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Autism: a Chemical Perspective- Current Research Indicates the Root Cause of

Autism is GABA-Transaminase.

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Autism: a chemical perspective
Current research indicates the root cause of autism is GABA-Transaminase
by Brett I. Cohen, PhD © 2020
A
utism is a complex genetic disorder that is
characterised by significant disturbances in social,
communicative and behavioural functioning. An
autistic subject can have disturbances that include serious
impairment of social relationships, delayed or deviant
language development, and repetitive and/or ritualistic
play and interests. Onset of autism occurs before the age
of three years, and the symptoms described above
usually continue throughout the lifetime of the autistic
person. Pervasive Developmental Disorder (PDD) or
autism is defined by the presence of abnormal and
impaired development that is observed before the age
of three years old.
Autism affects males in the population more than
APRIL – MAY 2021 www.nexusmagazine.com
HEALTH
females in a ratio of about 4:1 (Cohen, 2004, 2016). At
present, a real medical mystery exists as to why autism is
considered primarily a male disorder. The diagnosis for
autism is usually made through clinical observation using
current DSM-5 criteria. To date, no cure has been found
for autism. Over 20 years ago, the rate or frequency of
autism observed in the United States of America was one
in 10,000 births and was considered fairly uncommon
(Cohen, 1998).
Just over 15 years ago, Cohen (2004) reported that the
rate of autistic disorder was one in 1,000 births in the
United States of America. When a broader definition was
used (which included all PDDs), the prevalence of autism
was one per 500 births.
NEXUS • 23
Nuclear Radiation Connection callosum. Fifty-one age- and gender-matched volunteer
In 2014, the Centers for Disease Control and Prevention normal control subjects were also included. The results
estimated that the autism rate was one in 68 births in the illustrated overall size reduction, concentrated in the
United States of America (CDC, 2014). Autism rates (as posterior regions of the corpus callosum in the autistic
described above) are therefore rising alarmingly. group. In other words, the finding showed consistently
Recently, Cohen (2015) postulated that a link due to an reduced size of the corpus callosum in autistic patients
epigenetic response (transgenerational response) to with the results being localised to posterior regions. The
environmental factors like nuclear
radiation fallout (due to worldwide
exposure to nuclear radiation from
the mid-1940s; for example, from the
atomic bomb explosions over
Hiroshima and Nagasaki in August
1945) may be the reason for this
observed phenomenon.
Cohen (2015) also postulated that
this transgenerational response to
nuclear radiation exposure will be
more pronounced two or three
generations later, and this coincides
with the reported data found today
regarding rising rates of autism. The
current rate of autism from the
Centers for Disease Control and
Prevention (CDC) in 2018 was
reported to be 1 in 59 births in the Corpus callosum (Images:Life Science Databases(LSDB))
United States of America—1 in 37
births for boys and 1 in 151 births for girls (Autism researchers suggested that the finding supports the idea
Speaks). that reduced corpus callosum regions in the brain may
be a consistent feature in autism.
GABA and the Corpus Callosum In the study by Piven et al. (1997), 35 autistic subjects
Cohen (1999) was the first researcher to illustrate (26 males and nine females with a mean age of 18 years)
extremely high gamma-aminobutyric acid (GABA) levels previously diagnosed with autistic disorder and 36
in the plasma and urine and high plasma ammonia levels healthy comparison subjects who matched with age,
as possibly the root cause of autism. GABA is a major serving as the control group, were chosen. This study
inhibitory neurotransmitter in the mammalian brain and utilised detailed MRI (Magnetic Resonance Imaging) to
responsible for axon(s)-to-oligodendrocyte signalling in examine the size of the anterior, middle and posterior
the corpus callosum. regions of the corpus callosum in the autistic and normal
Located in the centre of the brain, the corpus callosum subjects. Relative to total brain size, the cross-sectional
is responsible for language, intelligence and speech; area of the middle and posterior regions of the corpus
when this area is damaged, cognitive disorders and callosum was found to be smaller (thinner) in autistic
language delays are usually found. The finding of individuals compared with healthy subjects.
