Fragile X Treatment: Medicine's Next Big Thing?

FRESNO, Calif. (KFSN) -- Fragile X syndrome is a genetic condition that causes intellectual disability, learning challenges, autism and behavioral problems. It occurs in more boys than girls and you may be a carrier of the gene and not show any signs or symptoms. Now, medicine's next big thing may open the door for treating the most common cause of this condition.

You may not have ever heard of it, but, Fragile X is a developmental disorder that can be diagnosed before your baby is even born.

Vicki Davis, mother of Fragile X patient Holly, told Ivanhoe, "I had to prepare myself mentally and emotionally for the most severe affected child."

Holly's mom was told her little girl had Fragile X while she was still in the womb. It's a mutation of a gene on the X chromosome that leads to a lack of protein production, critical for development.

Neuroscientist and Neurologist at Washington University in St. Louis, Azad Bonni, MD, PhD, explained, "The mutations that happen in this gene that causes Fragile X syndrome, is the most common inherited single gene cause of autism."

Now, researchers at the Washington University School of Medicine have identified a potential target for treatments for Fragile X carriers. Dr. Bonni said, "In the brain, nerve cells communicate with each other by synapsis."

Dr. Bonni found that a problem on the X chromosome causes a gene, called FMR1, to stop making a special protein that helps the nerve cells talk to one another. Now that researchers know this is happening, they can find a way to turn on the FMR1 gene to make the protein. The results could be life-changing.

"Reduce the symptoms in the carriers. Basically they just have milder versions," said Dr. Bonni. Giving kids like Holly a chance of growing up without outward signs of Fragile X.

The average age of diagnosis for Fragile X is between three and four years old. Parents usually notice the first symptoms before the age of two. By targeting this protein, it could impact a significant number of the one million women carriers and 320,000 men who carry the mutation in the United States.

Research Summary

BACKGROUND: Fragile X syndrome is a genetic condition that causes mental disabilities, most commonly learning disabilities and cognitive impairment. More often seen in male children, it's the most common inherited form of intellectual disability, learning and behavioral problems such as ADD, ADHD and autism. About one in 4,000 males and one in 8,000 females are affected. Fragile X occurs when the mutated FMR1 gene doesn't produce enough of the protein FMRP to allow the brain to function normally. It is inherited through an X-linked dominant pattern by changes in the single X chromosome. People affected by Fragile X syndrome can have symptoms that range from mild to severe, but men most frequently suffer the most severe physical and mental ailments. The physical signs continue to worsen as men get older and seizures occur in about 15 percent of males, and only 5 percent of females. (Source: http://ghr.nlm.nih.gov/condition/fragile-x-syndrome)

SIGNS AND SYMPTOMS: By age two, infants with Fragile X will show signs of delayed development of speech and language. Children continue to show low IQ's, stuttering or speech issues and sensitivity to sensory activities such as certain sounds. They may also have balance issues. Males with Fragile X syndrome show physical characteristics of a long face, large ears and soft skin. Males may suffer from ear infections, double-jointed or extremely flexible fingers, flat feet and enlarged testicles after puberty. Females may not show many signs as women suffer from Fragile X syndrome with milder intellectual disability and less physical signs than men. Women most often have strong emotional issues and social anxiety. Symptoms do vary, but autistic-like behavior and Fragile X syndrome overlap most frequently. Fragile X syndrome can be diagnosed before a baby is born with a prenatal test. (Source: http://www.medicinenet.com/fragile_x_syndrome/article.htm)

NEW TECHNOLOGY: People with Fragile X syndrome do not have a shortened life expectancy. But carriers of Fragile X syndrome may pass it on to their children, even if they have a mild case. Azad Bonni, M.D., PhD, the Edison Professor of Neurobiology at Washington University School of Medicine in St. Louis has found a potential solution for carriers with this mild version. Researchers have found that an issue with the X chromosome causes the FMR1 gene to stop making the protein that helps nerve cells communicate, so they can now find a way to turn on the FMR1 gene to make the proper protein. "In contrast, carriers of the mutation make the protein but produce significantly less of it than people without the mutation. We've just identified a potential way to boost levels of protein," Bonni said. The results could be life changing for carriers. (Source: http://news.wustl.edu/news/Pages/Discovery-may-open-door-for-treating-fragile-X-carriers.aspx)

Doctor's In-depth Interview

What is fragile X syndrome?

Dr. Bonni: Fragile X syndrome is an inherited disorder that causes intellectual disability in children. It's an X linked disorder so it affects the gene on the X chromosome. Boys have one X chromosome and girls have two so it typically causes intellectual disability in boys. In addition to intellectual disability, about half the patients have autism spectrum disorder. It's is the most common single gene inherited cause of autism. About one percent of autism cases are caused by fragile X syndrome. The problem in fragile X syndrome is that there's a number of repeats that happen in the genetic code. In the normal population it's less than forty five but carriers can have between fifty and two hundred of these repeats. In a normal person this inherited gene encodes a protein called FMRP. In fragile X syndrome, there's so many of these repeats, which turn off the gene entirely and the gene becomes silent so there's no FMRP produced. In carriers, some protein is produced but it's less than the normal population. What's interesting is that in addition to the full-blown syndrome, a substantial fraction of these patients, males as well as females, will also have neuropsychiatric symptoms including cognitive and behavioral impairment with autistic features, attention deficits, hyperactivity, anxiety, and mood disorders.

