Autism 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 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. In 2014, the Centers for Disease Control and Prevention estimated that the autism rate was one in 68 births in the United States of America (CDC, 2014). Autism rates (as described above) are therefore rising alarmingly. Recently, Cohen (2015) postulated that a link due to an epigenetic response (transgenerational response) to 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 United States of America (1 in 37 births for boys and 1 in 151 births for girls){autism speaks}.
Cohen (1999) was the first researcher to illustrate extremely high gamma-aminobutyric acid (GABA) levels in the plasma and urine and high plasma ammonia levels as possibly the root cause of autism. GABA is a major inhibitory neurotransmitter in the mammalian brain and responsible for axon(s)-to-oligodendrocyte signalling in the corpus callosum. Located in the centre of the brain, the corpus callosum is responsible for language, intelligence and speech; when this area is damaged, cognitive disorders and language delays are usually found. The finding of elevated levels of GABA in the urine and plasma could explain why autistic features such as self-stimulatory behaviour and language delays are found, and this is possibly due to the abnormal development of the axon(s) in the corpus callosum (Cohen, 1999, 2002, 2002a, 2004, 2004a). Magnetic resonance imaging studies found in the literature illustrate this observation regarding damage to the corpus callosum area in the brain in autistic subjects. In the study by Egaas et al. (1995), 51 autistic patients (45 males and six females, ranging in age from three to 42 years) who met several diagnostic criteria for autism were selected. Magnetic resonance imaging was used to measure and observe the posterior region of the corpus callosum. Fifty-one age- and gender-matched volunteer normal control subjects were also included. The results illustrated overall size reduction, concentrated in the posterior regions of the corpus callosum in the autistic group. In other words, the finding showed consistently reduced size of the corpus callosum in autistic patients with the results being localised to posterior regions. The researchers suggested that the finding supports the idea that reduced corpus callosum regions in the brain may be a consistent feature in autism. In the study by Piven et al. (1997), 35 autistic subjects (26 males and nine females with a mean age of 18 years) previously diagnosed with autistic disorder and 36 healthy comparison subjects who matched with age, serving as the control group, were chosen. This study utilized detailed MRI (Magnetic Resonance Imaging) to examine the size of the anterior, middle and posterior regions of the corpus callosum in the autistic and normal subjects. Relative to total brain size, the cross-sectional area of the middle and posterior regions of the corpus callosum was found to be smaller (thinner) in autistic individuals compared with healthy subjects.
Cohen (2002, 2004) proposed a possible link between the liver and infantile autism via the measurements of elevated plasma ammonia and lower gamma-aminobutyric acid–transaminase (GABA-T, EC 2.6.1.19) enzyme activity. GABA-T is the enzyme responsible for GABA catabolism (chemical breakdown in the liver during regulation). Cohen (2002, 2004) showed that the GABAT enzyme activity for an autistic child was approximately 45.5 percent (approximately half) lower than for the average control group. Elevated levels of ammonia in the plasma result 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 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 percent (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 percent as compared to the control group. 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 behavior and social interaction were also monitored. A GABA-T 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).
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 subjects. Magnetic resonance imaging of autistic subjects confirms this with the observation that the corpus callosum is thinner or smaller compared with normal controls (Cohen, 2016).
Many researchers have observed high plasma GABA levels in autistic subjects. Dhossche et al. (2002) reported high or elevated levels of GABA in autistic subjects and suggested the hypothesis that GABAergic mechanisms may play a role in the aetiology or pathophysiology of 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-Tranaminase Model") and the second involves GABA receptors that are found in the autistic brain (called the "GABA Receptors Model"). The leading hypothesis for the root cause of autism from the autism scientific community is an imbalance where inhibitory GABA neurotransmission in the brain exists. Preliminary studies however, in the scientific literature, have suggested that both γ-aminobutyric acid type A (GABAA) receptors and GABAA α5 subtype are deficient in autism subjects (Horder, et al., 2018). These studies utilized 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 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 the subjects studied by Horder, et al. (2018) (both normal controls and autistic subjects) were free of medication. This is important because prior studies on autistic subjects were confounded by the effects of medication. In addition, Horder, et al. (2018) found no differences in GABAA receptor or GABAA α5 subunit availability in any of the three mouse models they studied. They conclude that GABAA receptor availability is normal for adults with autism and that the GABA signaling may be functionally impaired for the autistic subjects studied. The findings of Horder et al. (2018) clearly brings to the forefront the "GABA-Transaminase model" for the epidemiology of autism. In other words, since GABAA receptor or GABAA α5 subunit availability in the brain for adults with autism are normal ("GABA Receptor Model") as compared to normal controls, this rules out the possiblity where receptor failure in the autistic brain could cause high plasma GABA. The "GABA-Transaminase Model" however, set forth by Cohen is sound and most pausible after reviewing the GABAA receptor or GABAA α5 subunit finding above. Cohen (2002, 2002a, 2004, 2004a, 2015, 2016) illustrated that the GABA-T enzyme activity for an autistic child was approximately 45.5 percent (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-Tranaminase Model") and its effect on GABA regulation should be the main objective for autism research moving forward.
References
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
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