elevated levels of GABA in the urine and plasma could
explain why autistic features such as self-stimulatory Link Between Infantile Autism and Liver
behaviour and language delays are found, and this is Cohen (2002, 2004) proposed a possible link between
possibly due to the abnormal development of the axon(s) the liver and infantile autism via the measurements of
in the corpus callosum (Cohen, 1999, 2002, 2002a, 2004, elevated plasma ammonia and lower gamma-
2004a). aminobutyric acid–transaminase (GABA-T, EC 2.6.1.19)
Magnetic resonance imaging studies found in the enzyme activity. GABA-T is the enzyme responsible for
literature illustrate this observation regarding damage to GABA catabolism (chemical breakdown in the liver during
the corpus callosum area in the brain in autistic subjects. regulation). Cohen (2002, 2004) showed that the GABA-
In the study by Egaas et al. (1995), 51 autistic patients T enzyme activity for an autistic child was approximately
(45 males and six females, ranging in age from three to 45.5 per cent (approximately half) lower than for the
42 years) who met several diagnostic criteria for autism average control group. Elevated levels of ammonia in the
were selected. Magnetic resonance imaging was used to plasma result in a decrease in the efficiency of the
measure and observe the posterior region of the corpus enzyme GABA-T, and this results in higher GABA

24 • NEXUS www.nexusmagazine.com APRIL – MAY 2021

concentrations in the plasma after
liver regulation.
In order to illustrate the
importance of GABA-T enzyme
activity and its relationship with
plasma GABA levels in the brain,
Cohen (2001) reported an
experiment where GABA-T enzyme
activity was inhibited with the use of
1(n-decyl-)3-pyrazolidinone (BW
357U) (a potent, selective inhibitor of
GABA-T enzyme activity in vitro) by
oral administration to rat subjects.
This experiment resulted in an
approximate 50 per cent reduction
of GABA-T enzyme activity, and this
corresponded to a threefold increase
in plasma GABA levels in the brain.
Cohen (2001) also demonstrated
that the GABA-T enzyme activity for
an autistic subject (a nine-year-old
white male diagnosed with infantile
autism) was inhibited or inefficient by approximately 45.5
per cent (almost half), and this resulted in a measured
plasma GABA level of approximately 2.25-fold more than
the norm. GABA-T enzyme activity for the control group
(normal control) ranged from 110 to 147 pmol/min/mg
of protein with an average of 128.5 pmol/min/mg of
protein. The value measured for the autistic child was 70
pmol/min/mg of protein, and this represents a value of
54.5 per cent GABA-T enzyme activity compared to 100
per cent for the control group. In other words, the GABA-
T enzyme activity was inhibited or hindered by
approximately 45.5 per cent as compared to the control
group.
Plasma GABA and Plasma Ammonia Levels
Cohen (2004, 2004a, 2015, 2016) also illustrated that
genes associated with chromosome 16p13.3 could be
implicated with the disorder of autism. This chromosome
region is important for the regulation of GABA-T enzyme
activity since the enzyme GABA-T implicates a mapping
region (as the unigene-identified by the National Center
for Biotechnology Information, NCBI in Homo sapiens) of
chromosome 16p13.3 (Cohen, 2004, 2004a, 2015, 2016).
In order to demonstrate that plasma GABA and plasma
ammonia levels are crucial and important regarding
autism, Cohen (2002a) described the use of a GABA-
transaminase agonist, imipramine, for the treatment of
autism. Imipramine was chosen as the GABA-T agonist
due to its long-term safety record as a drug suitable for
a child. In this case report by Cohen, an approximate
one-third reduction of plasma GABA and plasma
ammonia levels was observed for an autistic child being
treated with a GABA-T agonist. The patient's behaviour
and social interaction were also monitored. A GABA-T
APRIL – MAY 2021 www.nexusmagazine.com
agonist can be used to activate
GABA-T enzyme activity selectively,
and this can result in significant
lowering of plasma GABA and
ammonia in the brain. A reduction of
the plasma GABA (by administering
a GABA-T agonist, imipramine)
probably resulted in more axon(s)-to-
oligodendrocyte signalling in the
corpus callosum. Cohen (2002a)
observed that this also resulted in a
significant reduction of autistic
features including repetitious,
ritualistic, self-stimulatory behaviour
(stimming), an increase in the
patient's social interactions and an
improvement in verbal/language
skills.
In addition, Cohen (2002, 2004)
postulated that a link (a cause and
effect) between plasma ammonia
and plasma GABA exists, where the
concentration of plasma ammonia and plasma GABA is
directly related to one another. In fact, a ratio of
approximately 0.3 (plasma ammonia to plasma GABA)
seems to exist for normal subjects as well as for autistic
subjects and individuals with liver disorders (e.g., hepatic
encephalopathy) (Cohen, 2002, 2002a, 2004, 2004a,
2015).
Cohen observed that this also
resulted in a significant reduction
of autistic features including
repetitious, ritualistic, self-
stimulatory behaviour (stimming),
an increase in the patient's social
interactions and an improvement
in verbal/language skills.
