Author and Contributing Experts to this Guide include:
What Is Fragile X Syndrome?
Fragile X Syndrome (FXS) is a genetic condition that causes several developmental problems including learning disabilities, behavioral issues, and cognitive impairment.
It is so named because when researchers first looked at chromosomes under special conditions, they discovered an unusual broken appearance to the X chromosome in families where signs and symptoms were present. When FXS is present, it looks like the tip of the X chromosome is breaking off. It appears fragile.
The features of the condition are caused by changes in a gene called the Fragile X mental retardation 1 (FMR1). The FMR1 gene makes a protein called Fragile X mental retardation protein (FMRP), which is needed for normal brain development.
However, in individuals with FXS, their FMR1 gene is turned off and there is no production of the FMRP protein. There are other conditions associated with fragile-X syndrome that we will discuss later.
These conditions also have an FMR1 gene that is not functioning correctly, but they do still make a small amount of the FMRP protein 1.
Usually, males are more severely affected by FXS. This is because the FMR1 gene resides on the X chromosome of which males only have one.
Females, on the other hand, have two copies of the X chromosome, so if one chromosome contains a non-functioning FMR1 gene, they have a backup copy. Most males and about half of all females with FXS have physical features characteristic of the disease.
These features become more apparent with age and include a long and narrow face, large ears, overly flexible fingers, a prominent jaw and forehead, flat feet, and in males, enlarged testicles after puberty 2.
While each individual with FXS is unique, there are some features that are commonly seen. Most people with FXS also have delayed speech and language development 3.
About half of all males one-third of females have mild to moderate intellectual disabilities 4. In addition, about one-third of people with Fragile X Syndrome have features of autism spectrum disorder, affecting their ability to communicate and have social interactions 5.
“In a group of patients, you can have some who are very low functioning, don't talk, and have rudimentary skills. That can go anywhere from patients who are almost normal and functioning,” said Dr Elizabeth Berry-Kravis, a child neurologist at Rush University Medical Center in Chicago who has done research in Fragile X Syndrome since 1988.
“Most of my patients are generally, when they're not upset about something, are quite friendly and social. They really want to please people and be with people,” added Berry-Kravis.
Children with FXS may also have anxiety and hyperactive behaviors including attention deficit disorder (ADD) 6.
About 15% of males and 5% of females may also suffer from seizures 7.
Causes of Fragile X Syndrome
There is a section in the FMR1 gene called a CGG triplet repeat. This means that the three nucleotides “CGG” repeat over and over again.
This is a naturally occurring repeat seen in all FMR1 genes, what is important is now many times it repeats. In its typical form, this section repeats 5 to around 40 times 8.
Individuals with 45 to 54 CGG repeats will not have Fragile X Syndrome. However, there is a chance that if a mother is carrying a repeat in this range, when she has a child might pass on a copy of FMR1 with more repeats.
If she passes on a copy with more repates, it is typically not enough to put her children at risk for having Fragile X Syndrome, but it could put her grandchildren or great grandchildren at risk 9.
People who have 55 to 200 repeats of the CGG segment are considered premutation carriers. These individuals typically have normal intellect, but might produce less of the FMRP protein and therefore might experience mild features of FXS.
Some children with an FMR1 premutation may have learning disabilities or display autistic behaviors 10. Additionally, permutation carriers are at risk for two Fragile-X Associated syndromes: premature ovarian failure (FXPOI) and tremor/ataxia syndrome (FXTAS) 11.
Roughly 20% of women who are premutation carriers will develop FXPOI 12. Some associated symptoms include: irregular menstrual cycles, infertility, early menopause, and elevated levels of a hormone known as follicle stimulating hormone (FSH).
Approximately 45% of men (> 50 years of age) and 16% of women who are premutation carriers will develop FXTAS. Symptoms of this condition usually start between 50 and 70 years of age and are progressive.
Features typically begin as minor tremor issues or issues balancing and they continue to progress until they are severe. Individuals may also experience mental and behavioral changes 13.
Finally, if the CGG repeats reach 200 or more repeats, then an individual will have Fragile X Syndrome. Having this many repeats causes the gene to turn off entirely and no protein will be produced.
Sometimes, FXS is caused by a deletion of part or all of FMR1. Both types of changes cause dysfunction of the nervous system, specifically synapse development, and leads to the signs and symptoms associated with the condition.
The Genetic Pattern of Inheritance of Fragile X Syndrome
Fragile X Syndrome (FXS) is caused by harmful differences in the FMR1 gene which is located on the X chromosome. Typically, humans have 46 chromosomes arranged into 23 pairs.
We get one set from our mom and one set from our dad. The last pair of chromosomes are called sex chromosomes.
Females have two X chromosomes (XX), and males have one X and one Y chromosome (XY). Due to the different number of X chromosomes between males and females, the prevalence and features of Fragile X Syndrome will vary between the sexes.
It is inherited in an X-linked dominant manner. A condition is X-linked if the responsible gene is located on the X chromosome.
The inheritance is dominant if only one non-working copy of the responsible gene is enough to cause symptoms of the condition.
“Our DNA is spelled out in letters, the exact same way that words in a book are. Similarly, those letters are supposed to be in a very specific order for our body to be able to work like we would typically expect. Sometimes though, some of those letters can be changed, almost like a typo or a misspelling,” said Becky Sheedy, a genetic counselor currently working at the Autism and Developmental Medicine Institute (ADMI) at Geisinger in Lewisburg, Pennsylvania.
She also works with the Simon Searchlight project, a patient registry linking families and researchers to learn more about genetic changes related to autism.
“When this happens, these genetic spelling differences can change the way that our bodies work. With Fragile X Syndrome, we're looking at a section of the DNA called the FMR1 gene. You can think of it like a chapter of that whole instruction booklet.
“At the very beginning of this FMR1 gene, there's a section that has different numbers of three repeating letters. The technical name for this is a trinucleotide repeat. Essentially thinking about those DNA letters, the letters CGG are just repeating over and over again and this is normal. We'd expect that most people have anywhere from five up to about 44 of these CGG repeats,” she added.
If somebody has 45 to 54 CGG repeats, they are called intermediate carriers and have a slightly higher chance of having some FXS symptoms.
“Sometimes this group is also called the gray zone. People with 45 to 54 CGG repeats don't show us any signs of Fragile X Syndrome. We flag these results because they have the chance to expand and have more copies in future generations. We'd say that not necessarily their own children, but maybe their grandchildren or great grandchildren, maybe at higher chances to have Fragile X Syndrome,” said Sheedy.
Women who carry an FMR1 gene premutation, which means they have approximately 55 to 200 CGG repeats, could have the repeats expand to more than 200 in number in their cells that develop into eggs. This means that women with a premutation have an increased risk to have a child with FXS 14.
