Genetics

Research has shown that genes play a role in the development of autism.

Twin and familial studies have shown that autism runs in families. Whereas the incidence of autism in the general population is 1 in 600 or .16%, siblings of children with autism have a 3-8% chance of being autistic. Although 3-8% is a much higher figure than .16%, it is not as high as 50% which is the percentage resulting from one parent passing on a single dominant faulty gene. Also, 3-8% is not as high as 25% which is the percentage resulting from both parents each passing on a single recessive gene.

Therefore, we must conclude that there is no single gene associated with autism. Instead, it is most likely that variants of several genes are present for the susceptibility to occur.

This theory is further supported by the fact that family members of autistic children do show characteristics of autism but not necessarily the full blown symptoms of the disorder.

On the other hand, if the disorder was purely genetic, in twin studies, mono zygotic twins would both be autistic, 100% of the time. In actuality however, there is only a 60% concordance rate between mono zygotic twins and an 86% concordance rate of the second twin having some features of autism or associated disorders. (Fraternal twins have a 3% concordance rate)

As a result, we must conclude that although a genetic susceptibility exists, there must also be an environmental component leading to the onset of Autism.

In particular, four research groups have conducted "genome scan by linkage analysis" studies in which they have examined random DNA markers in an attempt to identify any single area where Autism susceptibility gene or genes may lie. Unfortunately, the results of these studies were not found to be significant from a research standpoint.

The Finding's of These Studies are as Follows:

1. Neil Risch et al (Stanford):

   This group reported that autism sibling pairs did show more sharing of genetic markers than sibling pairs where one was autistic and the other was not. However, the difference could not be attributed to a small number of genes. The increased sharing observed in pairs concordant for autism was most consistent with a large number (20) of susceptibility genes, none of which has a large effect on it's own. The most significant results were seen for a region on chromosomes number 1, followed by a region on chromosome number 17.

2. The IMG SAC Study:

   An international convention tested ninety-nine autistic families.
   This study found some evidence of linkage on chromosome 7q and another positive region on chromosome 16p (the short arms of chromosomes are called P and the long arms are called Q).

3. The PARISS Study:

   A council of French researchers studied fifty-one autistic families and found some linkage on chromosomes 6q and 7q.

4. A U.S Study:

   Researchers from Tufts University of Iowa, John Hopkins and Vanderbilt studied seventy-five families and found some evidence of linkage on chromosome 13q and 7q.

5. Thalidomide Study (Miller and Stromland):

   Sample… Adults of mothers who had received Thalidomide

Timeline of Malformations…
Age of Embryo (days):	20	21	22	23	24	25	26	27	28	29	30	31	32	33	34	35	36
Damage caused by thalidomide exposure at this time:	Missing Ears				Small Ears and Other Ear Malformations
			Missing Small Thumbs										Thumbs with Extra Joint
					Stunted Arms
								Stunted Legs

Findings…

• 5% of the sample was Autistic. This figure is 30 times higher than the incidence in the general population
• The Autistic sample had ear malformations but no other malformations

Conclusions...

• The Thalidomide damage in the Autistic sample must have occurred between 20-22 days after conception
• Therefore, any possible brain damage in this sample, would have occurred as early as the 4th week of gestation
• The only neurons that develop as early as the 4th week of gestation are neurons in the cerebellum and brain stem
6. This study serves to exemplify how scientists have discovered the involvement of one particular gene in Autism:
   Children whose mothers were given the drug Thalidomide were born with malformations such as stunted arms and legs, mis-shaped or missing ears and thumbs, as well as neurological dysfunctions of the eye and facial muscles.

   Scientists know the exact period of development of each of these areas and as a result, they know that a child with thumb abnormalities would have been exposed to thalidomide around day 22 after conception, a child with ear malformations would have been exposed around day 20-33 after conception and one with arm or leg malformations would have had exposure around day 25-35 after conception.

   It was discovered that 5% of the sample studied (adults whose mothers had been given thalidomide) were autistic. This figure is 30 times higher than the incidence in the general population. The subjects who had autism also were found to have ear malformations but no limb malformations. As a result, it was concluded that the injury must have occurred between 20-24 days after conception.

   Very few neurons form as early as the 4th week of gestation; most neurons developing that early are motor neurons of the cranial nerves which control the muscles of the eyes, ears, face, jaw, throat ant tongue. So the researchers went back and checked their autistic subjects and interestingly enough, they found that they also had abnormalities of eye movement or facial expression, or both.

   Soon after, one of the autistic subjects passed away and it was possible to do an autopsy of her brain. On examining her brain stem, they found two distinct areas missing :

(click to enlarge)

• The Facial Nucleus (this controls the muscles relating to facial expression. In normal people there are about 9000 neurons in the facial nucleus but in this woman there were about 400).
• The Superior Olive (this is a relay station for auditory information).

The researchers (Patricia Rodier) recognized a similarity in research they had previously seen with mice. That is, a former experiment had resulted in shortening of the brain stem, smaller than normal facial nucleus and no superior olive in mice who also had developed ear malformations and difficulty controlling eye movement. These rats were transgenic mice who had been engineered to lack a gene known as Hoxa 1.

Scientists have found Hoxa 1 to be active in the brainstem when the very first neurons are forming (the same period that Thalidomide damage could have occurred).

HOXA 1

HOXA 1 is the gene which produces a type of protein called a transcription factor protein. This protein modulates the activity of other genes.