Gender Brain Differences
Recently, Cohen (2016) illustrated gender difference
regarding the corpus callosum for males and females and
this finding can explain the phenomenon (described
above) that autism is primarily a male disorder. It was also
illustrated by Cohen (2016) that because males have less
density, cross-sectional area and thickness in the corpus
callosum (including the anterior, middle and posterior
subregions) as compared with females, males are more
susceptible to autism via damage to the region of the
corpus callosum. Since high plasma GABA is found in
autism and high plasma GABA affects axon(s)-to-
oligodendrocyte signalling in the corpus callosum, this
results in damage to the corpus callosum in autistic
NEXUS • 25
 type A (GABAA) receptors and GABAA α5
subtype are deficient in autism subjects
(Horder, et al., 2018). These studies utilised
autistic subjects that were on medications and
the results were described as confusing at
best.
Interestingly, recently Horder, et al. (2018)
found no differences in GABAA receptor or
GABAA α5 subunit availability and/or GABAA
receptor binding (total GABAA and GABAA α5
receptor availability in two positron emission
tomography [PET] imaging studies) in any
brain region of adults with autism as compared
to normal controls. PET is a nuclear medicine
functional imaging technique that is used to
Cell GABA Receptor (Image: Blausen Medical, Bruce Blaus) observe metabolic processes in the body (in
this case the brain) as an aid to the diagnosis
of disease. It should also be noted that all of
subjects. Magnetic resonance imaging of autistic subjects the subjects studied by Horder, et al. (2018) (both normal
confirms this with the observation that the corpus controls and autistic subjects) were free of medication.
callosum is thinner or smaller compared with normal This is important because prior studies on autistic
controls (Cohen, 2016). subjects were confounded by the effects of medication.
In addition, Horder, et al. (2018) found no differences in
GABA Levels and Research Observations GABAA receptor or GABAA α5 subunit availability in any
Many researchers have observed high plasma GABA of the three mouse models they studied. They conclude
levels in autistic subjects. Dhossche et al. (2002) reported that GABAA receptor availability is normal for adults with
high or elevated levels of GABA in autistic subjects and autism and that the GABA signalling may be functionally
suggested the hypothesis that GABAergic mechanisms impaired for the autistic subjects studied. The findings of
may play a role in the aetiology or pathophysiology of Horder et al. (2018) clearly brings to the forefront the
autistic disorder.
Russo (2013) observed that the increase in GABA levels
in autistic children resulted in increasing hyperactivity,
impulsivity severity, tiptoeing severity, light sensitivity and
tactile sensitivity. He also suggested that plasma GABA
levels are related to symptom severity in autistic children.
These findings support the observation that high plasma
GABA levels are found in autism.
Since it has been established by Cohen and other
researchers (see above) that high plasma GABA is found
in autism, two possible routes may exist to describe this
phenomenon chemically for autistic subjects. The first
involves the research by Cohen (2001, 2002, 2002a,
2004, 2004a, 2015, 2016) where regulation of plasma
GABA in the liver by the enzyme GABA-Transaminase
(GABA-T) has been illustrated to be inhibited or hindered
(called the "GABA-Transaminase Model") and the second "GABA-Transaminase model" for the epidemiology of
involves GABA receptors that are found in the autistic autism. In other words, since GABA receptor or GABA
A A
brain (called the "GABA Receptors Model"). α5 subunit availability in the brain for adults with autism
are normal ("GABA Receptor Model") as compared to
Autism Research Moving Forward normal controls, this rules out the possibility where
The leading hypothesis for the root cause of autism receptor failure in the autistic brain could cause high
from the autism scientific community is an imbalance plasma GABA.
where inhibitory GABA neurotransmission in the brain The "GABA-Transaminase Model" however, set forth
exists. Preliminary studies however, in the scientific by Cohen is sound and most plausible after reviewing the
literature, have suggested that both γ-aminobutyric acid GABAA receptor or GABAA α5 subunit finding above.

26 • NEXUS www.nexusmagazine.com APRIL – MAY 2021

Cohen (2002, 2002a, 2004, 2004a, 2015,
2016) illustrated that the GABA-T enzyme
activity for an autistic child was
approximately 45.5 per cent (approximately
half) lower than for the average control
group. Elevated levels of ammonia,
therefore, in the plasma for autistic subjects
results in a decrease in the efficiency of the
enzyme GABA-T, and this results in higher
GABA concentrations in the plasma after
liver regulation.