“It's important to note that nothing anybody does or does not do causes these repeats to be copied again. This is a totally random by chance process,” explained Sheedy.
Who Gets Fragile X Syndrome?
Approximately 1 in 4,000 males and 1 in 8,000 females have Fragile X Syndrome (FXS). While males are affected with FXS about twice as often as females, there are more female premutation carriers than males (1 in 250 vs. 1 in 800) 15.
Determining if some people are more likely to be carriers than others requires a bit of an explanation.
“Because females have two X chromosomes, they have almost a backup copy that they can use if one of their FMR1 genes has those higher number of repeats. This is why symptoms are typically milder in females compared to males, who only have one copy of their X chromosome.
“Females are therefore called carriers. These female carriers have a 50 percent chance of passing on the X with the FMR1 gene with a higher number of repeats with each pregnancy. We would expect each son to show symptoms if the FMR1 gene with the more repeats is inherited.
“If inherited in daughters, that daughter would also be a carrier and may show milder signs or symptoms. Males pass on their one X chromosome to all of their daughters, so every daughter would inherit this increased number of repeats. Conversely, all sons would inherit their father's Y chromosome and therefore would not have Fragile X Syndrome,” explained Sheedy.
Signs & Symptoms of Fragile X Syndrome
It’s critical to note that no one person will have all FXS symptoms.
Females often have milder intellectual disabilities and milder versions of the syndrome’s behavioral and physical features. Some physical features will also develop after puberty.
“There are certain physical features that suggest Fragile X Syndrome. Those are the classic features like large ears, a long face, a small midface, and many of the patients will have hyper flexible joints. There is this typical facial appearance, but not all of the patients have that and so that's not absolutely diagnostic,” said Dr. Berry-Kravis.
“You cannot use the physical features to determine who does and does not have Fragile X, because some of the kids will really have almost none of the physical features, and you really have to do the genetic test to know whether the patient has Fragile X or not,” she added.
Symptoms will vary from person to person but may include:
- Low muscle tone, acid reflux, cross eyes, seizures, sleeping disorders, lax joints, flat feet, a curved spine, frequent ear infections, and soft skin.
- Normal growth patterns, but some individuals might have a larger head size
- Developmental delays including not sitting, walking, or talking at the same time as other children the same age.
- Learning disabilities such as trouble learning new skills.
- Intellectual disability (average IQ is between 40 and 45) 16
- Behavioral differences: hyperactivity, difficulty with impulse control, hand flapping, anxiety, shyness, poor eye contact, repeating phrases, irritability, and aggression
- Autism Spectrum Disorder: Present in 50-70% of individuals with FXS 17
- Physical Features: long face, large forehead, ears, and jaw, the roof of their mouth might be very high, large testes
- Cardiac Complications: mitral valve prolapse, aortic root dilation (enlarge section of the artery right above the heart)
- Anxiety: social phobia or specific phobia, anticipatory anxiety, performance anxiety, separation anxiety, generalized anxiety
Females with FXS may experience some of the symptoms mentioned above. However, the symptoms will occur less frequently and tend to me more mild.
“All boys with Fragile X Syndrome have developmental delays, meaning that they may not meet their milestones like walking and talking. Males with Fragile X Syndrome also have intellectual disability and behavioral considerations that are common as well. Over half of males with Fragile X Syndrome have autism spectrum disorder,” said Sheedy.
Dr. Peter Todd is a neurologist who co-directs the Fragile X clinic at the University of Michigan, As a physician scientist, he also runs a research lab trying to develop new Fragile X therapies.
He further explained, “Fragile X is a developmental disorder and because of that symptoms in young children often present as delays in development, difficulty with early motor tasks, and difficulty with early language skills.
“There are a lot of symptoms you often see early. Unfortunately, those symptoms are not very specific. They're parts of lots of conditions, and so it's not uncommon for people with Fragile X Syndrome to go months or years after symptoms are first noticed before they get a diagnosis.
“It's very common for Fragile X kids to not do well in very loud social settings, and that hyperstimulation can really make it difficult for them,” he added.
Also, because there is no cure, “symptoms don't go away when people turn 18. Fragile X Syndrome is a lifelong disease, and these people who start off as kids become adults who are affected with the same issues.”
There is also a definite connection between Fragile X Syndrome and autism. Not all children with Fragile X Syndrome have autism, and not all children with autism have Fragile X Syndrome.
But many features seen in autism, such as difficulties with language, communication and socialization, are features that are common in Fragile X Syndrome.
As previously mentioned, individuals who are premutation carriers, do not have FXS but are at risk to develop Fragile X Associated conditions such as FXTAS and FXPOI.
“Individuals with Fragile X-Associated Tremor and Ataxia Syndrome do not typically have developmental differences. The first signs can include things like tremors and changes in how somebody walks. This is called ataxia typically present in somebody's 60s,” said Sheedy.
“We also may see psychiatric considerations like dementia and anxiety. Our studies show that about 40 percent of males with premutations, may develop these conditions. That percentage drops to about 20 percent of females.
“Another condition that we think about for people who are in this premutation group is called Fragile X-Associated Primary Ovarian Insufficiency. About 20 percent of females who are premutation carriers experience this, with symptoms like irregular menstrual periods, fertility issues or early menopause,” added Sheedy.
Diagnosis of Fragile X Syndrome
“To get a diagnosis of Fragile X Syndrome, either a health care provider like a pediatrician, neurodevelopmental provider, geneticist or genetic counselor would order Fragile X testing. This is usually a polymerase chain reaction test, or PCR. It is a test that counts the number of CGG repeats in the FMR1 gene,” said Sheedy.
Prenatal testing also is available and may be recommended in families where a history of FXS has been diagnosed.
Before becoming pregnant, a family can meet with a prenatal genetic counselor who will help initiate a carrier screening. This determines how many CGG repeats a woman has.
Based on those results, it’s possible to help frame the chances for a mother to have a child with Fragile X Syndrome.
Prenatal diagnosis is also possible through chorionic villus sampling or amniocentesis. A prenatal genetic counselor can provide additional information and help find the best testing path and resources for those who are interested.
When prenatal testing does not take place, the average age of FXS diagnosis for boys is 35 to 37 months while girls are diagnosed at an average age of 42 months. Parents may seek a diagnosis when they first start to see developmental delays, typically at about 12 months old for boys and 16 months old for girls.
Studies indicate that health care professionals typically diagnose someone with FXS about 16 months on average after confirming a developmental delay 18.
“It’s important to know that with Fragile X Syndrome, we see it frequently in kids that don't look all that different, especially when they're young, and it's really important to do testing if you see a child with developmental delay. This is a recommendation of the American Academy of Pediatrics and the Child Neurology Society,” said Dr. Berry-Kravis.
