Autism and X-Fragile Syndrome

According to the World Health Organization, the definition of autism is based on a specific pattern of behavior characteristics, as neither its naetiology nor pathology is defined. This is why a search for autism markers is proposed at three levels: morphological, cytogenetic and molecular. In the 80s, a research group at the Leioa campus of the University of the Basque Country worked on dermatoglyphs, an analysis technique applied to autistic children. Dermatoglyphs, or handprints and footprints, are useful
in the morphological analysis of the symmetry of the human body.

That initial study of dermatoglyphs enabled the fluctuating asymmetry
between the sides of the body to be seen, i.e. that asymmetry with a
non-definable pattern being the more common amongst autistic children than
in the rest of the population.

Fragile sites
Following on from this initial morphological study, the research took
a cytogenetic turn. In this second phase, chromosomes of autistic children
were analyzed. This was undertaken with the knowledge that certain sites on the chromosomes were more prone to breaking than others. One of these
fragile locations is found on the X chromosome and is known as FRAXA.

The results show that children with autism had a significantly greater
frequency of expression of these fragile sites than the control population.
The FRAXA fragile site expressed itself only amongst autistic children,
although not in all. Thus, at a cytogenetic level, FRAXA s the most
important marker for a genetic alteration that underlies autism.

Too many repetitions
Effectively, the genetic alteration on this location of the X chromosome was identified at the beginning of the 1990s. The gene known as FMR1 (Female Mental Retardation 1) is responsible for the X-fragile syndrome related to autism.

But not all autistic children showed this genetic alteration and, so,
an analysis at a molecular level was undertaken in order to determine the
prevalence of the X-fragile syndrome amongst individuals with mental
backwardness in the Basque Country.

From a simple blood DNA analysis, it is known that the FMR1 gene has a
CGG (cytosine- guanine-guanine) tri-nucleotide, usually repeated between 6
and 54 times in normal persons. On the other hand, amongst premutated
persons, these repetitions appear between 55 and 200 times and, in those who have the mutated gene – i.e. those suffering from the X fragile syndrome -, they appear more than 200 times, reaching 1,000 repetitions in some cases.

The results of this analysis show that none of the individuals with
the X-fragile mutation was of Basque origin though they had mental
backwardness or autistic characteristics. These results led to the
investigation of the stability of the FMR1 gene amongst the Basque
population. The project was subsequently widened to undertake separate
analyses of the different Basque regions. This study showed that there exist
different mutational paths of the FMR1 gene amongst the Basque population
and which may be of a relatively recent origin – thus explaining the absence
of the X fragile syndrome amongst this population.

With this conclusion reached, the studies now target persons with the
permutated form of the gene given that three pathologies associated with
this CGG premutation have been discovered: moderate mental backwardness and autistic characteristics, premature ovarian failure before the age of 45 and ataxia – a pathology with trembling similar to that of Parkinson’s. In
short, there is still much to investigate regarding the X fragile syndrome.