In conclusion, more focus on the GABA-
Transaminase enzyme ("GABA-Transaminase
Model") and its effect on GABA regulation Ball-and-stick model of the GABA molecule.
should be the main objective for autism This image shows the electrically neutral
research moving forward.
About the Author:
Dr Brett I. Cohen holds a PhD in inorganic
and bioinorganic chemistry from the State University
of New York at Albany and was a postdoctoral fellow
at Rutgers University from 1988–1989. Dr Cohen has
been awarded 16 US patents and has had over 100
papers published in peer-reviewed journals, such as
Journal of the American Chemical Society, Inorganic
Chemistry, Journal of Dental Research, Journal of
Prosthetic Dentistry, Journal of Endodontics and
Autism, etc. These papers cover a variety of areas such
as inorganic and bioinorganic chemistry, biomedicine,
autism, physical chemistry, dentistry and more. Dr
Cohen has also published articles on a variety of
subjects in the alternative arena. His previous
contributions to NEXUS Magazine include: Unravelling
the Mystery of Autism as a Male Disorder", NEXUS
volume 23, number 3 (Apr–May 2016), "The Great
Pyramid of Giza and the Queen's Chamber Shafts: A
Chemical Perspective", NEXUS, vol. 22, no. 5 (Aug–
Sept 2015) and "Rising Autism Rates and the Link with
Epigenetics", NEXUS, vol. 22, no. 6 (Oct–Nov 2015).
Dr Cohen can be reached via email at
ebicbis@aol.com.
References
• Autism Speaks, https://www.autismspeaks.org/autism-
facts-and-figures
• Centers for Disease Control and Prevention, "CDC
estimates 1 in 68 children has been identified with
autism spectrum disorder", March 2014,
http://tinyurl.com/l5jy5va
• Cohen, B.I., "Possible Connection between Autism,
Narcolepsy and Multiple Sclerosis", Autism 1998 Dec;
2(4):425-427.
• Cohen, B.I., "Elevated levels of plasma and urine
gammaaminobutyric acid: A case study for an autistic
child", Autism 1999 Jan; 3(4):437-440.
• Cohen, B.I., "GABA-transaminase, the liver and
APRIL – MAY 2021 www.nexusmagazine.com
View publication stats
form. (Image: Jynto, wikipedia)
infantile autism", Med. Hypotheses 2001 Dec;
57(6):673-74.
• Cohen, B.I., "The significance of ammonia/gamma
aminobutyric acid (GABA) ratio for normality and liver
disorders", Med. Hypotheses 2002 Dec; 59(6):757-58.
• Cohen, B.I., "Use of a GABA-transaminase agonist for
treatment of infantile autism", Med. Hypotheses 2002a
Jul; 59(1):115-16.
• Cohen, B.I., "Gamma aminobutyric Acid (GABA) and
Methylmalonic Acid: The Connection with Infantile
Autism", in O.T. Ryaskin (ed.), Trends in Autism
Research, Nova Science Publishers, Hauppauge, New
York, 2004, ch. IX, pp. 177-186.
• Cohen, B.I., "Rationale for further investigation of
chromosome 16p13.3, a region implicated for autism",
Autism 2004a Dec; 8(4):445-47.
• Cohen, Brett I., "Rising Autism Rates and the Link with
Epigenetics", NEXUS 2015 Oct-Nov; 22(6): 21-25.
• Cohen, Brett I. "Unravelling the Mystery of Autism as
a Male Disorder", NEXUS 2016 April-May; 23(3): 37-40.
• Dhossche, D. et al., "Elevated plasma gamma-
aminobutyric acid (GABA) levels in autistic youngsters:
stimulus for a GABA hypotheses of autism", Med. Sci.
Monit. 2002; 8(8): 1-6.
• Egaas, B., Courchesne, E., Saitoh, O., "Reduced size
of corpus callosum in autism", Arch. Neurol. 1995 Aug;
52(8): 794-801.
• Horder, J. et al."GABAA receptor availability is not
altered in adults with autism spectrum disorder or in
mouse models", Science Translational Medicine. 2018;
Oct;10 (461). pii: eaam8434.
• Piven, J., Bailey, J., Ranson, B.J., Arndt, S., "An MRI
Study of the Corpus Callosum in Autism", Am. J.
Psychiatry 1997 Aug; 154(8): 1051-56.
• Russo, A.J., "Correlation Between Hepatocyte Growth
Factor (HGF) and Gamma-Aminobutyric Acid (GABA)
Plasma Levels in Autistic Children", Biomarker Insights
2013; 8: 69-75.
NEXUS • 27