“When we test those kids and diagnose them early, they have the opportunity to benefit from Fragile X clinics and specialized care and to participate in clinical trials that hopefully someday will target the underlying disease and change the trajectory of Fragile X,” she added.
Another important issue to consider before undergoing a genetic test is that the results can affect other family members. They may be made aware that they potentially have FXS genetic issues which is why genetic counseling prior to testing is essential.
Treatments and Care Options for Fragile X Syndrome
There is no cure for Fragile X Syndrome, but there are certain therapies that are used to mitigate the negative symptoms for someone who has the condition. Specific courses of treatments will depend on what symptoms need to be addressed.
Some of those treatments and care options may include:
- Special education classes to help with behavioral problems and to avoid excessive stimulation.
- Early education intervention with courses that are tailored to specific learning difficulties. This can include small class sizes, and individualized attention.
- Medications to reduce social anxiety or other types of stressful social interactions
- Routine care for ear infections, reflux, seizures, high blood pressure, strabismus and mitral valve prolapse.
- Annual visions and hearing exams.
“After a diagnosis, children with Fragile X Syndrome will follow a course of treatment from their developmental pediatrician, who will help monitor and track the child's development. They can also help coordinate appropriate services and therapies like speech language therapy, physical therapy, occupational therapy and behavioral supports to help each child reach their fullest potential,” said Sheedy.
Many Fragile X Clinics are opening across the United States and around the world. Clinics can guide parents to experts who can help develop a management plan for their children.
These clinics will serve as a home base for families as the children continue to grow and their needs change.
Premutation carriers must also concern themselves with treatment options. Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) have their own set of signs and symptoms (described above) that require a management plan.
In addition to medical management, individuals with these conditions should meet with a genetic counselor to discuss reproductive risks and options.
Some individuals with FXPOI are unable to conceive, and therefore might explore fertility options such as egg donation, adoption, or in vitro fertilization with preimplantation genetic diagnosis. After an individual has conceived, prenatal diagnosis through either amniocentesis or chorionic villus sampling (CVS) is available.
While each individual with FXTAS is different, most will have tremors and balance problems that vary in severity. At this time, there is not a specific treatment for FXTAS, but care should be supportive and tailored to the patient.
It is recommended that care is provided by multiple disciplines including neurology and psychology.
Possible treatments for FXTAS include:
- Rehabilitative treatments such as speech, occupational, and physical therapy
- Gait training
- Family supportive services and counseling
The Prognosis of Fragile X Syndrome
Although a person with Fragile X Syndrome may face several challenges in their life, the good news is that the life expectancy for someone with the condition is generally normal.
Many people lead full and active lives and overall remain in good health.
“There's not a lot of information on really old patients, because many of them weren't identified when they were young. But when we look at patients with Fragile X in their 50s or 60s, they’re maybe a little more susceptible to certain things like Parkinsonism. But I have seen patients in their 70s and 80s, they're not dying young. They don't have such a big motor deficit or problem with eating or anything that causes them to die. They have a pretty normal lifespan,” said Dr. Berry-Kravis.
Societal attitudes toward people with FXS are also changing as well. In the past, the trend was to place people in residential facilities.
More recently, increased inclusion means that many people with FXS go to regular schools and have lots of typical friends.
“We're really making an effort to get these people out into the community, working in supported employment, and have them incorporated into the community that way. I think just the trends in terms of care of individuals with developmental disabilities are improving quality of life,” added Dr. Berry- Kravis.
Regular medical checkups and staying abreast of current treatments and advancements are important to treat various symptoms that may flare up.
While Fragile X Syndrome can be managed with various therapies, there is still no treatment to compensate for the loss of the protein that triggers FXS.
“We can manage medical problems, like ear infections and sleep apnea and things like that, that patients with Fragile X get, so we're optimizing their medical situation. While there's supportive treatment, there's no treatment currently approved that attacks the actual cause of the Fragile X that works on the mechanism of Fragile X in the brain,” said Dr. Berry-Kravis.
But that may be changing. There are several new drugs and therapies in development to attack the root causes of Fragile X Syndrome.
Dr. Berry-Kravis added, “We've already had a number of big trials of drugs that did work on one aspect of the mechanism or another. So far, we haven't been able to get a medication approved, but there are quite a number of things that are either in preclinical or clinical development.
What to do Next: Living with Fragile X Syndrome
After a diagnosis, some adjustments and an ongoing education effort are helpful in managing FXS.
The good news is that in many cases, people with FXS can still enjoy full lives. For example, a national family survey of adults with FXS showed that 19:
- About 4 in 10 women with FXS achieved a high or very high level of independence in adult life compared to about 1 in 10 men.
- About 4 in 10 women with FXS lived independently, often with a spouse or romantic partner, compared to 1 in 10 men who lived independently, and rarely with a spouse or romantic partner.
- About 8 in 20 women with FXS required no assistance with activities of daily living compared to 1 in 20 men.
- The majority of women with FXS had at least a high school diploma; the majority of men did not have a high school diploma.
- Almost half of women with FXS had full-time jobs, compared to 2 in 10 men.
This is not to say that there are challenges that lie ahead.
“It's very difficult for the families when your child with a developmental disorder is 40 and you're 70. You're not really at a stage where you would be expected to be caring for your child in that context. It places a huge burden on families and a lot of difficulties for the patients, because they have a hard time establishing their own independence.
“Just because they have intellectual disability and developmental delay doesn't mean they don't go through puberty and don't go through a desire to be independent, and all those same features that happen in all of us,” explained Dr. Todd.
Progress is being made, but there is still a ways to go.
“We've learned a lot about the biology of the brain and a lot about how certain elements in your DNA work through Fragile X Syndrome and research on its associated diseases,” added Dr. Todd.
“We've known that the loss of a protein causes the disease. Obviously, if we could develop a way to make more of that protein, that would be really helpful. That would be potentially a cure. At the same time in Fragile X Tremor/Ataxia Syndrome or the ovarian insufficiency diseases is a big repeat but it doesn't get turned off, so you still do make the RNA.
“So, now we know that that RNA can be a problem. It causes toxicity, it causes nerve cells to die. What that's led to is a lot of complexity in how you would approach this problem. If we turn that Fragile X gene back on, now we have to deal with that big RNA repeat, and it's potential to cause toxicity, so we have to build in a separate set of solutions for these problems. One of our goals has been to try and do that, to try and figure out ways to creatively prevent the toxicity of the repeat when it's RNA made into proteins, and also to try and boost expression of this gene to get that Fragile X protein made enough to help people with these diseases,” said Dr. Todd.
