributing factor in Autism Spectrum Disorder (ASD) development [179]. The
complex interaction between selenium and mercury may have implications for
Autism Spectrum Disorder (ASD) and other neurological disorders, though further
research is needed to better understand this relationship and its clinical
significance.

Alterations in the gut microbiota have also been associated with Autism Spectrum
Disorder (ASD), and selenium deficiency has been shown to cause changes in
bacterial populations that promote lipopolysaccharide (LPS) overproduction and
translocation. Selenium may influence LPS-induced inflammation by modulating
p38 MAPK and NF-κB signaling pathways to protect against endotoxemia [175].
Although the evidence regarding selenium’s role in Autism Spectrum Disorder
(ASD) is limited and sometimes contradictory, it is an essential micronutrient that
may provide benefits for alleviating some Autism Spectrum Disorder (ASD)
symptoms. More research is required to identify the optimal dosage and duration
for selenium supplementation and to clarify its role in Autism Spectrum Disorder
(ASD) treatment.

15.3. Calcium and Magnesium

Calcium (Ca) and magnesium (Mg) are essential minerals that are vital for various
bodily functions, including neurological development and function [180].
Imbalances or deficiencies in these minerals have been implicated in the
pathogenesis of Autism Spectrum Disorder (ASD) [181].

Calcium is the most abundant mineral in the body, playing essential roles in muscle
contraction, blood clotting, nerve function, and regulating neuronal communication,
which is crucial for proper brain function [182]. Studies suggest that calcium
dysregulation may contribute to Autism Spectrum Disorder (ASD) development,
with research showing that children with Autism Spectrum Disorder (ASD) have
lower serum Ca levels compared to neurotypical children [184]. Calcium
dysregulation is also linked to oxidative stress, inflammation, and mitochondrial
dysfunction, which are common in individuals with Autism Spectrum Disorder
(ASD) [183]. Calcium channel blockers, which regulate Ca influx into cells, have been
shown to improve social behavior in Autism Spectrum Disorder (ASD) mouse
models.
Magnesium is another crucial mineral involved in muscle and nerve function, energy
production, and protein synthesis. It plays a key role in regulating calcium levels in
the body [185], and its dysregulation has also been associated with oxidative stress,
inflammation, and mitochondrial dysfunction in Autism Spectrum Disorder (ASD)
[186]. Some studies have indicated that children with Autism Spectrum Disorder
(ASD) have lower serum Mg levels compared to neurotypical children [187, 188].

The interaction between calcium and magnesium is critical for proper body
function. Magnesium regulates calcium levels by activating vitamin D, which is
necessary for calcium absorption in the intestines [189]. Magnesium also controls
the influx of calcium into cells, essential for neurological function, and helps inhibit
glutamate release, a neurotransmitter that can lead to excessive calcium influx and
oxidative stress [190]. Studies have shown that children with Autism Spectrum
Disorder (ASD) have a higher calcium-to-magnesium ratio compared to
neurotypical children, and this ratio correlates with autism severity. Additionally,
children with both Autism Spectrum Disorder (ASD) and ADHD exhibit more
significant changes in magnesium levels in their hair and urine compared to
neurotypical children [188]. Magnesium may help protect against the harmful
effects of calcium dysregulation and has anti-inflammatory properties that could
help mitigate mitochondrial dysfunction, commonly observed in children with
Autism Spectrum Disorder (ASD).

The role of calcium and magnesium in Autism Spectrum Disorder (ASD) is complex,
and further research is needed to clarify their exact mechanisms. However, evidence
suggests that dysregulation of these minerals may contribute to Autism Spectrum
Disorder (ASD) pathogenesis, and supplementation with calcium and magnesium
may alleviate some Autism Spectrum Disorder (ASD) symptoms [192]. The optimal
doses and duration for supplementation still require further investigation.

16. Vitamins
Vitamin supplementation is a common adjunct therapy for individuals with Autism
Spectrum Disorder (ASD) due to the links between certain vitamins and Autism
Spectrum Disorder (ASD) pathology [193-195]. Vitamins A, C, and E are known to
enhance antioxidant capabilities, while vitamin D plays roles in anti-inflammatory
processes and serotonin regulation [162, 196, 197]. Vitamin B1 is involved in
energy regulation [198], and vitamin B6 helps balance excitation and inhibition in
the brain through neurotransmitter synthesis, particularly in regulating GABA [199,
200]. Vitamins B9 and B12 contribute to methylation processes [201].
Individuals with Autism Spectrum Disorder (ASD) often experience metabolic and
nutritional abnormalities, including issues with sulfation, methylation, glutathione
redox imbalances, oxidative stress, and mitochondrial dysfunction [202-204].
Vitamin supplementation may support these physiological processes. A non-
randomized double-blind study involving 16 children with Autism Spectrum
Disorder (ASD), who received high doses of B6 and magnesium, found significant
behavioral improvements [205]. However, the role of B6 supplementation in Autism
Spectrum Disorder (ASD) remains unclear. Vitamin D supplementation may also
benefit individuals with Autism Spectrum Disorder (ASD) due to its immune-
modulating and inflammation-reducing properties [206].

The optimal dosages and duration of vitamin supplementation for individuals with
Autism Spectrum Disorder (ASD) are still unclear. Moreover, vitamin
supplementation may not be effective for all individuals with Autism Spectrum
Disorder (ASD) and should be tailored on a case-by-case basis [194].

17. Tryptophan
Tryptophan, an essential amino acid and precursor to serotonin, may benefit
individuals with Autism Spectrum Disorder (ASD) by improving social behavior,
reducing repetitive behaviors, and increasing cognitive flexibility [207, 208]. While
its exact mechanism in Autism Spectrum Disorder (ASD) is not fully understood, it
may enhance serotonin levels in the brain and exert anti-inflammatory effects.
However, tryptophan supplementation should be approached cautiously due to
potential side effects and the risk of serotonin syndrome when combined with
certain medications. While tryptophan may be deficient in some individuals with
Autism Spectrum Disorder (ASD), supplementation with B vitamins and magnesium
may influence tryptophan metabolism [207]. More research is necessary to better
understand the benefits and risks of tryptophan supplementation in Autism
Spectrum Disorder (ASD).

18. Immunotherapy
Individuals with Autism Spectrum Disorder (ASD) often exhibit immune system
dysregulation, which includes alterations in T cells, B cells, monocytes, natural killer
cells, dendritic cells, and elevated cytokine levels leading to neuroinflammation.
Immune dysfunction and inflammation are key aspects of Autism Spectrum
Disorder (ASD) diagnosis and treatment [209]. Understanding immune
dysregulation and inflammation in Autism Spectrum Disorder (ASD) can
significantly improve diagnostic and therapeutic approaches. Immunotherapy, such
as intravenous immunoglobulin (IVIG) injections, has shown promise in improving
Autism Spectrum Disorder (ASD) symptoms [210]. However, further research is
needed to identify additional immune biomarkers and explore the long-term risks
and effects of such treatments.

Reference:-

1) Maenner MJ, Shaw KA, Bakian AV, Bilder DA, Durkin MS, Esler A, et al.
Prevalence and characteristics of autism spectrum disorder among children aged 8
years — autism and developmental disabilities monitoring network, 11 sites,
United States, 2018. Morbidity and mortality weekly report Surveillance
summaries (Washington, DC : 2002). 2021;70(11):1–16.
2) Johnson J, Spitzer R, Williams J. Diagnostic and Statistical Manual of Mental
Disorders-IV TR. Washington, DC: American Psychiatric Association; 2000.
3) Hyman SL, Levy SE, Myers SM. Identification, evaluation, and management of
children with autism spectrum disorder. Paediatrics. 2020;145(1).
4) Association D-AP. Diagnostic and statistical manual of mental disorders.
Arlington: American Psychiatric Publishing. 2013.
5) Weitlauf AS, Gotham KO, Vehorn AC, Warren ZE (2014) Brief report: DSM-5
“levels of support:” a comment on discrepant conceptualizations of severity in
ASD. J Autism Dev Disord 44(2):471–476
6) The Autism Cafe. AUTISM SEVERITY LEVELS: FROM MILD TO SEVERE
2017 [Available from: https://theautismcafe.com/autism-severity-levels-mild-to-
severe/
7) PsychCentral Levels of Autism: Understanding the Different Types of ASD 2019
[Available from: https://psychcentral.com/pro/child-therapist/2019/11/levels-of-
autism-understanding-the-different-types-of-asd
8) Kolvin I. Studies in childhood psychoses: I. Diagnostic criteria and classification.
Brit J Psychiatry.1971; 118:381–4. [PubMed]
9) Klin A. Asperger syndrome: an update. Rev Bras Psiquiatr. 2003; 25:103–9.
[PubMed]
10) Al-Beltagi M (2021) Autism medical comorbidities. World J Clin Pediatr
10(3):15–28
11) World Health Organisation. Autism 2022 [Available from:
https://www.who.int/newsroom/factsheets/detail/autismspectrumdisorders?
msclkid=1ad10a2ab8c311eca388b42ff641e1c3
12) Autism South Africa. What is Autism 2020 [Available from:
https://aut2know.co.za/?msclkid=d3e8069ab8bc11ec826c587a8f 7e508a
Fombonne E, Zakarian R, Bennett A, Meng L, McLean Heywood D. Pervasive
evelopmental disorders in Montreal, Quebec, Canada: prevalence and links with
immunizations. Pediatrics. 2006; 118:e139–50. Available from:
http://pediatrics.aappublications.org/cgi/reprint/118/1/e139 [lastcited on 2009 Jun
19] [PubMed}.
13) Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool
children. JAMA.2001; 285:3093–9. [PubMed]
14) Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool
children: confirmation of high prevalence. Am J Psychiatry. 2005; 162:1133–41.
