Should Autism Definition Be Changed?

by Albina Tskhay and Dr. Kenneth Alibek

We would like to consider approaches to the definition, diagnosis, and treatment of autism and then to offer our vision of the disorder.

 

Official definition:

 

Autism, or autism spectrum disorder (ASD), refers to a wide range of conditions characterized by problems with social skills, repetitive behavior, speech, and nonverbal communication.

Officially, the causes of autism are unknown but:

 

- Most scientists agree that genes are one of the risk factors that can increase the risk of developing autism.

 

- Children who have a brother or sister with autism have a higher risk of autism

 

- Autism is usually more common in people with certain genetic or chromosomal conditions, such as tuberous sclerosis.

 

- Taking prescription drugs valproic acid and thalidomide during pregnancy is also associated with a higher risk of autism.

 

- There is some evidence that a critical period for the development of autism occurs before, during and immediately after birth.

 

- Children born to older parents are at greater risk of autism.

Treatment focuses on the use of corrective therapies to improve the quality of life of children and increase their level of independence.

 

Anamnesis

Abnormal or impaired development occurs before the age of 3 years in at least one of the following areas:

* receptive or expressive speech used in social communication;

* development of selective social attachments or reciprocal social interaction;

* functional or symbolic game.

 

We see is that these formulations do not correspond to the processes that actually occur in autism.

 

First, all definitions of autism focus on the symptoms of the disorder rather than the actual anatomical/physiological processes that underlie autism and autism spectrum disorders.

 

In autism, the child's brain, starting with the period of intrauterine development, is formed atypically, which causes autistic behavior as a result.

For example, consider some of the changes that occur in the brain in autism:

 

For example, differences in brain structure between children with autism and neurotypical children were found in the cerebral cortex, temporal cortex, and cerebellum. In particular, the cerebral cortex is responsible for language and social functions, as well as for the perception of faces. MRI of the brain revealed that some areas of the cerebral cortex in children with autism were significantly asymmetric compared to healthy controls.

 

The cerebral cortex allows facial recognition, and when autistic children were shown images of faces, they were shown activation of the cortex, which was similar to the activation in the brain of children without autism, when they were shown inanimate objects.

The main role of the cerebellum is the planning and coordination of movements. However, recent evidence suggests that this part of the brain is also responsible for connections between different parts of the brain that play a role in mental imagery, reflexes, planning, attention, affective behavior, visual organization, and sensory perception. Almost all brain samples of children with autism studied to date, regardless of age, gender and cognitive abilities, revealed differences in the cerebellum, including increased brain volume at an early age, a marked accumulation of monocytes and macrophages in the cerebellum, a decrease in the thickness of the cortex with age and abnormalities of the deep nuclei of the cerebellum.

 

In addition, there was a significant decrease in the number of Purkinje cells, the formation of which occurs only before birth, and this suggests that autism-related changes in the brain occur even before birth.

 

Second, the genetic component of autism is considered in some definitions (particularly in the US), but as an inherited factor.

 

Scientists say about 120 genes, but at the same time information is beginning to appear that the number of genes involved in autism is much larger. Even as many as 1,000 genes are mentioned.

 

For example, some of the proteins that are encoded by genes include:

 

  • Neuroligin 3 is the formation and functioning of synapses

  • Neuroligin 4-formation and functioning of synapses

  • Neurexin 1 - intersynaptic compound of neuroligins

  • SH3 and multiple ankyrin repeat domains-neuroligin compound

  • Contactin-associated protein-like 2-neuronal movement

  • Contactin 4 and Contactin 3 - connecting neurons

  • Protocadherin 10-neural receptors

  • Methyl CpG-binding protein 1-transcriptional repressor

  • Engraved 2 - development of the midbrain and cerebellum

  • Homeobox A1 – development of the hindbrain

  • Homeobox B1-posterior brain development

  • Reelin-movement of neurons

  • FOXP2-embryo development and neuronal function

  • GABA receptor subunits-functioning of neurotransmitters

  • Serotonin transporter-serotonin feed

  • Mitochondrial aspartate/glutamate transporter – mitochondrial functioning and energy metabolism

  • Oxytocin receptor-oxytocin receptors

  • MET - growth and development of cerebellum and cortex, immune system

 

But in recent publication it was found something different (Yuen R. et al. 2017). In this paper, the authors identified 61 genes associated with autism by analyzing whole-genome sequences in 5,193 participants, about half of whom were diagnosed with autism. The researchers found that people with autism have an average of 54 acquired, or de novo, mutations. That is, mutations that were not transmitted from parents, but spontaneously appeared during development.