For more Information on Fragile X Syndrome
Organizations that provide various levels of support and information for FXS include:
FRAXA Research Foundation
10 Prince Place
Newburyport, MA 01950
Telephone: (978) 462-1866
E-mail: email@example.com Website: http://www.fraxa.org
National Fragile X Foundation
2100 M St., NW
Ste.170 Box 302
Washington, DC 20037-1233 Toll-free: 800-688-8765
E-mail: firstname.lastname@example.org Website: http://www.FragileX.org
The Fragile X Society
Road End House
6 Stortford Road
Great Dunmow, Essex, CM6 1DA
United Kingdom Telephone: 00 44 (0)1371 875100
Fax: 00 44 (0)1371 859915
E-mail: email@example.com Website: http://www.fragilex.org.uk
- What is Fragile X Syndrome (FXS)? (2020, June 12). Retrieved July 09, 2020.
- Hagerman, R. J. (2005). Fragile X Syndrome. Management of Genetic Syndromes. doi:10.1002/0471695998
- Finestack, L. H., Richmond, E. K., & Abbeduto, L. (2009). Language Development in Individuals with Fragile X Syndrome. Topics in language disorders, 29(2), 133–148.
- Hagerman RJ, Berry-Kravis E, Hazlett HC, et al. Fragile X Syndrome. Nat Rev Dis Primers. 2017;3:17065. Published 2017 Sep 29. doi:10.1038/nrdp.2017.65
- Fragile X Syndrome - Genetics Home Reference - NIH. (2020, July 7). Retrieved July 09, 2020.
- Hagerman RJ, Berry-Kravis E, Hazlett HC, et al. Fragile X Syndrome. Nat Rev Dis Primers. 2017;3:17065. Published 2017 Sep 29. doi:10.1038/nrdp.2017.65
- Lozano, R., Azarang, A., Wilaisakditipakorn, T., & Hagerman, R. J. (2016). Fragile X Syndrome: A review of clinical management. Intractable & rare diseases research, 5(3), 145–157.
- Nolin SL, Glicksman A, Tortora N, Allen E, Macpherson J, Mila M, Vianna-Morgante AM, Sherman SL, Dobkin C, Latham GJ, Hadd AG. Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles. Am J Med Genet A. 2019;179:1148–56.
- Nolin SL, Glicksman A, Tortora N, Allen E, Macpherson J, Mila M, Vianna-Morgante AM, Sherman SL, Dobkin C, Latham GJ, Hadd AG. Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles. Am J Med Genet A. 2019;179:1148–56.
- Raspa, M., Wylie, A., Wheeler, A. C., Kolacz, J., Edwards, A., Heilman, K., & Porges, S. W. (2018). Sensory Difficulties in Children With an FMR1 Premutation. Frontiers in genetics, 9, 351.
- Wheeler, A. C., Bailey, D. B., Jr, Berry-Kravis, E., Greenberg, J., Losh, M., Mailick, M., Milà, M., Olichney, J. M., Rodriguez-Revenga, L., Sherman, S., Smith, L., Summers, S., Yang, J. C., & Hagerman, R. (2014). Associated features in females with an FMR1 premutation. Journal of neurodevelopmental disorders, 6(1), 30.
- Hipp, H. S., Charen, K. H., Spencer, J. B., Allen, E. G., & Sherman, S. L. (2016). Reproductive and gynecologic care of women with Fragile X primary ovarian insufficiency (FXPOI). Menopause (New York, N.Y.), 23(9), 993–999.
- Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the Fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291:460–9.
- Nolin SL, Glicksman A, Tortora N, Allen E, Macpherson J, Mila M, Vianna-Morgante AM, Sherman SL, Dobkin C, Latham GJ, Hadd AG. Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles. Am J Med Genet A. 2019;179:1148–56.
- Stone WL, Basit H, Los E. Fragile X Syndrome. [Updated 2020 May 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-.
- Sansone SM, Schneider A, Bickel E, Berry-Kravis E, Prescott C, Hessl D. Improving IQ measurement in intellectual disabilities using true deviation from population norms. J Neurodev Disord. 2014;6:16.
- Kidd SA, Berry-Kravis E, Choo TH, Chen C, Esler A, Hoffmann A, Andrews HF, Kaufmann WE. Improving the diagnosis of autism spectrum disorder in Fragile X Syndrome by adapting the Social Communication Questionnaire and the Social Responsiveness Scale-2. J Autism Dev Disord. 2019.
- Bailey, D. B., Raspa, M., Bishop, E., & Holiday, D. (2009). No change in the age of diagnosis for Fragile X Syndrome: findings from a national parent survey. Pediatrics, 124, 527–533
- Bailey DB, Raspa M, Holiday D, Bishop E, Olmsted M. Functional skills of individuals with fragile x syndrome: a lifespan cross-sectional analysis. Am J Intellect Dev Disabil. 2009;114(4):289-303. doi:10.1352/1944-7558-114.4.289-303
Brenna: You're listening to the Rare Disease Connection, a production of Aspect Health and raredisease.com. Two of the most common indications for a pediatric genetics referral is developmental delay and intellectual disability. While there are a lot of reasons that a child might be experiencing these symptoms, the majority of inherited cases are due to Fragile X Syndrome. Today, you're going to hear from four experts in Fragile X Syndrome, and take a closer look at this rare disease. For families facing a new diagnosis, you likely have more questions than answers and that's why we're here. Brenna: Rare Disease Connection and our additional resources on raredisease.com and yourdna.com brings together the people whose expertise can explain what you're facing, from diagnosis to prognosis to treatment options, all the way to questions like, "Who do I talk to?" "Where are the people who've been through this before?" You'll find those answers here. From doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, they're all within your reach. We're here to connect you. This is Rare Disease Connection. Brenna: Hey, everyone, this is Brenna, co-host of Rare Disease Connection and Director of Patient Education at yourdna.com. Today, I'm going to bring you conversations with four experts in Fragile X Syndrome. Before we get started, you should know that this podcast is just the beginning. We have taken the information from this episode and added additional resources, explanations, links and references for you in a downloadable guide. You can get your free copy by going to raredisease.com/fragilex. That's raredisease.com/fragilex. Let's dive in. Our first guest is Rebecca Smith, a licensed genetic counselor in Lewisburg, Pennsylvania. Brenna: Rebecca works for the Autism and Developmental Institute at Geisinger, and has several connections to the Fragile X Syndrome community. Welcome, Rebecca. Why don't you start off by telling us a little bit about yourself? Rebecca Sheedy: Sure. My name is Becky Sheedy and I'm a genetic counselor. I studied at the University of Maryland Genetic Counseling training program in Baltimore, and I currently work at the Autism and Developmental Medicine Institute at Geisinger in Pennsylvania. I also split my time working on the Simon Searchlight project, which is a patient registry, linking families and researchers to learn more about genetic changes related to autism. Here at ADMI, we are a Center of Excellence for the Fragile X Community, and we also are a site for the forward project. Rebecca Sheedy: FORWARD stands for Fragile X Online Registry With Accessible Research Database. Essentially, it's a registry for families with Fragile X Syndrome, where lots of data is collected about the patients and families to help researchers better understand Fragile X Syndrome. You could say that we're right in the heart of the Fragile X community. Brenna: Speaking from all of the experience, being at the heart of the Fragile X community and as a genetic counselor, when you hear Fragile X Syndrome, what immediately comes to mind? Rebecca Sheedy: I think about that tremendous community, not only between families, but between providers as well. It's absolutely incredible to see all the way families from all across the world come and grow together. There's a tremendous network of providers who care so deeply for our patients and their families. I think it's this wonderfully strong, Fragile X community that just means so much for so many of our families. Brenna: Using you and your experience as a genetic counselor, let's think about the genetics, so Fragile X Syndrome, what's actually occurring on that genetic level that causes this condition? Rebecca Sheedy: To answer this, I'm going to take a step back first and go back to high school biology class just for a couple of seconds, so bear with me. Our DNA is essentially our body's instruction booklet. It tells our body how to grow, develop, learn, look, essentially