[PubMed]
15) Centers for Disease Control and Prevention. Mental health in the United States:
parental report of diagnosed autism in children aged 4-17 years, United States,
2003-2004. MMWR Morb Mortal WklyRep. 2006; 55:481–6. [PubMed]
16) Bertrand J, Mars A, Boyle C, Bove F, Yeargin-Allsop M, DeCoufle P. Prevalence
of autism in a United States population: the Brick Township, New Jersey,
investigation. Pediatr. 2001; 108:1155–61. [PubMed]
17) Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C.
Prevalence of autismin a US metropolitan area. JAMA. 2003; 289:49–55.
[PubMed]
18) GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8
October 2016). "Global, regional, and national incidence, prevalence, and years
lived with disability for 310 diseases and injuries, 1990–2015: a systematic
analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053):
1545–602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID
27733282.
19) Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell
DS, Miller LA, Pinto-Martin J, Reaven J, Reynolds AM, Rice CE, Schendel D,
Windham GC (2007). "The epidemiology of autism spectrum disorders". Annual
Review of Public Health. 28: 235–58. doi:
10.1146/annurev.publhealth.28.021406.144007. PMID 17367287
20) Landa RJ (2008). "Diagnosis of autism spectrum disorders in the first 3 years of
life". Nat Clin Pract Neurol. 4 (3): 138–47. doi:10.1038/ncpneuro0731. PMID
18253102.
21) Abrahams BS, Geschwind DH (May 2008). "Advances in autism genetics: on the
threshold of a new neurobiology". Nature Reviews. Genetics. 9 (5): 341– PMC
2756414. PMID 18414403.
22) Buxbaum JD (2009). "Multiple rare variants in the etiology of autism spectrum
disorders". Dialogues in Clinical Neuroscience. 11 (1): 35–43. PMC 3181906.
PMID 19432386.
23) Lyall K, Schmidt RJ, Hertz-Picciotto I (April 2014). "Maternal lifestyle and
environmental risk factors for autism spectrum disorders". Int J Epidemiol. 43 (2):
443–PMC 3997376. PMID 24518932.
24) American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed.Arlington, VA: American Psychiatric Publishing, Inc; 2000. pp.
69–84.
25) World Health Organization. International Statistical Classification of Diseases
and Related HealthProblems, 10th Revision. World Health Organization; 2007
Available from: http://www.who.int/classifications/apps/icd/icd10°nline/ [last
cited on 2009 Mar 19]
26) Mattila ML, Kielinen M, Jussila K, Linna SL, Bloigu R, Ebeling H, Moilanen I.
An epidemiological and diagnostic study of Asperger syndrome according to four
sets of diagnostic criteria. J Am Acad Child Adolesc Psychiatry. 2007; 46:636–
46. [PubMed]
27) London E (2007). "The role of the neurobiologist in redefining the diagnosis of
autism". Brain Pathol. 17 (4): 408–11. doi:10.1111/j.1750-3639.2007.00103.x.
PMID 17919126.
28) Baird G, Cass H, Slonims V (2003). "Diagnosis of autism". BMJ. 327 (7413):
488–93. doi:10.1136/bmj.327.7413.488. PMC 188387. PMID 12946972.
29) Autism Spectrum Disorder, 299.00 (F84.0). In: American Psychiatric association.
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American
Psychiatric Publishing; 2013.
30) Gotham K, Risi S, Dawson G, Tager-Flusberg H, Joseph R, Carter A, Hepburn S,
McMahon W, Rodier P, Hyman SL, Sigman M, Rogers S, Landa R, Spence MA,
Osann K, Flodman P, Volkmar F, Hollander E, Buxbaum J, Pickles A, Lord C
(June 2008). "A replication of the Autism Diagnostic Observation Schedule
(ADOS) revised algorithms". Journal of the American Academy of Child and
Adolescent Psychiatry. 47 (6): 642–. PMC 3057666. PMID 18434924.
31) Volkmar FR, Paul R, Pelphrey KA, Rogers SJ, eds. (2014). Handbook of Autism
and Pervasive Developmental Disorders: Volume Two: Assessment,
Interventions, and Policy. 2 (4th ed.). Hoboken, New Jersey: John Wiley & Sons.
p. 301. ISBN 978-1- 118-28220-5. LCCN 2013034363. OCLC 946133861.
Retrieved 1 March 2019 – via Google Books.
32) Kan CC, Buitelaar JK, van der Gaag RJ (June 2008). "[Autism spectrum disorders
in adults]". Nederlands Tijdschrift voor Geneeskunde. 152 (24): 1365–9. PMID
18664213.
33) Why Many Autistic Girls are Overlooked (Report). Child Mind Institute.
Retrieved 13 February 2018.
34) Penn HE (2006). "Neurobiological correlates of autism: a review of recent
research". Child Neuropsychol. 12 (1): 57–79. doi:10.1080/09297040500253546.
PMID 16484102.
35) London E (2007). "The role of the neurobiologist in redefining the diagnosis of
autism". Brain Pathol. 17 (4): 408–11. doi:10.1111/j.1750-3639.2007.00103.x.
PMID 17919126.
36) Wasilewska J, Klukowski M (2015). "Gastrointestinal symptoms and autism
spectrum disorder: links and risks - a possible new overlap syndrome". Paediatric
Health Med Ther(Review). 6: 153– 166. doi:10.2147/PHMT.S85717. PMC
5683266. PMID 29388597
37) Rao M, Gershon MD (September 2016). "The bowel and beyond: the enteric
nervous system in neurological disorders". Nat Rev Gastroenterol Hepatol
(Review). 13 (9): 517–28. doi:10.1038/nrgastro.2016.107. PMC 5005185. PMID
27435372.
38) Betancur C, Sakurai T, Buxbaum JD (2009). "The emerging role of synaptic cell-
adhesion pathways in the pathogenesis of autism spectrum disorders". Trends
Neurosci. 32 (7): 402–12. doi:10.1016/j.tins.2009.04.003. PMID 19541375.
39) Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". Int J Dev
Neurosci. 23 (2–3): 189–99. doi:10.1016/j.ijdevneu.2004.11.001. PMID
15749245.
40) Amaral DG, Schumann CM, Nordahl CW (2008). "Neuroanatomy of autism".
Trends Neurosci. 31 (3): 137–45. doi:10.1016/j.tins.2007.12.005.PMID18258309
41) Bourgeron, T. The possible interplay of synaptic and clock genes in autism
spectrum disorders. Cold Spring Harb. Symp. Quant. Biol., 2007, 72(1), 645-654.
http://dx.doi.org/10.1101/sqb.2007.72.020 PMID:18419324
42) Gogolla, N.; LeBlanc, J.J.; Quast, K.B.; Südhof, T.C.; Fagiolini, M.; Hensch, T.K.
Common circuit defect of excitatory-inhibitory balance in mouse models of
autism. J. Neurodev. Disord., 2009, 1(2), 172-181.
http://dx.doi.org/10.1007/s11689-009-9023-x PMID:20664807
43) Cellot, G.; Cherubini, E. GABAergic signaling as therapeutic target for autism
spectrum disorders. Front Pediatr., 2014, 2, 70.
http://dx.doi.org/10.3389/fped.2014.00070 PMID:25072038
44) Nelson, S.B.; Valakh, V. Excitatory/inhibitory balance and circuit homeostasis in
autism spectrum disorders. Neuron, 2015, 87(4), 684-698.
http://dx.doi.org/10.1016/j.neuron.2015.07.033 PMID:26291155
45) Bjorklund, G. The role of zinc and copper in autism spectrum disorders. Acta
Neurobiol. Exp., 2013, 73(2), 225-236. PMID: 23823984
46) Campbell, M.; Rapoport, J.L.; Simpson, G.M. Antipsychotics in children and
adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 1999, 38(5), 537-545.
http://dx.doi.org/10.1097/00004583-199905000-00015 PMID:10230185
47) Chopko, T.C.; Lindsley, C.W. Classics in chemical neuroscience: Risperidone.
ACS Chem. Neurosci., 2018, 9(7), 1520-1529.
http://dx.doi.org/10.1021/acschemneuro.8b00159 PMID:29695153
48) Vardanyan, R. Piperidine-Based Drug Discovery; Elsevier, 2017.
49) Robert, L. Cross-discipline team leader review memo. 2012. Available From:
https://www.accessdata.fda.gov/-
drugsatfda_docs/summary_review/2008/021817se1-001_- SUMR.pdf
50) Kent, J.M.; Kushner, S.; Ning, X.; Karcher, K.; Ness, S.; Aman, M.; Singh, J.;
Hough, D. Risperidone dosing in children and adolescents with autistic disorder:
A double-blind, placebo-controlled study. J. Autism Dev. Disord., 2013, 43(8),
1773-1783. http://dx.doi.org/10.1007/s10803-012-1723-5PMID:23212807
51) Kent, J.M.; Hough, D.; Singh, J.; Karcher, K.; Pandina, G. An open-label
extension study of the safety and efficacy of risperidone in children and
adolescents with autistic disorder. J. Child Adolesc. Psychopharmacol., 2013,
23(10), 676-686. http://dx.doi.org/10.1089/cap.2012.0058PMID:24350813
52) Jesner, O.S.; Aref-Adib, M.; Coren, E. Risperidone for autism spectrum disorder.
Cochrane Libr., 2007, 2010(1),
CD005040.http://dx.doi.org/10.1002/14651858.CD005040.pub2 PMID:17253538
53) West, L.; Waldrop, J. Risperidone use in the treatment of behavioural symptoms
in children with autism. Pediatr. Nurs., 2006, 32(6), 545-549. PMID:17256292
54) Kim, J.-W.; Seung, H.; Kim, K. C.; Gonzales, E. L. T.; Oh, H. A.; Yang, S. M.;
Ko, M. J.; Han, S.-H.; Banerjee, S.; Shin, C. Y. Agmatine rescues autistic
behaviors in the valproic acid-induced animal model of autism.