 

When the researchers also looked at inherited mutations on the X chromosome in boys and men with autism, they identified seven additional genes associated with autism, bringing the total number to 61 genes. Of the 61 genes found in the new study, 49 play a role in chromatin remodeling, RNA processing, or linking neurons. These results are consistent with the results of previous studies. The authors emphasize the fact that these genes are functionally related and tend to work together.

 

It is clear that even this number is extremely large and predetermines the severity of this disorder. Many of these genes encode very important proteins that are involved in varying degrees in the formation of the brain, from the embryo stage to the formation of a full-fledged fetus.

In reality, less than 20% of the genes involved in autism are inherited. All other genetic changes are acquired (de novo).

 

According to this year's study, when trying to find "inherited autism genes," only 2 loci (gene locations on a chromosome) were found to be inherited. And these loci are not found in all children with autism. At the same time, the author points out that two de Novo changes: variations in the number of copies of DNA and single – nucleotide polymorphism-phenomena that are common in children with autism. Moreover, it has been shown that the more such changes a child has, the more severe his/her autism symptoms are. That is, directly genetic mutations in autism are not so frequent as less serious changes. But at the same time, the result of variation in the number of copies of DNA, such as for example,  a decrease or increase in the number of copies of a certain gene, and therefore, reduced or increased expression of the gene product. Increased or decreased genetic expression completely changes the outcome of the gene compared to normal expression.

 

At the same time, most often de novo changes are genes responsible for internal biological and neurological processes.  For example, genes NCKAP1, ADNP, DSCAM, which are responsible for regulating the size of intracellular components, genes SCN2A, ANK2, CACNA2D3, responsible for the transport of ions across cell membranes, genes SCN2A, ANK2, CACNA2D3, responsible for cell signals, genes ARID1B, TNRC6B, PHF2, responsible for the expression of other genes.

 

Third, all definitions lack a component associated with inflammation, despite the fact that it has been proven many times that inflammation plays a crucial role in autism. 60% of all children with autism have chronic inflammation. Symptoms of chronic encephalitis (neuroinflammation) overlap closely with those of autism and include reduced muscle tone, lack or impairment of verbal function, changes in behavior and character, distracted attention, and problems with concentration.

 

It has been shown that a decrease in the level of inflammation with probiotics has resulted in animals with behavior similar to autistic one, begin to behave neurotypical. Moreover, genetic de novo changes are the result of inflammation and oxidative stress in most cases.

 

We know that DNA is a double-stranded molecule consisting of nucleotide bases, which are adenine, guanine, cytosine, and thymine, and also have ribose and phosphate groups in its structure. Because free radicals lack one electron, they become very reactive (that is, they can easily join other molecules). Thus, these radicals are attached to the nucleotide bases (easiest to guanine, in view of its chemical structure). When oxygen is attached to a nucleotide base, such as guanine, the reaction produces another molecule – 8-hydroxo-guanine. Since it's a different molecule now, it's not capable of performing its function, so this oxidation is DNA damage. Of course, the body has the ability to repair DNA, and the degree of damage depends not only on the number of reactions of DNA with free radicals but also on the ability of DNA to repair.

 

With chronic infection and chronic inflammation, the body may not have time to restore DNA, as there are too many free radicals in the body.

In the presence of so-called vulnerable genes, i.e. certain genes, the expression or suppression of which can lead to disease, such permanent DNA damage leads to the fact that the genes responsible for the disease go into the mode in which the disease is activated.

 

 

Fourth, these definitions do not address the original cause of all these changes. A huge amount of research points to the role of infection during pregnancy as the root cause of autism.

 

In the above mentioned study on animals, in order to achieve chronic inflammation of the offspring, which led to autism, animals were injected simulating a viral infection. The burden of infections (several chronic infections at the same time), which is rarely found in a healthy person, especially in a child, is the case in almost every child with autism (of course, there are exceptions, when one chronic infection can lead to such changes).