how to work. Our DNA is spelled out in letters, the exact same way that words in a book are. Similarly, those letters are supposed to be in a very specific order for our body to be able to work like we would typically expect. Sometimes though, some of those letters can be changed, almost like a typo or a misspelling. Rebecca Sheedy: When this happens, these genetic spelling differences can change the way that our bodies work. With Fragile X Syndrome, we're looking at a section of the DNA called the FMR1 gene. You can think of it like a chapter of that whole instruction booklet. At the very beginning of this FMR1 gene, there's a section that has different numbers of three repeating letters. The technical name for this is a trinucleotide repeat. Essentially thinking about those DNA letters, the letters CGG are just repeating over and over again and this is normal. We'd expect that most people have anywhere from five up to about 44 of these CGG repeats. Rebecca Sheedy: However, what can happen is that this section of the gene can be repeated extra times. It's important to remember that nothing anybody does or does not do causes these repeats to be copied again. This is a totally random by chance process. People can show different signs based on how many number of repeats they have. Let's dive into that. Like I mentioned earlier, a negative or normal result would be if somebody has five to 44 of those CGG repeats or trinucleotide repeats. However, if somebody has 45 to 54 CGG repeats, they are called intermediate carriers. Rebecca Sheedy: Sometimes this group is also called the gray zone. People with 45 to 54 CGG repeats don't show us any signs of Fragile X Syndrome. We flag these results because they have the chance to expand and have more copies in future generations. We'd say that not necessarily their own children, but maybe their grandchildren or great grandchildren, maybe at higher chances to have Fragile X Syndrome. Let's move on to the next group. Now we're talking about people with more of those CGG trinucleotide repeats anywhere from 55 to 200. People in this group are at increased chances to develop two different conditions. Rebecca Sheedy: The first is called Fragile X-Associated Tremor and Ataxia Syndrome. Individuals with this condition do not typically have developmental differences. The first signs which can include things like tremors and changes in how somebody walks called ataxia typically present in somebody's 60s. We can also psychiatric considerations like dementia and anxiety. Our studies show that about 40% of males with pre-mutations, those 55 to 200 repeats may develop this Fragile X-Associated Tremor and Ataxia Syndrome, whereas 20% of females may. The second condition that we think about for people who are in this pre-mutation group is called Fragile X-Associated Primary Ovarian Insufficiency. Rebecca Sheedy: About 20% of females who are pre-mutation carriers experience this, with symptoms like irregular menstrual periods, fertility issues or early menopause. Finally, before we move on, people with pre-mutations can pass on these CGG repeats, which may expand, meaning that individuals with pre-mutations are at increased chances to have a child with Fragile X Syndrome. A genetic counselor would be able to help you figure out exactly what those chances may be. Now we get to Fragile X Syndrome. Somebody is said to have Fragile X Syndrome if they have more than 200 of their CGG repeats. Rebecca Sheedy: Sometimes this can be up into the thousands of repeats. When somebody has Fragile X Syndrome, they can show us different signs. All boys with Fragile X Syndrome have developmental delays, meaning that they may meet their milestones like walking and talking after we would typically expect. Males with Fragile X Syndrome have intellectual disability. Also very common or behavioral considerations. Over half of males with Fragile X Syndrome have autism spectrum disorder. Other behavioral things we think about include anxiety, ADHD and impulsivity. Rebecca Sheedy: Sometimes people with Fragile X Syndrome may have slightly different facial features than other family members. Other signs we can see include weak or floppy muscles called hypotonia, Gi Reflux, seizures and sleeping difficulties. On the other hand, not all females with Fragile X Syndrome show signs or symptoms and we'll get to why that is. We think that about half of females with Fragile X Syndrome have developmental delays and intellectual disability. Typically, though, the signs we see in females with Fragile X Syndrome are more mild than the signs that we see with males. Brenna: Thank you for going through all of that. I know that's a lot of information. As you'll hear later on this podcast from Dr. Peter Todd, he does research into Fragile X, but also in some of the associated conditions that you've touched on. Thinking about the inheritance, which is something that genetic counselors are fantastic at explaining and walking families through them. I know you've talked about how these repeats can be expanded and passed on through generations. But as you mentioned, there are some individuals that carry that expanded repeat and they don't have Fragile X Syndrome. Brenna: This would make them considered a carrier of this condition, correct? Rebecca Sheedy: Exactly. Yep. Brenna: Are there certain individuals that are more likely to be carriers and are they at risk for symptoms outside of what you've already discussed? Rebecca Sheedy: Great question. Let's go back to my biology class briefly. If you remember, our DNA is wound up into structures called chromosomes, the same way that yarn is wound up into balls. Typically, we have 46 chromosomes. We get half from our mothers and half from our fathers. This is the important part. We know that males have an X and a Y chromosome, whereas females have two X chromosomes. The FMR1 gene that has the CGG repeats with Fragile X Syndrome is located on the X chromosome. This is why we see different signs of Fragile X Syndrome in boys and men compared to girls and women. Rebecca Sheedy: Because females have two X chromosomes, they have almost a backup copy that they can use if one of their FMR1 genes has those higher number of repeats. This is why symptoms are typically more mild in females compared to males, who only have one copy of their X chromosome. Females are therefore called carriers. These female carriers have a 50% or one in two chance of passing on the X with the FMR1 gene with a higher number of repeats with each pregnancy. We would expect each son to show symptoms if the FMR1 gene with the more repeats is inherited. Rebecca Sheedy: If inherited in daughters, that daughter would also be a carrier and may show more mild signs or symptoms. For males who pass on their X chromosome to all of their daughters, every daughter would inherit this increased number of repeats. Conversely, all sons would inherit their father's Y chromosome and therefore would not have Fragile X Syndrome. Brenna: That makes sense when you break it down. Thinking about diagnosis of Fragile X Syndrome, how does someone actually go about getting a diagnosis? Rebecca Sheedy: To get a diagnosis of Fragile X Syndrome, either a health care provider like a pediatrician, neurodevelopmental provider, geneticist or genetic counselor would order Fragile X testing. This is usually called PCR. [inaudible 00:12:10] is a test that counts the number of CGG repeats in the FMR1 gene. Brenna: Is there an opportunity to diagnose someone prenatally or to provide a risk to parents who might be concerned about their child having Fragile X Syndrome? Rebecca Sheedy: Absolutely. Before becoming pregnant, your family can meet with a prenatal genetic counselor who can help facilitate carrier screening. This is testing to determine how many of those CGG repeats a woman has. The genetic counselor can use these results to help shape the chance for their family to have a child with Fragile X Syndrome. Prenatal diagnosis is also possible. This would include testing called either chorionic villus sampling or