Neuropharmacology, 2017, 113(Pt A), 71-81.
http://dx.doi.org/10.1016/j.neuropharm.2016.09.014
55) Raasch, W.; Schäfer, U.; Chun, J.; Dominiak, P. Biological significance of
agmatine, an endogenous ligand at imidazoline binding sites. Br. J. Pharmacol.,
2001, 133(6), 755-780. http://dx.doi.org/10.1038/sj.bjp.0704153 PMID:11454649
56) Uzbay, T.; Goktalay, G.; Kayir, H.; Eker, S.S.; Sarandol, A.; Oral, S.;
Buyukuysal, L.; Ulusoy, G.; Kirli, S. Increased plasma agmatine levels in patients
with schizophrenia. J. Psychiatr. Res., 2013, 47(8), 1054-1060.
http://dx.doi.org/10.1016/j.jpsychires.2013.04.004 PMID:23664672
57) Esnafoglu, E.; İrende, İ. Decreased plasma agmatine levels in autistic subjects. J.
Neural Transm., 2018, 125(4), 735-740. http://dx.doi.org/10.1007/s00702-017-
1836-2 PMID:29302750
58) Silverman, J.M.; Brunet, Y.R.; Cascales, E.; Mougous, J.D. Structure and
regulation of the type VI secretion system. Annu. Rev. Microbiol., 2012, 66(1),
453-472. http://dx.doi.org/10.1146/annurev-micro-121809-151619
PMID:22746332
59) Lee, K.; Mills, Z.; Cheung, P.; Cheyne, J.E.; Montgomery, J.M. The role of zinc
and NMDA receptors in autism spectrum disorders. Pharmaceuticals, 2022, 16(1),
1. http://dx.doi.org/10.3390/ph16010001 PMID:36678498
60) Vatankhah Ardestani, S.S.; Karahmadi, M.; Tarrahi, M.J.; Omranifard, V.;
Farzaneh, B. Efficacy of memantine as adjunct therapy for autism spectrum
disorder in children aged 14 years. Adv. Biomed. Res., 2018, 7(1), 131.
http://dx.doi.org/10.4103/abr.abr_100_18 PMID:30320040
61) Soorya, L.V.; Fogg, L.; Ocampo, E.; Printen, M.; Youngkin, S.; Halpern, D.;
Kolevzon, A.; Lee, S.; Grodberg, D.; Anagnostou, E. Neurocognitive outcomes
from memantine: A pilot, double-blind, placebo-controlled trial in children with
autism spectrum disorder. J. Child Adolesc. Psychopharmacol., 2021, 31(7), 475-
484. http://dx.doi.org/10.1089/cap.2021.0010 PMID:34543081
62) Aman, M.G.; Findling, R.L.; Hardan, A.Y.; Hendren, R.L.; Melmed, R.D.;
Kehinde-Nelson, O.; Hsu, H.A.; Trugman, J.M.; Palmer, R.H.; Graham, S.M.;
Gage, A.T.; Perhach, J.L.; Katz, E. Safety and efficacy of memantine in children
with autism: Randomized, placebo-controlled study and open-label extension. J.
Child Adolesc. Psychopharmacol., 2017, 27(5), 403-412.
http://dx.doi.org/10.1089/cap.2015.0146 PMID:26978327
63) Modi, M.E.; Young, L.J. D-cycloserine facilitates socially reinforced learning in
an animal model relevant to autism spectrum disorders. Biol. Psychiatry, 2011,
70(3), 298-304. http://dx.doi.org/10.1016/j.biopsych.2011.01.026PMID:21481844
64) Minshawi, N.F.; Wink, L.K.; Shaffer, R.; Plawecki, M.H.; Posey, D.J.; Liu, H.;
Hurwitz, S.; McDougle, C.J.; Swiezy, N.B.; Erickson, C.A. A randomized,
placebo-controlled trial of d-cycloserine for the enhancement of social skills
training in autism spectrum disorders. Mol. Autism, 2016, 7(1), 2.
http://dx.doi.org/10.1186/s13229-015-0062-8 PMID:26770664
65) Burket, J.A.; Benson, A.D.; Tang, A.H.; Deutsch, S.I. d-- Cycloserine improves
sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders
with altered Ras/Raf/ERK1/2 signaling. Brain Res. Bull., 2013, 96, 62-70.
http://dx.doi.org/10.1016/j.brainresbull.2013.05.003 PMID:23685206
66) Zhao, H.; Mao, X.; Zhu, C.; Zou, X.; Peng, F.; Yang, W.; Li, B.; Li, G.; Ge, T.;
Cui, R. GABAergic system dysfunction in autism spectrum disorders. Front. Cell
Dev. Biol., 2022, 9, 781327.
http://dx.doi.org/10.3389/fcell.2021.781327PMID:35198562
67) Braat, S.; D’Hulst, C.; Heulens, I.; De Rubeis, S.; Mientjes, E.; Nelson, D.L.;
Willemsen, R.; Bagni, C.; Van Dam, D.; De Deyn, P.P.; Kooy, R.F. The GABA A
receptor is an FMRP target with therapeutic potential in fragile X syndrome. Cell
Cycle, 2015,14(18),2985-2995.
http://dx.doi.org/10.4161/15384101.2014.989114PMID:25790165
68) Silverman, J.L.; Pride, M.C.; Hayes, J.E.; Puhger, K.R.; Butler-Struben, H.M.;
Baker, S.; Crawley, J.N. GABAB receptor agonist r-baclofen reverses social
deficits and reduces repetitive behavior in two mouse models of autism.
Neuropsychopharmacology, 2015, 40(9), 2228-2239.
http://dx.doi.org/10.1038/npp.2015.66 PMID:25754761
69) Mahdavinasab, S.M.; Saghazadeh, A.; Motamed-Gorji, N.; Vaseghi, S.;
Mohammadi, M.R.; Alichani, R.; Akhondzadeh, S. Baclofen as an adjuvant
therapy for autism: A randomized, double-blind, placebo-controlled trial. Eur.
Child Adolesc. Psychiatry, 2019, 28(12), 1619-1628.
http://dx.doi.org/10.1007/s00787-019-01333-5PMID:30980177
70) Tan, T.; Wang, W.; Xu, H.; Huang, Z.; Wang, Y.T.; Dong, Z. Low-frequency
rTMS ameliorates autistic-like behaviors in rats induced by neonatal isolation
through regulating the synaptic GABA transmission. Front. Cell. Neurosci., 2018,
12, 46. http://dx.doi.org/10.3389/fncel.2018.00046 PMID:29541022
71) Desarkar, P.; Rajji, T.K.; Ameis, S.H.; Blumberger, D.M.; Lai, M.C.; Lunsky, Y.;
Daskalakis, Z.J. Assessing and stabilizing atypical plasticity in autism spectrum
disorder using rTMS: Results from a proof-of-principle study. Clin.
Neurophysiol., 2022, 141, 109-118.
http://dx.doi.org/10.1016/j.clinph.2021.03.046 PMID:34011467
72) Enticott, P.G.; Barlow, K.; Guastella, A.J.; Licari, M.K.; Rogasch, N.C.;
Middeldorp, C.M.; Clark, S.R.; Vallence, A.M.; Boulton, K.A.; Hickie, I.B.;
Whitehouse, A.J.O.; Galletly, C.; Alvares, G.A.; Fujiyama, H.; Heussler, H.;
Craig, J.M.; Kirkovski, M.; Mills, N.T.; Rinehart, N.J.; Donaldson, P.H.; Ford,
T.C.; Caeyenberghs, K.; Albein-Urios, N.; Bekkali, S.; Fitzgerald, P.B. Repetitive
transcranial magnetic stimulation (rTMS) in autism spectrum disorder: Protocol
for a multicentre randomised controlled clinical trial. BMJ Open, 2021, 11(7),
e046830. http://dx.doi.org/10.1136/bmjopen-2020-046830 PMID:34233985
73) Dai, Y.C.; Zhang, H.F.; Schön, M.; Böckers, T.M.; Han, S.P.; Han, J.S.; Zhang,
R. Neonatal oxytocin treatment ameliorates autistic-like behaviors and oxytocin
deficiency in valproic acid-induced rat model of autism. Front. Cell. Neurosci.,
2018, 12, 355. http://dx.doi.org/10.3389/fncel.2018.00355 PMID:30356897
74) Tyzio, R.; Nardou, R.; Ferrari, D.C.; Tsintsadze, T.; Shahrokhi, A.; Eftekhari, S.;
Khalilov, I.; Tsintsadze, V.; Brouchoud, C.; Chazal, G.; Lemonnier, E.;
Lozovaya, N.; Burnashev, N.; Ben-Ari, Y. Oxytocin-mediated GABA inhibition
during delivery attenuates autism pathogenesis in rodent offspring. Science, 2014,
343(6171), 675-679. http://dx.doi.org/10.1126/science.1247190 PMID:24503856
75) Parker, K.J.; Oztan, O.; Libove, R.A.; Sumiyoshi, R.D.; Jackson, L.P.; Karhson,
D.S.; Summers, J.E.; Hinman, K.E.; Motonaga, K.S.; Phillips, J.M.; Carson, D.S.;
Garner, J.P.; Hardan, A.Y. Intranasal oxytocin treatment for social deficits and
biomarkers of response in children with autism. Proc. Natl. Acad. Sci. USA,
 2017, 114(30), 8119-8124. http://dx.doi.org/10.1073/pnas.1705521114
PMID:28696286
76) Bernaerts, S.; Boets, B.; Bosmans, G.; Steyaert, J.; Alaerts, K. Behavioral effects
of multiple-dose oxytocin treatment in autism: A randomized, placebo-controlled
trial with long-term follow-up. Mol. Autism, 2020, 11(1), 6.