In some children, the number of chronic infections can reach 5 or even more. It is known that some viruses can directly affect DNA. For example, cytomegalovirus has the potential to alter cell gene expression (Zhu et al. 1998). Its initial interaction with the cell surface can trigger a regulatory signal. Virions gB and glycoproteins gH induce cellular transcription factors when added to uninfected cells.  Virion constituents such as the tegument protein pp71 migrate to the nucleus and activate transcription after infection and viral proteins synthesized after infection modulate transcription.  The virus encodes several receptors associated with protein G, which are likely to initiate gene regulatory signal cascades in response to ligands, disrupting cell cycle regulation, leading to changes in cell gene expression.

 

What we see in the blood tests of children with autism is the presence of antibodies to Epstein-Barr viruses, rubella and cytomegalovirus. They are almost always found in 70-75% of cases (some might say it can be found in every person now, which is true, but for people much older). According to various data, the presence of antibodies to cytomegalovirus is detected in about 10% of cases in childhood. In our cases, we detect antibodies many times more. Further, back in 1977, a study showed that congenital rubella infection in children with autism is 200 times more common than in children without autism (Chess 1977). (5% of women are known to have a chronic rubella infection despite vaccination (Hutton 2016)

 

Someone may wonder why many people have chronic infections, but only a small percentage of children develop autism.

 

There are several reasons for this:

 

First, some genes whose increased or decreased expression leads to autism are actually inherited from parents. Such genes are called vulnerability genes or plasticity genes. In normal expression, they have no negative effect, but when exposed to infection and inflammation, changes in gene expression lead to physiological abnormalities.

 

Second, de novo changes involving DNA copy number variations and single-nucleotide polymorphism further increase vulnerability to infections. That is, those infections that in other children would not cause serious changes, in children who inherit from their parents or for some other reason have these de Novo changes, the infection can seriously affect the body.

 

Considering all these points, we propose the following definition of autism:

 

Autism is a congenital disease associated with the neurological development of a child. It begins as a mother-to-fetus infection causing aberrant immune activation and is transmitted to the child in the prenatal period, which continues throughout the postnatal period causing somatic genetic changes and atypical brain development, manifesting as impaired social interaction and language skills and restricted/repetitive behavior.

 

Components of the hypothesis:

 

1.Autism is the result of anatomical and physiological changes in some areas of the brain, which are mainly responsible for behavioral, communication and language skills.

 

2. These changes in brain regions result in genetic disorders, including genes responsible for the formation and functioning of these brain regions.

 

3. These genetic changes occur in the so-called vulnerability genes (plastic genes), which can be transmitted from parents or become vulnerable as a result of negative external factors.

 

4. Changes in these genes are not inherited, but vulnerability can be transmitted from parents.

 

5. De novo changes in genes occur during fetal development.

 

6. These genetic changes are caused by an excess of reactive oxygen species and a number of other inflammatory mediators.

 

7. Initially, the source of inflammatory mediators is the aberrantly activated immune system as a result of maternal infection.

 

8. During the prenatal period, continuously produced maternal inflammatory mediators and excitatory infectious agents are transmitted to the fetus, leading to congenital infection, immune system disorders, and inflammation.

 

9. Congenital infection and inflammatory mediators cause pathological changes that develop in the prenatal and postnatal periods, altering brain development and creating an autistic phenotype in the first years of life.

 

10. Inflammatory mediators caused by the aberrant immune system can be caused by a variety of persistent infectious agents or combinations thereof.

 

11. The established state of infection, inflammation, and destruction of the immune system trigger a "vicious circle" of autism, consisting of mutual pathological events that reinforce and exacerbate each other, manifesting itself in the form of autistic symptoms.

 

The treatment should aim at: 

- Suppression and "keeping under control" of chronic / latent infection

 

- Reduction of systemic inflammation and neuroinflammation

 

- Modulation of the immune system

 

- Reduction of oxidative stress

 

- Restoration of neural connections of the brain

 

- Development of lost skills through corrective techniques

 

 

 

 

 

 

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