amniocentesis. Again, your prenatal genetic counselor would be able to give your family additional information and help you find the best testing path for your family. Brenna: Now that someone has a diagnosis, what does the care and management of these patients look like? Rebecca Sheedy: Typically, children with Fragile X Syndrome will follow within their developmental pediatrician, who will help monitor and track the child's development. They can also help coordinate appropriate services and therapies like speech language therapy, physical therapy, occupational therapy and behavioral supports to help each child reach their fullest potential. Genetics can also sometimes be involved in helping make sure the patient is seeing all of the appropriate healthcare providers. For example, if somebody has seizures, genetics will make sure they're hooked up with neurology. It's also important to make sure every child is having annular vision and hearing exams. Brenna: Thank you again for joining us today, Becky. I think with your wealth of experience and knowledge, you've really been able to break down Fragile X and make it much more understandable for our listeners. In closing, I'd like to give you a chance to let me know one thing that you would like people to know about Fragile X Syndrome. Rebecca Sheedy: Other than those couple extra DNA letters, people with Fragile X Syndrome are just like you and me. Go up to them, be friends with them, tell them a joke or just play with them. A kind smile makes all the difference in the world and I bet you'll get a huge smile back. Brenna: Thanks, Rebecca for joining us today. Whether you've interacted with a genetic counselor yet or not, they play an invaluable role in the journey of anyone diagnosed with a rare genetic disease. If you think you or someone in your family might have Fragile X Syndrome, I would recommend looking at nsgc.com to find a genetic counselor near you. Our next guest is Dr. Elizabeth Berry-Kravis, a pediatric neurologist at the Rush University Medical Center in Chicago, Illinois. Dr. Berry-Kravis works with a number of rare disease populations, one of which being Fragile X Syndrome. Brenna: Thank you so much for joining us today. Why don't you start out just by telling us a little bit about you? Dr. Elizabeth Berry-Kravis: My name is Elizabeth Berry-Kravis and I'm a child neurologist at Rush University Medical Center in Chicago, and I've been working in the developmental disabilities field for a very long time. Specifically, I've had a Fragile X clinic since 1992, and have done research in Fragile X since 1988, and have been involved in all manner of Fragile X research including clinical, basic and then a lot of translational research with clinical trials and natural history studies, and work on developing outcome measures and biomarkers for people with Fragile X. Brenna: Speaking from that breadth of knowledge, when you hear Fragile X Syndrome, what initially comes to mind for you? Dr. Elizabeth Berry-Kravis: Well, all my patients for one. I have like 700 patients. I think the thing that is most obvious in terms of thinking about the group of patients that I have is that there are so variable, in other words you can have patients who are very low functioning and don't talk, and have rudimentary skills and that can go anywhere from patients who are almost normal and functioning. The variability and the general, I think most of my patients are generally, when they're not upset about something quite friendly and social and really want to please people and be with people. Brenna: Taking a step back and thinking about the syndrome as a whole, where does the name Fragile X Syndrome come from? Dr. Elizabeth Berry-Kravis: Well, originally, the syndrome was discovered as a fragile marker X chromosome that you could see when you did a chromosome test under special conditions that were full light deprived under the microscope. What they discovered was that that unusual broken appearance to the X chromosome, where it looks like the tip of the X chromosome was breaking off, was appearing in the family members that were affected with Fragile X Syndrome in some large families. That was the initial diagnostic test for Fragile X was to get a blood sample and do chromosomes and grow them in special media, and then determine whether the fragile site was there. Dr. Elizabeth Berry-Kravis: Once the gene was discovered, we no longer really do the Fragile X chromosome test anymore, we just test the gene to see if the mutation is there, and is the mutation which is a big amplification of a CGG repeat in DNA that causes the fragile side. But the name of the syndrome wasn't changed when we found the gene. It's remained Fragile X Syndrome. Brenna: If you've got a good name, stick with it. thinking about it as well, how common is this syndrome? Is it more prevalent in certain populations or areas of the world? Dr. Elizabeth Berry-Kravis: Fragile X loss occurs in about one in 4,000 people in the USA and they're of course different. There's a range depending on what study was done. I think the frequency ranges go anywhere from one in 2500 to one and five or 6,000. The mutation frequency is actually probably the same in men and women, but women are less likely to manifest the symptoms of the condition, and so the syndrome, the clinical syndrome is less frequent in women because some of them will appear normal. There is some variation in the frequency of the condition. The Asian groups like in China and so forth, the syndrome appears to be less frequent there and more frequent in certain areas like Spain and Israel. Dr. Elizabeth Berry-Kravis: There's some population differences, but it's rare. It's rare in all populations, meaning the frequency is generally one in 1,000 or less, and it's seen at some frequency in virtually all populations. Brenna: You've seen a number of patients, I think you mentioned like over 700. When you're doing a physical exam, are there certain features that might make you suspicious of Fragile X Syndrome? Dr. Elizabeth Berry-Kravis: Well, there are certain physical features that suggest Fragile X Syndrome. Those are the classic features like large ears, a long face, a small mid face, many of the patients will have hyper flexible joints. There is this typical facial appearance, but not all of the patients have that and so that's not absolutely diagnostic. You cannot use the physical features to determine who does and does not have Fragile X, because some of the kids will really have almost none of the physical features, and you really have to do the genetic test in order to know whether the patient has Fragile X or not. Brenna: I'm guessing it sounds like you might be seeing patients more so after they're diagnosed. Dr. Elizabeth Berry-Kravis: In Fragile X clinic, the patient is usually already diagnosed with Fragile X and that's why they come to Fragile X clinic. Actually we require them to have Fragile X Syndrome to come to Fragile X clinic. But I have general neurology clinics and I've diagnosed a fair number of patients in my general neurology clinics. What happens is the patient gets referred in for developmental delay or in sometimes in the case of the girls, learning disability or behavioral issues. Then we do the Fragile X testing in that general neuralgia clinic and when it's positive, then they switch over to coming to Fragile X clinic. Brenna: I know you mentioned as well that you've been involved in a lot of research studies with Fragile X Syndrome, is there a cure currently? Dr. Elizabeth Berry-Kravis: There's no cure for Fragile X right now. That doesn't mean there isn't treatment. There are clearly better ways to manage patients with Fragile X and less good ways to manage patients in that. The realm of treatment is all the things that we do in Fragile X clinic, which means treating sometimes when there's very difficult behavior, treating that with medication, helping with behavior plans, helping with educational management, because there's certain ways that kids with Fragile X will learn better and certain ways, certain things