http://dx.doi.org/10.1186/s13229-020-0313-1 PMID:31969977
77) Bernaerts, S.; Boets, B.; Steyaert, J.; Wenderoth, N.; Alaerts, K. Oxytocin
treatment attenuates amygdala activity in autism: A treatment-mechanism study
with long-term follow-up. Transl. Psychiatry, 2020, 10(1), 383.
http://dx.doi.org/10.1038/s41398-020-01069-w PMID:33159033
78) Yenkoyan, K.; Harutyunyan, H.; Harutyunyan, A. A certain role of SOD/CAT
imbalance in pathogenesis of autism spectrum disorders. Free Radic. Biol. Med.,
2018, 123, 85-95. http://dx.doi.org/10.1016/j.freeradbiomed.2018.05.070
PMID:29782990
79) Harutyunyan, A.A.; Harutyunyan, H.A.; Yenkoyan, K.B. Novel probable glance
at inflammatory scenario development in autistic pathology. Front. Psychiatry,
2021, 12, 788779. http://dx.doi.org/10.3389/fpsyt.2021.788779 PMID:35002805
80) Manivasagam, T. Role of oxidative stress and antioxidants in autism. In:
Personalized Food Intervention and Therapy for Autism Spectrum Disorder
Management. Advances in Neurobiology; Essa, M.; Qoronfleh, M., Eds.;
Springer: Cham, 2020; vol 24, pp. 193-206. http://dx.doi.org/10.1007/978-3-030-
30402-7_7
81) Robea, M.A.; Jijie, R.; Nicoara, M.; Plavan, G.; Ciobica, A.S.; Solcan, C.; Audira,
G.; Hsiao, C.D.; Strungaru, S.A.; Vitamin, C. Vitamin C attenuates oxidative
stress and behavioral abnormalities triggered by fipronil and pyriproxyfen
insecticide chronic exposure on zebrafish juvenile. Antioxidants, 2020, 9(10),
944. http://dx.doi.org/10.3390/antiox9100944 PMID:33019596
82) McGuinness, G.; Kim, Y. Sulforaphane treatment for autism spectrum disorder: A
systematic review. EXCLI J., 2020, 19, 892-903.
http://dx.doi.org/10.17179/excli2020-2487 PMID:33013262
83) Abraham, D.A.; Undela, K.; Narasimhan, U.; Rajanandh, M.G. Effect of L-
Carnosine in children with autism spectrum disorders: A systematic review and
meta-analysis of randomised controlled trials. Amino Acids, 2021, 53(4), 575-
585. http://dx.doi.org/10.1007/s00726-021-02960-6 PMID:33704575
84) Hajizadeh-Zaker, R.; Ghajar, A.; Mesgarpour, B.; Afarideh, M.; Mohammadi,
M.R.; Akhondzadeh, S. LCarnosine as an adjunctive therapy to risperidone in
children with autistic disorder: A randomized, double-blind, placebo-controlled
trial. J. Child Adolesc. Psychopharmacol., 2018, 28(1), 74-81.
85) Demarquoy, C.; Demarquoy, J. Autism and carnitine: A possible link. World J.
Biol. Chem., 2019, 10(1), 7-16. http://dx.doi.org/10.4331/wjbc.v10.i1.7
PMID:30622681
86) Fahmy, S.F.; El-hamamsy, M.H.; Zaki, O.K.; Badary, O.A. l-Carnitine
supplementation improves the behavioral symptoms in autistic children. Res.
Autism Spectr. Disord., 2013, 7(1), 159-166.
http://dx.doi.org/10.1016/j.rasd.2012.07.006
87) Guevara-Campos, J.; González-Guevara, L.; Guevara-- González, J.; Cauli, O.
First case report of primary carnitine deficiency manifested as intellectual
disability and autism spectrum disorder. Brain Sci., 2019, 9(6), 137.
http://dx.doi.org/10.3390/brainsci9060137 PMID:31200524
88) Shakibaei, F.; Jelvani, D. Effect of adding l-carnitine to risperidone on behavioral,
cognitive, social, and physical symptoms in children and adolescents with autism:
A randomized double-blinded placebo-controlled clinical trial. Clin.
Neuropharmacol., 2023, 46(2), 55-59.
http://dx.doi.org/10.1097/WNF.0000000000000544 PMID:36735565
89) Eeckhaut, V.; Van Immerseel, F.; Croubels, S.; De Baere, S.; Haesebrouck, F.;
Ducatelle, R.; Louis, P.; Vandamme, P. Butyrate production in phylogenetically
diverse Firmicutes isolated from the chicken caecum. Microb. Biotechnol., 2011,
4(4), 503-512. http://dx.doi.org/10.1111/j.1751-7915.2010.00244.x
PMID:21375722
90) Hakalehto, E.; Hänninen, O. Gaseous CO 2 signal initiates growth of butyric-
acid-producing Clostridium butyricum in both pure culture and mixed cultures
with Lactobacillus brevis. Can. J. Microbiol., 2012, 58(7), 928-931.
http://dx.doi.org/10.1139/w2012-059 PMID:22697044
91) Liu, S.; Li, E.; Sun, Z.; Fu, D.; Duan, G.; Jiang, M.; Yu, Y.; Mei, L.; Yang, P.;
Tang, Y.; Zheng, P. Altered gut microbiota and short chain fatty acids in Chinese
children with autism spectrum disorder. Sci. Rep., 2019, 9(1), 287.
http://dx.doi.org/10.1038/s41598-018-36430-z PMID:30670726
92) Kratsman, N.; Getselter, D.; Elliott, E. Sodium butyrate attenuates social behavior
deficits and modifies the transcription of inhibitory/excitatory genes in the frontal
cortex of an autism model. Neuropharmacology, 2016, 102, 136-145.
http://dx.doi.org/10.1016/j.neuropharm.2015.11.003 PMID:26577018
93) Stilling, R.M.; van de Wouw, M.; Clarke, G.; Stanton, C.; Dinan, T.G.; Cryan,
J.F. The neuropharmacology of butyrate: The bread and butter of the microbiota-
gut-brain axis? Neurochem. Int., 2016, 99, 110-132.
http://dx.doi.org/10.1016/j.neuint.2016.06.011 PMID:27346602
94) Barone, R.; Rizzo, R.; Tabbì, G.; Malaguarnera, M.; Frye, R.E.; Bastin, J. Nuclear
peroxisome proliferator-activated receptors (PPARs) as therapeutic targets of
resveratrol for autism spectrum disorder. Int. J. Mol. Sci., 2019, 20(8), 1878.
http://dx.doi.org/10.3390/ijms20081878 PMID:30995737
95) Deckmann, I.; Schwingel, G.B.; Fontes-Dutra, M.; Bambini-Junior, V.; Gottfried,
C. Neuroimmune alterations in autism: A translational analysis focusing on the
animal model of autism induced by prenatal exposure to valproic acid.
Neuroimmunomodulation, 2018, 25(5-6), 285-299.
http://dx.doi.org/10.1159/000492113 PMID:30157484
96) Kumar, P.; Raman, T.; Swain, M.M.; Mishra, R.; Pal, A. Hyperglycemia-induced
oxidative-nitrosative stress induces inflammation and neurodegeneration via
augmented tuberous sclerosis complex-2 (TSC-2) activation in neuronal cells.
Mol. Neurobiol., 2017, 54(1), 238-254. http://dx.doi.org/10.1007/s12035-015-
9667-3 PMID:26738854
97) Das, A.; Durrant, D.; Koka, S.; Salloum, F.N.; Xi, L.; Kukreja, R.C. Mammalian
target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function
 in type 2 diabetic mice: Potential role of attenuated oxidative stress and altered
contractile protein expression. J. Biol. Chem., 2014, 289(7), 4145-4160.
http://dx.doi.org/10.1074/jbc.M113.521062 PMID:24371138
98) Kotajima-Murakami, H.; Kobayashi, T.; Kashii, H.; Sato, A.; Hagino, Y.; Tanaka,
M.; Nishito, Y.; Takamatsu, Y.; Uchino, S.; Ikeda, K. Effects of rapamycin on
social interaction deficits and gene expression in mice exposed to valproic acid in
utero. Mol. Brain, 2019, 12(1), 3. http://dx.doi.org/10.1186/s13041-018-0423-2
PMID:30621732
99) Schafer, F.Q.; Buettner, G.R. Redox environment of the cell as viewed through
the redox state of the glutathione disulfide/glutathione couple. Free Radic. Biol.
Med., 2001, 30(11), 1191-1212. http://dx.doi.org/10.1016/S0891-5849(01)00480-
4PMID:11368918
100) Bala, K.A.; Doğan, M.; Mutluer, T.; Kaba, S.; Aslan, O.; Balahoroğlu, R.;
Çokluk, E.; Üstyol, L.; Kocaman, S. Plasma amino acid profile in autism
spectrum disorder (ASD). Eur. Rev. Med. Pharmacol. Sci., 2016, 20(5), 923-929.