	HOXA 1
HOXA 1 is a gene which resides on Chromosome 7. It is responsible for producing a type of protein (called Transcription Factor) that modulates the activity of other genes. 2 Variant alleles of HOXA 1 have been found. The rate of one of these alleles is much higher in Autistics (40%) than in the general population (20%). Thus, HOXA 1 has been established as one of the genes present in Autism.

HOXA 1 is not active in any tissue after early embryogenesis. If a gene is active throughout life, altered functioning of that gene usually leads to problems that increase with age. A gene active only during embryo development is a better candidate to explain a congenital disability which seems to be stable after childhood, like autism.
HOXA 1 resides on chromosome 7. Two variant alleles of HOXA 1 have been found. The rate of one of these alleles is much higher in autistics (40% of people with autism have this allele) than in their family members who are not autistic or in the general population (20%). Therefore, this is clearly one of the genes involved with autism.

However, it is not the only one because the variant allele also occurs in 20% of people who do not have autism. Therefore, the presence of the allele doubles the chances of having autism.

However, in 60% of people with autism, something else is causing it.

In conclusion, research seems to indicate that no single region contains a gene with large effects on the risk of Autism. It seems that a combination of genes produce a situation which leaves the individual susceptible to an environmental factor which then sets off the disorder.

Interestingly, given the observable variations we see in Autism, it is entirely possible that different genetic markers are responsible for different subtypes of Autism.

5-HTT

In 1997, Edwin Cook reported an association between Autism and a form of the serotonin transporter gene (5-H TT).

Deficiency in 5-HT Function

• In 1997, Edwin Cook reported an association between Autism and a form of the serotonin transporter gene (5-HTT)
• 5-HT receptors are found in high concentrations in the cerebellum and the Cingulate Girus. It is proposed that there is a deficiency in 5-HT function in Autism.
• The deficiency may arise from:
  • Increased inhibitory auto receptors
  • Decreased synthesis of 5-HT
  • Decreased post-synaptic receptor sensitivity
  • Decreased messenger or gene expression activity
  • Increased 5-HT transporter re-uptake resulting in less neurotransmitter in the synapse
• Researchers now suggest that the 5-HTT gene variants may be associated with specific subgroups of Autism, particularly those with obsessive compulsive behaviors, which may be resulting from serotonin abnormalities.

  
  (click to enlarge)

5-HT receptors are found in high concentrations in the cerebellum ( in the purkinje cells) as well as in the Cingulate Gyrus. It is proposed that there is a deficiency in 5-HT function in autism.

This deficiency may arise from

• Increased inhibitory auto receptors
• Decreased synthesis of 5-HT
• Decreased post-synaptic 5-HT receptor sensitivity
• Decreased messenger or gene expression activity
• Increased 5-HT transporter re-uptake resulting in less neurotransmitter in the synapse

Researchers suggest now that the 5-H TT gene variants may be associated with specific subgroups of Autism, particularly those with obsessive compulsive behaviors, which may be resulting from serotonin abnormalities.

G-Alpha Proteins

Mary Megson (Medical College of Virginia) reported on children she saw in her practice that develop "autistic regression" (lose skills between 18-24 months). She found that "in the vast majority of these cases, one parent reports night blindness or other rarer disorders which are caused by a genetic defect in a G alpha protein".

	G-Alpha Proteins
G proteins are cellular proteins, which turn on or off multiple metabolic pathways including those for glucose, lipid and protein metabolism, as well as cell growth differentiation. G protein deficits cause severe loss of rod function (retinal cells that allow night vision) in some autistic children. These children only get the true impression of the three-dimensional nature of objects from a "box"in the middle of their visual field and they see objects by adding these "boxes" together.

G proteins are cellular proteins, which turn on or off multiple metabolic pathways including those for glucose, lipid and protein metabolism as well as cell growth differentiation. They affect the signals in sensory organs regulating touch, taste, smell, hearing and vision. G protein defects cause severe loss of rod function (retinal cells that allow night vision) in some autistic children. These children are unable to see in the dark, they cannot see light and dark shades on objects in daylight, and instead only see color and shape in most of their visual field.

As a result, they can only get the true impression of the three - dimensional nature of objects from a "box" in the middle of their visual field and they must see objects by adding these "boxes" together.

Clearly, if this deficit exists, it would account for the autistic child's lining up of objects perhaps in an attempt to perceive the "boxes" they see, or the avoidance of eye contact in an attempt to direct light to portions of the retina where they still have some rod functioning.

This defect which is known as congenital stationary night blindness effects cell membrane calcium channels which can block certain receptors in the hippocampus, were we find the pathway connecting the left and right brain with the frontal lobe. A lack of cell growth and differentiation has been found in the hippocampus of autistic children (Baumann) and the frontal lobe is of course, the center for the executive functions.

Although Megson's findings are fascinating, formal research is needed to replicate her findings. However, also interesting with regards to Megson's conclusions is that certain toxins such as the
Pertussis antibody (the P in the DPT vaccine), which is for whooping cough, lead to complete disruption of the G alpha protein signals, and this in turn leads to glycogen and lipid breakdown. Perhaps it is not coincidental that G proteins are in high concentration in the gut wall as well as in the brain and therefore, when the toxin in the pertussis vaccine disrupts the G proteins, this can result in abnormalities in the gut as well as in the brain.

In conclusion then, it is safe to say that most experts assume that autism stems not from a single gene but from ten to twenty genes that occur in various combinations to result in a predisposition to Autism and it's related disorders. While there is clear agreement that there is a genetic predisposition; the question is: what factors can trigger Autism in people who are genetically predisposed?