that are very hard for them. Dr. Elizabeth Berry-Kravis: We can help with managing medical problems, like ear infections and sleep apnea and things like that, that patients with Fragile X get, so that we're optimizing their medical situation, in order to help them learn and behave as well as possible. There's supportive treatment, but there's no treatment currently approved that attacks the actual cause of the Fragile X, in other words works on the mechanism of Fragile X in the brain. In Fragile X, the FMRP protein, which is the product of the gene that's mutated is missing or reduced. Dr. Elizabeth Berry-Kravis: We don't have any treatments that actually work to compensate for the loss of that protein, although we are working on quite a number of things that work on different aspects of the mechanism in which FMRP is involved. Brenna: Yeah, so using that as a perfect segue into my next point, what are some of these new drugs or therapies that might be on the horizon for this Fragile X syndrome? Dr. Elizabeth Berry-Kravis: Yeah. We've already had a number of big trials of drugs that did work on one aspect of the mechanism or another. So far, we haven't been able to get a medication approved, but we have ... There actually are still quite a number of things that are either in preclinical or clinical development. Examples of those that are currently in trials include things like mGluR which is the metabotropic glutamate receptor, mGluR5 blockers, which have been shown to fix a lot of the phenotypes in the Fragile X mouse, fly and rat. Then also there's Metformin which works on insulin signaling and that's been shown to be abnormal in the Fragile X mouse and fly. Dr. Elizabeth Berry-Kravis: There are a number of agents that work on GABA that are in clinical trials, early clinical trials. Then we have a trial of a medication that's Phosphodiesterase. A type of Phosphodiesterase inhibitor that attacks a problem with producing cyclic AMP in the brain in people with Fragile X and normalizes that. We have a number of trials that are directed at the mechanism, and hopefully some of those will work out. There are also quite a number of things that target the mechanism in one place or another that are gradually working their way toward at least phase two trials. Brenna: It sounds like there's a lot on the road heading our way. Dr. Elizabeth Berry-Kravis: Yes, I think in Fragile X, we have no shortage of companies contacting us to talk about what would be a good development strategy. I think that is our biggest challenge, is taking something that appears to work really well in cells or in the mouse of Fragile X, and figuring out how can we identify whether this drug is having an impact in humans, and how can we measure that impact in a reasonable amount of time, because a lot of the problem is that to fix a development disorder, you may need a long time to actually see changes for instance, in learning or in developmental trajectory. Dr. Elizabeth Berry-Kravis: Behavioral changes, we can see more quickly. But some of these medications, if they're really targeting the underlying disorder, you would expect them to more work on language or thinking. We've done some novel things like try to put a learning intervention into our mGluR5 blocker trial, to see if you do a learning intervention, you can improve the speed of learning, and then you can see the effects of the drug accelerating learning more easily. We're developing a bunch of new markers, where we look at EEG waves in the brain of people with Fragile X that are abnormal, and that might change relatively quickly in a drug that in the long term is going to help with thinking. Dr. Elizabeth Berry-Kravis: We can use those markers as a flag that yes, this drug is doing what it should, and now we should do a big longer trial with it. Brenna: Thinking about everything that we have now in terms of treatment, and management and clinics, with the prognosis of Fragile X Syndrome what's the life expectancy and how's the quality of life? Dr. Elizabeth Berry-Kravis: Well, the life expectancy is pretty normal. Patients with Fragile X ... There's not a lot of information on really old patients, because many of them weren't identified when they were young. But when we look at ... Lots of the patients with Fragile X that are the ones we see that are in their 50s or 60s, they seem to have a little more ... They're maybe a little more susceptible to certain things like Parkinsonism. But I have seen patients in their 70s and 80s, they're not dying young. They don't have such a big motor deficit or problem with eating or anything that causes them to die. They have a pretty normal lifespan. Dr. Elizabeth Berry-Kravis: Quality of life is another thing and I think we are improving on that. In the past, I think a lot of the guys wound up just placed in residential facilities, and now with the increased inclusion that goes on, a lot of the patients go to regular schools, are spending part of their time in inclusion classrooms, may have typical friends, may even have girlfriends like in high school. Then we're really working to get these guys out into the community working in supported employment, and try to improve quality of life and really have them incorporated into the community that way. I think just the trends in terms of care of individuals with developmental disabilities are improving quality of life. Dr. Elizabeth Berry-Kravis: But of course, we would love to have a medication that would make the patient able to do more functionally and therefore even further improve that quality of life. Brenna: Thank you for spending so much time with us today. My closing question is, if there was one thing you had that you wanted people to know about Fragile X Syndrome, what would that be? Dr. Elizabeth Berry-Kravis: I think it's just really important to know that Fragile X Syndrome, we see it frequently in kids that don't look all that different, especially when they're young, and it's really important to do testing if you see a child with developmental delay. This is a recommendation of the American Academy of Pediatrics and the Child Neurology Society, and it's just really important to test those kids and diagnose them early, because then they have the opportunity to benefit from Fragile X clinics and specialized care and to participate in these clinical trials that hopefully someday will target the underlying disease and change the trajectory of Fragile X. Brenna: Thank you Dr. Berry-Kravis for spending time with us today. After receiving a diagnosis, it is important that you identify a team of physicians familiar with the condition. You can go to fragilex.org to find a clinic near you. Rounding out our physicians is Dr. Peter Todd, a neurologist and researcher at the University of Michigan Medical School in Ann Arbor. Dr. Todd has spent several years researching Fragile X Syndrome and its related conditions. Welcome Dr. Todd. Why don't you start off just telling us a little bit about you? Dr. Peter Todd:: Sure. I'm a neurologist at the University of Michigan, and I co-direct the Fragile X clinic there, which sees both pediatric and adult cases of Fragile X Syndrome and other Fragile X associated diseases. I'm a physician scientist, so I also run a research lab. Much of our lab works on Fragile X associated disorders and trying to develop new therapies for them. Brenna: Wonderful. Speaking from your experience, both as a physician who sees patients and also as a researcher, when you hear Fragile X Syndrome, what immediately comes to mind for you? Dr. Peter Todd:: Yeah, I think for me, Fragile X is something I've been involved in now for about 20 to 30 ... 