PMID:27010152
101) Moretti, P.; Peters, S.U.; del Gaudio, D.; Sahoo, T.; Hyland, K.; Bottiglieri, T.;
Hopkin, R.J.; Peach, E.; Min, S.H.; Goldman, D.; Roa, B.; Bacino, C.A.; Scaglia,
F. Brief report: Autistic symptoms, developmental regression, mental retardation,
epilepsy, and dyskinesias in CNS folate deficiency. J. Autism Dev. Disord., 2008,
38(6), 1170-1177. http://dx.doi.org/10.1007/s10803-007-0492-z PMID:18027081
102) Zhang, Z.; Yu, L.; Li, S.; Liu, J. Association study of polymorphisms in genes
relevant to vitamin B12 and folate metabolism with childhood autism spectrum
disorder in a han chinese population. Med. Sci. Monit., 2018, 24, 370-376.
http://dx.doi.org/10.12659/MSM.905567 PMID:29348398
103) Bertoglio, K.; Jill James, S.; Deprey, L.; Brule, N.; Hendren, R.L. Pilot study of
the effect of methyl B12 treatment on behavioral and biomarker measures in
children with autism. J. Altern. Complement. Med., 2010, 16(5), 555-560.
http://dx.doi.org/10.1089/acm.2009.0177 PMID:20804367
104) Zhang, Y.; Hodgson, N.W.; Trivedi, M.S.; Abdolmaleky, H.M.; Fournier, M.;
Cuenod, M.; Do, K.Q.; Deth, R.C. Decreased brain levels of vitamin B12 in
aging, autism and schizophrenia. PLoS One, 2016, 11(1), e0146797.
http://dx.doi.org/10.1371/journal.pone.0146797 PMID:26799654
105) Frye, R.E.; Slattery, J.C.; Quadros, E.V. Folate metabolism abnormalities in
autism: Potential biomarkers. Biomarkers Med., 2017, 11(8), 687-699.
http://dx.doi.org/10.2217/bmm-2017-0109 PMID:28770615
106) James, S.J.; Melnyk, S.; Fuchs, G.; Reid, T.; Jernigan, S.; Pavliv, O.; Hubanks,
A.; Gaylor, D.W. Efficacy of methylcobalamin and folinic acid treatment on
glutathione redox status in children with autism. Am. J. Clin. Nutr., 2009, 89(1),
425-430. http://dx.doi.org/10.3945/ajcn.2008.26615 PMID:19056591
107) An, S.; Feng, X.; Dai, Y.; Bo, H.; Wang, X.; Li, M.; Woo, J.Z.; Liang, X.; Guo,
C.; Liu, C.X.; Wei, L. Development and evaluation of a speech-generating AAC
mobile app for minimally verbal children with autism spectrum disorder in
Mainland China. Mol. Autism, 2017, 8(1), 52. http://dx.doi.org/10.1186/s13229-
017-0165-5 PMID:29026509
108) Sun, C.; Zou, M.; Zhao, D.; Xia, W.; Wu, L. Efficacy of folic acid
supplementation in autistic children participating in structured teaching: An open-
label trial. Nutrients, 2016, 8(6), 337.
http://dx.doi.org/10.3390/nu8060337PMID:27338456
109) Castro, K.; Klein, L.S.; Baronio, D.; Gottfried, C.; Riesgo, R.; Perry, I.S. Folic
acid and autism: What do we know? Nutr. Neurosci., 2016, 19(7), 310-317.
http://dx.doi.org/10.1179/1476830514Y.0000000142PMID:25087906
110) Kang, D.W.; Adams, J.B.; Gregory, A.C.; Borody, T.; Chittick, L.; Fasano, A.;
Khoruts, A.; Geis, E.; Maldonado, J.; McDonough-Means, S.; Pollard, E.L.;
Roux, S.; Sadowsky, M.J.; Lipson, K.S.; Sullivan, M.B.; Caporaso, J.G.;
Krajmalnik-Brown, R. Microbiota transfer therapy alters gut ecosystem and
improves gastrointestinal and autism symptoms: An open-label study.
Microbiome, 2017, 5(1), 10. http://dx.doi.org/10.1186/s40168-016-0225-7
PMID:28122648
111) Gondalia, S.V.; Palombo, E.A.; Knowles, S.R.; Cox, S.B.; Meyer, D.; Austin,
D.W. Molecular characterisation of gastrointestinal microbiota of children with
autism (with and without gastrointestinal dysfunction) and their neurotypical
siblings. Autism Res., 2012, 5(6), 419-427. http://dx.doi.org/10.1002/aur.1253
PMID:22997101
112) Chaidez, V.; Hansen, R.L.; Hertz-Picciotto, I. Gastrointestinal problems in
children with autism, developmental delays or typical development. J. Autism
Dev. Disord., 2014, 44(5), 1117-1127. http://dx.doi.org/10.1007/s10803-013-
1973-x PMID:24193577
113) Santocchi, E.; Guiducci, L.; Fulceri, F.; Billeci, L.; Buzzigoli, E.; Apicella, F.;
Calderoni, S.; Grossi, E.; Morales, M.A.; Muratori, F. Gut to brain interaction in
autism spectrum disorders: A randomized controlled trial on the role of probiotics
on clinical, biochemical and neurophysiological parameters. BMC Psychiatry,
2016, 16(1), 183. http://dx.doi.org/10.1186/s12888-016-0887-5 PMID:27260271
114) Cryan, J.F.; Dinan, T.G. Mind-altering microorganisms: The impact of the gut
microbiota on brain and behaviour. Nat. Rev. Neurosci., 2012, 13(10), 701-712.
http://dx.doi.org/10.1038/nrn3346 PMID:22968153
115) McElhanon, B.O.; McCracken, C.; Karpen, S.; Sharp, W.G. Gastrointestinal
symptoms in autism spectrum disorder: A meta-analysis. Pediatrics, 2014, 133(5),
872-883. http://dx.doi.org/10.1542/peds.2013-3995 PMID:24777214
116) Rao, G.M. Effects of prebiotics, probiotics intervention in children with autism
spectrum disorder: A systematic review. Biomedicine, 2020, 20, 119-122.
117) Strati, F.; Cavalieri, D.; Albanese, D.; De Felice, C.; Donati, C.; Hayek, J.;
Jousson, O.; Leoncini, S.; Renzi, D.; Calabrò, A.; De Filippo, C. New evidences
on the altered gut microbiota in autism spectrum disorders. Microbiome, 2017,
5(1), 24. http://dx.doi.org/10.1186/s40168-017-0242-1 PMID:28222761
118) Dhakal, R.; Bajpai, V.K.; Baek, K.H. Production of gaba (γ - aminobutyric acid)
by microorganisms: A review. Braz. J. Microbiol., 2012, 43(4), 1230-1241.
http://dx.doi.org/10.1590/S1517-83822012000400001 PMID:24031948
119) El-Ansary, A.; Bacha, A.B.; Bjørklund, G.; Al-Orf, N.; Bhat, R.S.; Moubayed, N.;
Abed, K. Probiotic treatment reduces the autistic-like excitation/inhibition
imbalance in juvenile hamsters induced by orally administered propionic acid and
 clindamycin. Metab. Brain Dis., 2018, 33(4), 1155-1164.
http://dx.doi.org/10.1007/s11011-018-0212-8 PMID:29582256
120) Ait-Belgnaoui, A.; Colom, A.; Braniste, V.; Ramalho, L.; Marrot, A.; Cartier, C.;
Houdeau, E.; Theodorou, V.; Tompkins, T. Probiotic gut effect prevents the
chronic psychological stress-induced brain activity abnormality in mice.
Neurogastroenterol. Motil., 2014, 26(4), 510-520.
http://dx.doi.org/10.1111/nmo.12295 PMID:24372793
121) Sanctuary, M.R.; Kain, J.N.; Angkustsiri, K.; German, J.B. Dietary considerations
in autism spectrum disorders: The potential role of protein digestion and
microbial putrefaction in the gut-brain axis. Front. Nutr., 2018, 5, 40.
http://dx.doi.org/10.3389/fnut.2018.00040 PMID:29868601
122) Grimaldi, R.; Gibson, G.R.; Vulevic, J.; Giallourou, N.; Castro-Mejía, J.L.;
Hansen, L.H.; Leigh Gibson, E.; Nielsen, D.S.; Costabile, A. A prebiotic
intervention study in children with autism spectrum disorders (ASDs).
Microbiome, 2018, 6(1), 133. http://dx.doi.org/10.1186/s40168-018-0523-3
PMID:30071894
123) Meguid, N.A.; Mawgoud, Y.I.A.; Bjørklund, G.; Mehanne, N.S.; Anwar, M.;
Effat, B.A.E.K.; Chirumbolo, S.; Elrahman, M.M.A. Molecular characterization
of probiotics and their influence on children with autism spectrum disorder. Mol.
Neurobiol., 2022, 59(11), 6896-6902. http://dx.doi.org/10.1007/s12035-022-
02963-8 PMID:36050597
124) MacFabe, D.F. Short-chain fatty acid fermentation products of the gut
microbiome: Implications in autism spectrum disorders. Microb. Ecol. Health
Dis., 2012, 23(0) http://dx.doi.org/10.3402/mehd.v23i0.19260 PMID:23990817
125) Sanctuary, M.R.; Kain, J.N.; Chen, S.Y.; Kalanetra, K.; Lemay, D.G.; Rose, D.R.;
Yang, H.T.; Tancredi, D.J.; German, J.B.; Slupsky, C.M.; Ashwood, P.; Mills,
D.A.; Smilowitz, J.T.; Angkustsiri, K. Pilot study of probiotic/- colostrum
supplementation on gut function in children with autism and gastrointestinal
symptoms. PLoS One, 2019, 14(1), e0210064.
http://dx.doi.org/10.1371/journal.pone.0210064 PMID:30625189
126) Witters, P.; Debbold, E.; Crivelly, K.; Vande Kerckhove, K.; Corthouts, K.;
Debbold, B.; Andersson, H.; Vannieuwenborg, L.; Geuens, S.; Baumgartner, M.;
Kozicz, T.; Settles, L.; Morava, E. Autism in patients with propionic acidemia.