Is fragile X syndrome the beginning and the least severe on the autism spectrum?

Dr. Bonni: Fragile X syndrome comes with significant intellectual disability. There used to be a classification that talked about high functioning autistic patients. Often patients who have autism or autism spectrum disorders have other features. Basically, the term spectrum just indicates that patients have some of the features of autism but they have other issues as well. With fragile X syndrome, it's not a pure autism because they have many other symptoms, most importantly intellectual disability. The incidence of intellectual disability is much higher than autism in fragile X syndrome. But autism is still very significant problem in Fragile X syndrome.

There's been a debate whether it is on autism spectrum or not.

Dr. Bonni: Right. If you talk to some clinicians, they will say that Fragile X syndrome looks different than sporadic autism. But there definitely are autistic features in these patients and it is considered an autism spectrum disorder.

Can fragile X syndrome cause autism?

Dr. Bonni: Patients who have fragile X syndrome have autism spectrum disorder. They have autistic features, so it is a cause. The mutations that happen in the gene that causes fragile X syndrome is the most common inherited single gene cause of autism.

Are there carriers that may not show symptoms?

Dr. Bonni: Some carriers will not show any symptoms but some carriers will.

And are carriers male and female?

Dr. Bonni: That's correct, they're both. According to the CDC, a million females and about three hundred and twenty thousand males are carriers in the United States.

Have you have been able to target these carriers?

Dr. Bonni: What we have found is a target that we think would be good to think about focusing on for carriers. This comes from very basic science work. We weren't working on fragile X at the time. We started trying to understand how the brain is designed and how the brain wires itself. What are the mechanisms that take place in the brain that make the nerve cells connect and communicate with each other? We were working on that and on a protein, an enzyme, that controls brain wiring and through a number of steps it led us to the protein, FMRP, which is impaired in fragile X syndrome.

What do you hope to target and how do you hope to target it?

Dr. Bonni: The enzyme that we work on is a ubiquitin ligase, which tags other proteins in the cell for disposal after they are no longer needed in the cell. This happens in a very dynamic fashion in the cells. We had been working on this protein called Cdh1-APC for over ten years. We found that it's important in the nerve cells, in patterning their axons, dendrites and synapses. More recently, we became really interested in understanding how it controls synapses communicating with each other because in the brain, nerve cells communicate with each other through synapses. This is where the neurons come together and contact each other. We looked at a very specific synapse in a structure of the brain called the hippocampus, which is important in learning and memory. Through our experiments with mice, we found that when we take out this enzyme, Cdh1, there is a very severe effect on the communication at a specific synapse in the hippocampus. It told us immediately that this particular change took place there and that connected us to the fragile X syndrome. We knew from other work that when you take out the fragile X syndrome protein, FMRP, you get a change there that is not exactly the same but is related. It told us that the way this enzyme, Cdh1-APC, works is through targeting FMRP for disposal. People knew before that FMRP is getting degraded in cells normally but they didn't know how it happened. Through this finding we were able to understand this enzyme, Cdh1-APC, is responsible for degrading FMRP. We have an idea of how it talks to other proteins and how it targets them. Each protein will have sort of a peptide, or a tag. Not all proteins will have it but we can look for them. We asked ourselves does FMRP have a tag and it turned out it did. That told us that there is a potential real link and we found that Cdh1-APC physically interacts with FMRP, the protein that's impaired in fragile X syndrome. We went on to show that Cdh1-APC functions at the synapse through degradation of FMRP. That link is important because you can imagine that if you inhibit the enzyme Cdh1-APC, then FMRP levels should go up. That's what we found in the mice when we inhibited Cdh1-APC by genetic means.

Would that change their status as carriers and enable them to produce offspring without fragile X syndrome?

Dr. Bonni: No. Also, because in fragile X, the gene is completely silent so no protein is made. Even if you inhibit the protein that's targeting FMRP for degradation, it won't help because there's no FMRP to begin with. But in the carriers there is some FMRP that's made so there is the possibility of increasing or boosting the levels of FMRP in the carriers. We think that it could be really interesting to pursue this and find out if we can increase the levels of FMRP in the carriers. First we have to do this in animal models and such models are available so we can test this idea. It would not affect the course of the disease or the problem of the carrier passing the syndrome to the next generation.

What would the experiments impact?

Dr. Bonni: What one would hope it would do is boost the levels of FMRP in the carriers and reduce their symptoms. A substantial fraction of these carriers actually have symptoms, they're milder than the full-blown syndrome but they do have the symptoms.

What would a carrier suffer from that might not be immediately recognized as fragile X syndrome?

Dr. Bonni: These patients have milder versions of all the symptoms that the full-blown sufferers have. It could be cognitive impairment, attention deficit, hyperactivity problems and autistic features.

Are we getting better at diagnosing autism spectrum disorders or is it that more kids are getting it?

Dr. Bonni: That's a great question and it's probably a combination. Definitely diagnosis has improved, there's more awareness so that leads to an increase in the numbers. But I think there has been a true increase as well over the past few decades. And why that is I don't know.

If you would like more information, please contact:

Judy Martin

Director, Media Relations

314-286-0105

martinju@wustl.edu