Autism

Related Disorders: Tuberous Sclerosis and Fragile X Syndrome

Date First Published: April 2, 2007

There are a variety of disorders or syndromes associated with autism. ¹  Two well known genetic conditions are at the top of this list: Tuberous Sclerosis and Fragile X Syndrome. ²  Can understanding how these disorders work, in terms of genetics and neurology, provide clues to what is happening in autism?

Tuberous Sclerosis, a genetic disorder caused by mutations in one of two genes, causes benign tumors and lesions to form in many different organs of the body, including the brain, skin, eyes, heart, kidneys, and lungs. ³   The impact it has on those who have it is extremely variable. Some are so mildly affected, they go undiagnosed. Others suffer severe impairments which may include seizures, mental retardation…and autism.

The frequency of autism among those who have Tuberous Sclerosis (TS) is about 25% --a number that increases to 44% if you include in your tally not only individuals with classic autism, but those with any pervasive developmental disorder. ⁴   Looking at it from the other direction – not at how many people with TS have autism, but at how many people with autism have TS -- it has been claimed that TS is found in .4 to 2.8% of those with autism. ⁵

Mental retardation or the presence of seizures increases the risk that a person with TS will also have autism. ⁶   In addition, the presence of tuberous growths in the temporal lobe has been associated with autism, especially when accompanied by any type of epileptic activity during the earliest stages of development. This suggests that “there is a critical early stage of brain maturation during which temporal lobe epilepsy perturbs the development of brain systems that underpin ‘social intelligence’ and possibly other cognitive skills, thereby inducing an autism spectrum disorder.” ⁷  In fact, it has been shown that controlling infantile spasms or other epileptic activity is associated with significant improvement in cognition and behavior for children with TS, ⁸ and is crucial to insure the best neurodevelopmental outcome possible. ⁹

Because its genetic cause is clear, and its impact on the brain is at least partly understood, Tuberous Sclerosis provides a “unique neurogenetic model” for testing theories about what may be occurring in the brain in autism spectrum disorders. ¹⁰

Fragile X Syndrome is a genetic disorder caused by the mutation of a single gene on the X chromosome. The gene, which is supposed to make a protein needed for normal brain development, is turned partially or totally off. ¹¹  Both boys and girls are affected, but because boys – who have one “X” and one “Y” chromosome -- have no back-up for a problem on the “X” chromosome, they are more severely impacted than girls, who have two “X” chromosomes.

Fragile X is the most common cause of inherited mental retardation, that is, of mental retardation caused by a genetic problem carried down through generations. Individuals with Fragile X often suffer a variety of developmental delays, and have a distinct physical appearance including a large head, long face, and prominent ears. ¹²  About 25-33% of them will also have autism. ^13,14   Those with both Fragile X and autism face even more challenges than those with Fragile X alone, and early intervention is especially crucial in these cases. ¹⁵

As for how many individuals with autism also have Fragile X, that is still being debated. The figure has been set at anywhere from 1% to 6%. ^16,17   Due to the fact that Fragile X was recognized only relatively recently, and is not routinely screened for, it is likely that we are underestimating the prevalence of Fragile X among those with ASDs. ¹⁸ 

Understanding that Fragile X and autism often occur together is important both clinically and scientifically. In clinical terms, the connection means that those with autism can be screened for Fragile X, while those with Fragile X can be carefully watched for signs of autism. Finding out Fragile X is playing a role is important to families because the condition is genetic, and can impact other members of the family. For example, the sibling of a child with Fragile X, who has been having more mild difficulties, may also be affected by Fragile X, though to a different degree. Other relatives, who may be carriers of the condition even if they do not have it themselves, will be able to benefit from genetic counseling when it comes time to make decisions about having children of their own.

In terms of science, it is hoped that the overlap between Fragile X and autism may point the way to answers. A diagnosis of autism is currently made based entirely on behavior. There is no known cause, and no known biological marker of the condition. (In other words, you can’t draw a blood sample, look at an MRI, or do a genetic test to tell if a person has autism.) In contrast, a diagnosis of Fragile X is made entirely based upon genetics, and the multiple influences of this one gene gone wrong on structure and processing in the brain are at least partially understood. It is hoped that, by using Fragile X as a starting point, progress may be made in solving the mysteries surrounding autism. ¹⁹

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