Mol. Genet. Metab., 2016, 119(4), 317-321.
http://dx.doi.org/10.1016/j.ymgme.2016.10.009 PMID:27825584
127) Choi, J.; Lee, S.; Won, J.; Jin, Y.; Hong, Y.; Hur, T.Y.; Kim, J.H.; Lee, S.R.;
Hong, Y. Pathophysiological and neurobehavioral characteristics of a propionic
acid-mediated autism-like rat model. PLoS One, 2018, 13(2), e0192925.
http://dx.doi.org/10.1371/journal.pone.0192925 PMID:29447237
128) Frye, R.E.; Rose, S.; Slattery, J.; MacFabe, D.F. Gastrointestinal dysfunction in
autism spectrum disorder: The role of the mitochondria and the enteric
microbiome. Microb. Ecol. Health Dis., 2015, 26(0), 27458.
http://dx.doi.org/10.3402/mehd.v26.27458 PMID:25956238
129) Williams, B.L.; Hornig, M.; Buie, T.; Bauman, M.L.; Cho Paik, M.; Wick, I.;
Bennett, A.; Jabado, O.; Hirschberg, D.L.; Lipkin, W.I. Impaired carbohydrate
digestion and transport and mucosal dysbiosis in the intestines of children with
 autism and gastrointestinal disturbances. PLoS One, 2011, 6(9), e24585.
http://dx.doi.org/10.1371/journal.pone.0024585 PMID:21949732
130) Tomova, A.; Husarova, V.; Lakatosova, S.; Bakos, J.; Vlkova, B.; Babinska, K.;
Ostatnikova, D. Gastrointestinal microbiota in children with autism in Slovakia.
Physiol. Behav., 2015, 138, 179-187.
http://dx.doi.org/10.1016/j.physbeh.2014.10.033 PMID:25446201
131) Hogan, S.; O’Gara, J.P.; O’Neill, E. Novel treatment of Staphylococcus aureus
device-related infections using fibrinolytic agents. Antimicrob. Agents
Chemother., 2018, 62(2), e02008-17. http://dx.doi.org/10.1128/AAC.02008-17
PMID:29203484
132) Zapotoczna, M.; McCarthy, H.; Rudkin, J.K.; O’Gara, J.P.; O’Neill, E. An
essential role for coagulase in Staphylococcus aureus biofilm development reveals
new therapeutic possibilities for device-related infections. J. Infect. Dis., 2015,
212(12), 1883-1893. http://dx.doi.org/10.1093/infdis/jiv319 PMID:26044292
133) Chang, Y.; Gu, W.; McLandsborough, L. Low concentration of
ethylenediaminetetraacetic acid (EDTA) affects biofilm formation of Listeria
monocytogenes by inhibiting its initial adherence. Food Microbiol., 2012, 29(1),
10-17. http://dx.doi.org/10.1016/j.fm.2011.07.009 PMID:22029913
134) Miyazaki, Y.; Yokota, H.; Takahashi, H.; Fukuda, M.; Kawakami, H.; Kamiya,
S.; Hanawa, T. Effect of probiotic bacterial strains of Lactobacillus,
Bifidobacterium, and Enterococcus on Enteroaggregative Escherichia coli. J.
Infect. Chemother., 2010, 16(1), 10-18. http://dx.doi.org/10.1007/s10156-009-
0007-2 PMID:20054601
135) Panksepp, J. A neurochemical theory of autism. Trends Neurosci., 1979, 2, 174-
177. http://dx.doi.org/10.1016/0166-2236(79)90071-7
136) Gillberg, C.; Terenius, L.; Lönnerholm, G. Endorphin activity in childhood
psychosis. Spinal fluid levels in 24 cases. Arch. Gen. Psychiatry, 1985, 42(8),
780-783. http://dx.doi.org/10.1001/archpsyc.1985.01790310042005
PMID:4015322
137) Guareschi Cazzullo, A.; Musetti, M.C.; Musetti, L.; Bajo, S.; Sacerdote, P.;
Panerai, A. β-Endorphin levels in peripheral blood mononuclear cells and long-
term naltrexone treatment in autistic children. Eur. Neuropsychopharmacol.,
1999, 9(4), 361-366. http://dx.doi.org/10.1016/S0924-977X(99)00010-3
PMID:10422898
138) Zioudrou, C.; Streaty, R.A.; Klee, W.A. Opioid peptides derived from food
proteins. The exorphins. J. Biol. Chem., 1979, 254(7), 2446-2449.
http://dx.doi.org/10.1016/S0021-9258(17)30243-0 PMID:372181
139) Whiteley, P.; Shattock, P. Biochemical aspects in autism spectrum disorders:
Updating the opioid-excess theory and presenting new opportunities for
biomedical intervention. Expert Opin. Ther. Targets, 2002, 6(2), 175-183.
http://dx.doi.org/10.1517/14728222.6.2.175 PMID:12223079
140) Camarca, A.; Anderson, R.P.; Mamone, G.; Fierro, O.; Facchiano, A.; Costantini,
S.; Zanzi, D.; Sidney, J.; Auricchio, S.; Sette, A.; Troncone, R.; Gianfrani, C.
Intestinal T cell responses to gluten peptides are largely heterogeneous:
Implications for a peptide-based therapy in celiac disease. J. Immunol., 2009,
182(7), 4158-4166. http://dx.doi.org/10.4049/jimmunol.0803181 PMID:19299713
141) Catassi, C.; Fasano, A. Celiac disease. Curr. Opin. Gastroenterol., 2008, 24(6),
687-691. http://dx.doi.org/10.1097/MOG.0b013e32830edc1e PMID:19122516
142) Ghalichi, F.; Ghaemmaghami, J.; Malek, A.; Ostadrahimi, A. Effect of gluten free
diet on gastrointestinal and behavioral indices for children with autism spectrum
disorders: A randomized clinical trial. World J. Pediatr., 2016, 12(4), 436-442.
http://dx.doi.org/10.1007/s12519-016-0040-z PMID:27286693
143) Pennesi, C.M.; Klein, L.C. Effectiveness of the glutenfree, casein-free diet for
children diagnosed with autism spectrum disorder: Based on parental report. Nutr.
Neurosci., 2012, 15(2), 85-91.
http://dx.doi.org/10.1179/1476830512Y.0000000003 PMID:22564339
144) Johnson, C.R.; Handen, B.L.; Zimmer, M.; Sacco, K.; Turner, K. Effects of gluten
free / casein free diet in young children with autism: A pilot study. J. Dev. Phys.
Disabil., 2011, 23(3), 213-225. http://dx.doi.org/10.1007/s10882-010-9217-x
145) Elder, J.H.; Shankar, M.; Shuster, J.; Theriaque, D.; Burns, S.; Sherrill, L. The
gluten-free, casein-free diet in autism: Results of a preliminary double blind
clinical trial. J. Autism Dev. Disord., 2006, 36(3), 413-420.
http://dx.doi.org/10.1007/s10803-006-0079-0 PMID:16555138
146) Lange, K.W.; Hauser, J.; Reissmann, A. Gluten-free and casein-free diets in the
therapy of autism. Curr. Opin. Clin. Nutr. Metab. Care, 2015, 18(6), 572-575.
http://dx.doi.org/10.1097/MCO.0000000000000228 PMID:26418822
147) Desai, A.; Sequeira, J.M.; Quadros, E.V. Prevention of behavioral deficits in rats
exposed to folate receptor antibodies: Implication in autism. Mol. Psychiatry,
2017, 22(9), 1291-1297. http://dx.doi.org/10.1038/mp.2016.153 PMID:27646260
148) Castro, K.; Baronio, D.; Perry, I.S.; Riesgo, R.S.; Gottfried, C. The effect of
ketogenic diet in an animal model of autism induced by prenatal exposure to
valproic acid. Nutr. Neurosci., 2017, 20(6), 343-350.
http://dx.doi.org/10.1080/1028415X.2015.1133029 PMID:26856821
149) Spilioti, M.; Evangeliou, A.E.; Tramma, D.; Theodoridou, Z.; Metaxas, S.;
Michailidi, E.; Bonti, E.; Frysira, H.; Haidopoulou, A.; Asprangathou, D.;
Tsalkidis, A.J.; Kardaras, P.; Wevers, R.A.; Jakobs, C.; Gibson, K.M. Evidence
for treatable inborn errors of metabolism in a cohort of 187 Greek patients with
autism spectrum disorder (ASD). Front. Hum. Neurosci., 2013, 7, 858.
http://dx.doi.org/10.3389/fnhum.2013.00858 PMID:24399946
150) El-Rashidy, O.; El-Baz, F.; El-Gendy, Y.; Khalaf, R.; Reda, D.; Saad, K.
Ketogenic diet versus gluten free casein free diet in autistic children: A case-
control study. Metab. Brain Dis., 2017, 32(6), 1935-1941.
http://dx.doi.org/10.1007/s11011-017-0088-z PMID:28808808
151) Evangeliou, A.; Vlachonikolis, I.; Mihailidou, H.; Spilioti, M.; Skarpalezou, A.;
Makaronas, N.; Prokopiou, A.; Christodoulou, P.; Liapi-Adamidou, G.; Helidonis,
E.; Sbyrakis, S.; Smeitink, J. Application of a ketogenic diet in children with
autistic behavior: Pilot study. J. Child Neurol., 2003, 18(2), 113-118.
http://dx.doi.org/10.1177/08830738030180020501 PMID:12693778
152) Hartman, R.E.; Patel, D. Dietary approaches to the management of autism
spectrum disorders. Advances in Neurobiology; Springer, 2020, Vol. 24, pp. 547-
571. http://dx.doi.org/10.1007/978-3-030-30402-7_19
153) Nurchi, V.M.; Buha Djordjevic, A.; Crisponi, G.; Alexander, J.; Bjørklund, G.;
Aaseth, J. Arsenic toxicity: Molecular targets and therapeutic agents.
Biomolecules, 2020, 10(2), 235. http://dx.doi.org/10.3390/biom10020235
PMID:32033229
154) Bjørklund, G.; Crisponi, G.; Nurchi, V.M.; Cappai, R.; Buha Djordjevic, A.;
Aaseth, J. A review on coordination properties of thiol-containing chelating
agents towards mercury, cadmium, and lead. Molecules, 2019, 24(18), 3247.
http://dx.doi.org/10.3390/molecules24183247 PMID:31489907
155) Bjørklund, G.; Mutter, J.; Aaseth, J. Metal chelators and neurotoxicity: Lead,
mercury, and arsenic. Arch. Toxicol., 2017, 91(12), 3787-3797.
http://dx.doi.org/10.1007/s00204-017-2100-0 PMID:29063135
156) Yassa, H.A. Autism: A form of lead and mercury toxicity. Environ. Toxicol.
Pharmacol., 2014, 38(3), 1016-1024. http://dx.doi.org/10.1016/j.etap.2014.10.005
PMID:25461563
157) James, S.; Stevenson, S.W.; Silove, N.; Williams, K. Chelation for autism
spectrum disorder (ASD). Cochrane Libr., 2015, 2016(10), CD010766.
http://dx.doi.org/10.1002/14651858.CD010766.pub2 PMID:26114777
158) T Schultz, S.; G Gould, G. Acetaminophen use for fever in children associated
with autism spectrum disorder. Autism Open Access, 2016, 6(2), 170.
http://dx.doi.org/10.4172/2165-7890.1000170 PMID:27695658
159) Wang, T.; Shan, L.; Du, L.; Feng, J.; Xu, Z.; Staal, W.G.; Jia, F. Serum
concentration of 25-hydroxyvitamin D in autism spectrum disorder: A systematic
review and meta-analysis. Eur. Child Adolesc. Psychiatry, 2016, 25(4), 341-350.
http://dx.doi.org/10.1007/s00787-015-0786-1 PMID:26514973
160) Fernell, E.; Bejerot, S.; Westerlund, J.; Miniscalco, C.; Simila, H.; Eyles, D.;
Gillberg, C.; Humble, M.B. Autism spectrum disorder and low vitamin D at birth:
A sibling control study. Mol. Autism, 2015, 6(1), 3.
http://dx.doi.org/10.1186/2040-2392-6-3 PMID:25874075
161) Huang, Y.N.; Ho, Y.J.; Lai, C.C.; Chiu, C.T.; Wang, J.Y. 1,25-Dihydroxyvitamin
D3 attenuates endotoxin-induced production of inflammatory mediators by
inhibiting MAPK activation in primary cortical neuron-glia cultures. J.
Neuroinflammation, 2015, 12(1), 147. http://dx.doi.org/10.1186/s12974-015-
0370-0 PMID:26259787
162) Patrick, R.P.; Ames, B.N.; Vitamin, D. Vitamin D hormone regulates serotonin
synthesis. Part 1: Relevance for autism. FASEB J., 2014, 28(6), 2398-2413.
http://dx.doi.org/10.1096/fj.13-246546 PMID:24558199
163) Saad, K.; Abdel-Rahman, A.A.; Elserogy, Y.M.; Al-Atram, A.A.; El-Houfey,
A.A.; Othman, H.A.K.; Bjørklund, G.; Jia, F.; Urbina, M.A.; Abo-Elela, M.G.M.;
Ahmad, F.A.; Abd El-Baseer, K.A.; Ahmed, A.E.; Abdel-Salam, A.M. Retracted:
Randomized controlled trial of vitamin D supplementation in children with autism
spectrum disorder. J. Child Psychol. Psychiatry, 2018, 59(1), 20-29.
http://dx.doi.org/10.1111/jcpp.12652 PMID:27868194
164) Kostiukow, A.; Samborski, W. The effectiveness of hyperbaric oxygen therapy
(HBOT) in children with autism spectrum disorders. Pol. Merkur. Lekarski, 2020,
48(283), 15-18.
165) Rossignol, D.A.; Rossignol, L.W.; Smith, S.; Schneider, C.; Logerquist, S.;
Usman, A.; Neubrander, J.; Madren, E.M.; Hintz, G.; Grushkin, B.; Mumper,
E.A. Hyperbaric treatment for children with autism: A multicenter, randomized,
double-blind, controlled trial. BMC Pediatr., 2009, 9(1), 21.
http://dx.doi.org/10.1186/1471-2431-9-21 PMID:19284641
166) Sakulchit, T.; Ladish, C.; Goldman, R.D. Hyperbaric oxygen therapy for children
with autism spectrum disorder. Can. Fam. Physician, 2017, 63(6), 446-448.
PMID:28615394
167) Choi, S.; Hong, D.K.; Choi, B.Y.; Suh, S.W. Zinc in the brain: Friend or foe? Int.
J. Mol. Sci., 2020, 21(23), 8941. http://dx.doi.org/10.3390/ijms21238941
PMID:33255662
168) Bitanihirwe, B.K.Y.; Cunningham, M.G. Zinc: The brain’s dark horse. Synapse,
2009, 63(11), 1029-1049. http://dx.doi.org/10.1002/syn.20683 PMID:19623531
169) Cope, E.C.; Levenson, C.W. Role of zinc in the development and treatment of
mood disorders. Curr. Opin. Clin. Nutr. Metab. Care, 2010, 13(6), 685-689.
http://dx.doi.org/10.1097/MCO.0b013e32833df61a PMID:20689416
170) Russo, A. J. Decreased zinc and increased copper in individuals with anxiety.
Nutr Metab Insights, 2011, 4, 1-5. http://dx.doi.org/10.4137/NMI.S6349
171) Krall, R.; Gale, J.R.; Ross, M.M.; Tzounopoulos, T.; Aizenman, E. Intracellular
zinc signaling influences NMDA receptor function by enhancing the interaction
of ZnT1 with GluN2A. Neurosci. Lett., 2022, 790, 136896.
http://dx.doi.org/10.1016/j.neulet.2022.136896 PMID:36202195
172) Miyata, S.; Nagata, H.; Yamao, S.; Nakamura, S.; Kameyama, M. Dopamine-β-
hydroxylase activities in serum and cerebrospinal fluid of aged and demented
patients. J. Neurol. Sci., 1984, 63(3), 403-409. http://dx.doi.org/10.1016/0022-
510X(84)90163-1PMID:6726279
173) Skalny, A.V.; Simashkova, N.V.; Klyushnik, T.P.; Grabeklis, A.R.; Radysh, I.V.;
Skalnaya, M.G.; Nikonorov, A.A.; Tinkov, A.A. Assessment of serum trace
elements and electrolytes in children with childhood and atypical autism. J. Trace
Elem. Med. Biol., 2017, 43, 9-14. http://dx.doi.org/10.1016/j.jtemb.2016.09.009
PMID:27707611
174) Wu, H.; Zhao, G.; Liu, S.; Zhang, Q.; Wang, P.; Cao, Y.; Wu, L. Supplementation
with selenium attenuates autism-- like behaviors and improves oxidative stress,
inflammation and related gene expression in an autism disease model. J. Nutr.
Biochem., 2022, 107, 109034. http://dx.doi.org/10.1016/j.jnutbio.2022.109034
PMID:35500829
175) Skalny, A.V.; Skalnaya, M.G.; Bjørklund, G.; Gritsenko, V.A.; Aaseth, J.;
Tinkov, A.A. Selenium and autism spectrum disorder. In: Selenium. Molecular
and Integrative Toxicology; Springer: Cham, 2018; pp. 193-210.
http://dx.doi.org/10.1007/978-3-319-95390-8_10
176) Raymond, L.J.; Deth, R.C.; Ralston, N.V.C. Potential role of selenoenzymes and
antioxidant metabolism in relation to autism etiology and pathology. Autism Res.
Treat., 2014, 2014, 1-15. http://dx.doi.org/10.1155/2014/164938 PMID:24734177
177) Bjørklund, G.; Aaseth, J.; Ajsuvakova, O.P.; Nikonorov, A.A.; Skalny, A.V.;
Skalnaya, M.G.; Tinkov, A.A. Molecular interaction between mercury and
 selenium in neurotoxicity. Coord. Chem. Rev., 2017, 332, 30-37.
http://dx.doi.org/10.1016/j.ccr.2016.10.009
178) Bjørklund, G. Selenium as an antidote in the treatment of mercury intoxication.
Biometals, 2015, 28(4), 605-614. http://dx.doi.org/10.1007/s10534-015-9857-5
PMID:25947386
179) El-Ansary, A.; Bjørklund, G.; Tinkov, A.A.; Skalny, A.V.; Al Dera, H.
Relationship between selenium, lead, and mercury in red blood cells of Saudi
autistic children. Metab. Brain Dis., 2017, 32(4), 1073-1080.
http://dx.doi.org/10.1007/s11011-017-9996-1 PMID:28326463
180) Kirkland, A.; Sarlo, G.; Holton, K. The role of magnesium in neurological
disorders. Nutrients, 2018, 10(6), 730. http://dx.doi.org/10.3390/nu10060730
PMID:29882776
181) Yasuda, H.; Tsutsui, T. Assessment of infantile mineral imbalances in autism
spectrum disorders (ASDs). Int. J. Environ. Res. Public Health, 2013, 10(11),
6027-6043. http://dx.doi.org/10.3390/ijerph10116027 PMID:24284360
182) Beto, J.A. The role of calcium in human aging. Clin. Nutr. Res., 2015, 4(1), 1-8.
http://dx.doi.org/10.7762/cnr.2015.4.1.1 PMID:25713787
183) Nguyen, R.L.; Medvedeva, Y.V.; Ayyagari, T.E.; Schmunk, G.; Gargus, J.J.
Intracellular calcium dysregulation in autism spectrum disorder: An analysis of
converging organelle signaling pathways. Biochim. Biophys. Acta Mol. Cell Res.,
2018, 1865(11), 1718-1732. http://dx.doi.org/10.1016/j.bbamcr.2018.08.003
PMID: 30992134
184) Chen, L.; Shi, X.J.; Liu, H.; Mao, X.; Gui, L.N.; Wang, H.; Cheng, Y. Oxidative
stress marker aberrations in children with autism spectrum disorder: A systematic
review and meta-analysis of 87 studies (N = 9109). Transl. Psychiatry, 2021,
11(1), 15. http://dx.doi.org/10.1038/s41398-020-01135-3 PMID: 33414386
185) Vetter, T.; Lohse, M.J. Magnesium and the parathyroid. Curr. Opin. Nephrol.
Hypertens., 2002, 11(4), 403-410. http://dx.doi.org/10.1097/00041552-
200207000-00006 PMID: 12105390
186) Pangrazzi, L.; Balasco, L.; Bozzi, Y. Oxidative stress and immune system
dysfunction in autism spectrum disorders. Int. J. Mol. Sci., 2020, 21(9), 3293.
http://dx.doi.org/10.3390/ijms21093293 PMID: 32384730
187) Saghazadeh, A.; Ahangari, N.; Hendi, K.; Saleh, F.; Rezaei, N. Status of essential
elements in autism spectrum disorder: Systematic review and meta-analysis. Rev.
Neurosci., 2017, 28(7), 783-809. http://dx.doi.org/10.1515/revneuro-2017-0015
PMID: 28665792
188) Skalny, A.V.; Mazaletskaya, A.L.; Ajsuvakova, O.P.; Bjørklund, G.; Skalnaya,
M.G.; Chernova, L.N.; Skalny, A.A.; Tinkov, A.A. Magnesium status in children
with attention-deficit/hyperactivity disorder and/or autism spectrum disorder. J.
Korean Acad. Child Adolesc. Psychiatry, 2020, 31(1), 41-45.
http://dx.doi.org/10.5765/jkacap.190036 PMID: 32612412
189) Uwitonze, A.M.; Razzaque, M.S. Role of magnesium in vitamin D activation and
function. J. Am. Osteopath. Assoc., 2018, 118(3), 181-189.
http://dx.doi.org/10.7556/jaoa.2018.037 PMID: 29480918
190) Muir, K.W. Magnesium in stroke treatment. Postgrad. Med. J., 2002, 78(925),
641-645. http://dx.doi.org/10.1136/pmj.78.925.641 PMID: 12496316
191) Schmunk, G.; Gargus, J.J. Channelopathy pathogenesis in autism spectrum
disorders. Front. Genet., 2013, 4, 222. http://dx.doi.org/10.3389/fgene.2013.00222
PMID: 24204377
192) Martineau, J.; Barthelemy, C.; Garreau, B.; Lelord, G. Vitamin B6, magnesium,
and combined B6-Mg: Therapeutic effects in childhood autism. Biol. Psychiatry,
1985, 20(5), 467-478. http://dx.doi.org/10.1016/0006-3223(85)90019-8 PMID:
3886023
193) Bjørklund, G.; Waly, M.I.; Al-Farsi, Y.; Saad, K.; Dadar, M.; Rahman, M.M.;
Elhoufey, A.; Chirumbolo, S.; Jóźwik-Pruska, J.; Kałużna-Czaplińska, J. The role
of vitamins in autism spectrum disorder: What do we know? J. Mol. Neurosci.,
2019, 67(3), 373-387. http://dx.doi.org/10.1007/s12031-018-1237-5 PMID:
30607900
194) Saad, K.; Abdel-rahman, A.A.; Elserogy, Y.M.; Al-Atram, A.A.; Cannell, J.J.;
Bjørklund, G.; Abdel-Reheim, M.K.; Othman, H.A.K.; El-Houfey, A.A.; Abd El-
Aziz, N.H.R.; Abd El-Baseer, K.A.; Ahmed, A.E.; Ali, A.M. Vitamin D status in
autism spectrum disorders and the efficacy of vitamin D supplementation in
autistic children. Nutr. Neurosci., 2016, 19(8), 346-351.
http://dx.doi.org/10.1179/1476830515Y.0000000019 PMID: 25876214
195) Chirumbolo, S.; Bjørklund, G.; Sboarina, A.; Vella, A. The role of vitamin D in
the immune system as a pro-survival molecule. Clin. Ther., 2017, 39(5), 894-916.
http://dx.doi.org/10.1016/j.clinthera.2017.03.021 PMID:28438353
196) Patrick, R.P.; Ames, B.N. Vitamin D and the omega-3 fatty acids control
serotonin synthesis and action, part 2: Relevance for ADHD, bipolar disorder,
schizophrenia, and impulsive behavior. FASEB J., 2015, 29(6), 2207-2222.
http://dx.doi.org/10.1096/fj.14-268342 PMID: 25713056
197) Cui, X.; Eyles, D.W. Vitamin D and the central nervous system: Causative and
preventative mechanisms in brain disorders. Nutrients, 2022, 14(20), 4353.
http://dx.doi.org/10.3390/nu14204353 PMID: 36297037
198) Zastre, J.A.; Sweet, R.L.; Hanberry, B.S.; Ye, S. Linking vitamin B1 with cancer
cell metabolism. Cancer Metab., 2013, 1(1), 16. http://dx.doi.org/10.1186/2049-
3002-1-16 PMID: 24280319
199) Jung, H.Y.; Kwon, H.J.; Kim, W.; Nam, S.M.; Kim, J.W.; Hahn, K.R.; Yoo,
D.Y.; Yoon, Y.S.; Choi, S.Y.; Kim, D.W.; Hwang, I.K. Role of pyridoxine in
GABA synthesis and degradation in the hippocampus. Tissue Cell, 2019, 61, 72-
78. http://dx.doi.org/10.1016/j.tice.2019.09.005 PMID: 31759410
200) Stover, P.J.; Field, M.S. Vitamin B-6. Adv. Nutr., 2015, 6(1), 132-133.
http://dx.doi.org/10.3945/an.113.005207 PMID: 25593152 Scott, J.M. Folate and
vitamin B 12
201) Proc. Nutr. Soc., 1999, 58(2), 441-448.
http://dx.doi.org/10.1017/S0029665199000580 PMID: 10466189
202) Bjørklund, G.; Doşa, M.D.; Maes, M.; Dadar, M.; Frye, R.E.; Peana, M.;
Chirumbolo, S. The impact of glutathione metabolism in autism spectrum
disorder. Pharmacol. Res., 2021, 166, 105437.
http://dx.doi.org/10.1016/j.phrs.2021.105437 PMID: 33493659
203) Bjørklund, G.; Tinkov, A.A.; Hosnedlová, B.; Kizek, R.; Ajsuvakova, O.P.;
Chirumbolo, S.; Skalnaya, M.G.; Peana, M.; Dadar, M.; El-Ansary, A.; Qasem,
 H.; Adams, J.B.; Aaseth, J.; Skalny, A.V. The role of glutathione redox imbalance
in autism spectrum disorder: A review. Free Radic. Biol. Med., 2020, 160, 149-
162. http://dx.doi.org/10.1016/j.freeradbiomed.2020.07.017 PMID: 32743
204) Bjørklund, G.; Meguid, N.A.; El-Bana, M.A.; Tinkov, A.A.; Saad, K.; Dadar, M.;
Hemimi, M.; Skalny, A.V.; Hosnedlová, B.; Kizek, R.; Osredkar, J.; Urbina,
M.A.; Fabjan, T.; El-Houfey, A.A.; Kałużna-Czaplińska, J.; Gątarek, P.;
Chirumbolo, S. Oxidative stress in autism spectrum disorder. Mol. Neurobiol.,
2020, 57(5), 2314-2332. http://dx.doi.org/10.1007/s12035-019-01742-2 PMID:
32026227
205) Rimland, B.; Callaway, E.; Dreyfus, P. The effect of high doses of vitamin B6 on
autistic children: A double- blind crossover study. Am. J. Psychiatry, 1978,
135(4), 472-475. http://dx.doi.org/10.1176/ajp.135.4.472 PMID: 345827
206) El-Ansary, A.; Cannell, J.J.; Bjørklund, G.; Bhat, R.S.; Al Dbass, A.M.; Alfawaz,
H.A.; Chirumbolo, S.; Al-Ayadhi, L. In the search for reliable biomarkers for the
early diagnosis of autism spectrum disorder: The role of vitamin D. Metab. Brain
Dis., 2018, 33(3), 917-931. http://dx.doi.org/10.1007/s11011-018-0199-1 PMID:
29497932
207) Kałużna-Czaplińska, J.; Gątarek, P.; Chirumbolo, S.; Chartrand, M.S.; Bjørklund,
G. How important is tryptophan in human health? Crit. Rev. Food Sci. Nutr.,
2019, 59(1), 72-88. http://dx.doi.org/10.1080/10408398.2017.1357534 PMID:
28799778
208) Kałużna-Czaplińska, J.; Jóźwik-Pruska, J.; Chirumbolo, S.; Bjørklund, G.
Tryptophan status in autism spectrum disorder and the influence of
supplementation on its level. Metab. Brain Dis., 2017, 32(5), 1585-1593.
http://dx.doi.org/10.1007/s11011-017-0045-x PMID: 28608247
209) Bjørklund, G.; Saad, K.; Chirumbolo, S.; Kern, J.K.; Geier, D.A.; Geier, M.R.;
Urbina, M.A. Immune dysfunction and neuroinflammation in autism spectrum
disorder. Acta Neurobiol. Exp., 2016, 76(4), 257-268.
http://dx.doi.org/10.21307/ane-2017-025 PMID: 28094817
210) Connery, K.; Tippett, M.; Delhey, L.M.; Rose, S.; Slattery, J.C.; Kahler, S.G.;
Hahn, J.; Kruger, U.; Cunningham, M.W.; Shimasaki, C.; Frye, R.E. Intravenous
immunoglobulin for the treatment of autoimmune encephalopathy in children
with autism. Transl. Psychiatry, 2018, 8(1), 148.
http://dx.doi.org/10.1038/s41398-018-0214-7 PMID: 30097568