25 years. I started when I was a graduate student, I worked with a pediatric neurologist as my PhD mentor, and he saw kids with Fragile X, and I had a chance to go and work with him in those contexts. I was always struck at that time by the behaviors and issues that those kids were facing and the families we're dealing with, but also really the amazing energy that those families have brought to the care of their children and to the broader Fragile X community. Dr. Peter Todd:: I think it's actually both those kids with Fragile X and the families in general and their interactions, which has caused me to keep coming back to work on Fragile X over the last 25 years. Brenna: It's definitely a condition that has captured your interest and probably your heart as well. Dr. Peter Todd:: Yeah, very much. I view the patients as partners in a long-term goal to try and improve our ability to care for this condition. Brenna: Yeah. Since you're a physician, you're seeing patients in clinic as well and it seems to be at a range of ages as well. What are some of the early signs and symptoms of Fragile X Syndrome that you might be seeing, I guess in your pediatric patients? Dr. Peter Todd:: Right, so Fragile X is a developmental disorder and because of that symptoms present very young, in young children and often present as delays in development, so difficulty with early motor tasks, difficulty with early language skills. Probably those kids also can sometimes have problems like seizures and can have behavioral problems and problems with anxiety. All those can play into the aspects of their early development. Those are the symptoms you often see early. Unfortunately, those symptoms are not very specific. Dr. Peter Todd:: They're parts of lots of conditions, and so it's not uncommon for people with Fragile X Syndrome to go months or years after symptoms are first noticed before they get a diagnosis. Brenna: Out of those children continue to age to adolescence and then into adulthood, how do those symptoms change? Dr. Peter Todd:: Right, one of the major features is they have intellectual disability and so their ability to learn is harder than it is for normal children. Because of that, they often have different ... They have to participate in special classes and their learning styles are often different. Fragile X kids also can have some aspects of their behavior that look a little bit like autism. They don't make very good eye contact with people, and so they can have problems with interacting with others. It's very common for Fragile X kids to not do well in very loud social settings, and that hyper stimulation ... too much stimulus can really make it difficult for them. Those are things we see. Dr. Peter Todd:: We also see a fair bit of attention deficit problems that are seen in other kids without Fragile X Syndrome. These problems also, I think, important to note, they don't go away when people turn 18. Fragile X Syndrome is a lifelong disease, and these people who start off as kids become adults who are affected with the same issues. Brenna: I think ... I've done some work here in Birmingham with an organization called the Exceptional Foundation, which tries to find placement for these kids, sort of not like a daycare but more like a camp for them to hang out with their friends and do activities during the day, because of the lack of infrastructure after these kids age out of the school system. I think that's something that's felt across several of these developmental delay intellectual disability communities. Dr. Peter Todd:: It's a real problem and a real unmet need. It obviously, it's very difficult for the families, when your child with a developmental disorder is 40 and you're 70, you're not really at a stage where you would be expected to be caring for your child in that context. It places a huge burden on families and a lot of difficulties for the patients, because they have a hard time establishing their own independence. Just because they have intellectual disability and developmental delay doesn't mean they don't go through puberty and don't go through a desire to be independent, and all those same features that happen in all of us. Brenna: Absolutely. Going back to a comment you made previously about autism. A lot of times you do hear Fragile X and autism used either in similar settings. Is there a connection between these two diagnoses? Do they overlap? Do they diverge? Dr. Peter Todd:: Yeah, so there is a connection. About a third of children with Fragile X Syndrome meet the diagnostic criteria for autism. But not all children with Fragile X Syndrome have autism, and certainly not all autism children have Fragile X Syndrome. However, there is many features we see in autism, which is often difficulties with language and communication and socialization are features that we do commonly see, at least to some degree in Fragile X Syndrome. What that means is that sometimes some of the behavioral interventions and things we use in autism can be helpful in Fragile X Syndrome. Dr. Peter Todd:: Potentially some of the things we're looking to use to develop in Fragile X Syndrome could be applicable in autism, especially at the behavioral level. Brenna: Switching gears a little bit and thinking about Fragile X Syndrome from a genetic standpoint, we heard earlier on this podcast from the genetic counselor, sort of what pre mutation carriers are but they themselves don't have Fragile X Syndrome, but maybe have the possibility of having a child with a condition. Should they be concerned for any health issues? Dr. Peter Todd:: Yes, there are a number of health conditions that specifically affect pre-mutation carriers. For women, there is the potential to develop early ovarian insufficiency, which is called Fragile X Premature Ovarian Insufficiency or FXPOI. In addition, both males and females with the permutation are at risk for developing a degenerative disease later in life called Fragile X Tremor/Ataxia Syndrome. The mechanism that underlies the disease is different in these pre-mutation cases versus Fragile X Syndrome, and so we don't think of people with Fragile X Syndrome as being at risk of those other conditions. Dr. Peter Todd:: But there is aspects of the molecular biology of these two that are probably interrelated, and from a broader clinical perspective, one of the complications is that these families have three different conditions happening in the same family that don't look anything alike by themselves, and which make it difficult for each member. If you have a degenerative brain disease and then you have a child with Fragile X Syndrome or grandchild with Fragile X Syndrome, that's very complicating. If you have early ovarian difficulties then that's very ... If you're thinking about having another child, the timing is difficult. Dr. Peter Todd:: If you're doing that in the context of already having a Fragile X kid that can put a lot of tax on families. I think that there is an important dynamics of this particular condition, which makes it different than many other genetic conditions. Brenna: Do you often see families in your practice that have both or all three of these going on? Dr. Peter Todd:: I would say it's very common for me. In fact, I see about half the patients I see have Fragile X Tremor/Ataxia Syndrome, half are the Fragile X associate disease patients. It's very common for me to have the patients come in. There'll be a grandchild or child who has Fragile X Syndrome that child's mother and then the mother's father, also there who has Fragile X Tremor/Ataxia Syndrome. You can imagine being that mother who is dealing with a father who has a degenerative brain disease and a child, a son that has a developmental disease and her being at risk for developing ovarian problems and cognitive problems and problems of her own. Dr. Peter Todd:: It's a very complicated dynamic and it also requires a lot of understanding from the families, because it's not a very easy thing to explain how the genetics of this work. Brenna: is there a metaphor that you use to try to help explain this to families or a common go to you that you pull out of your pocket? Dr. Peter Todd:: I probably give them more details than they need, but it's actually ... I will say that one of the amazing things about Fragile X associated diseases is how resilient these families are, and actually the knowledge base by especially the mothers in Fragile X Syndrome about this disease is often better than most clinicians. I think it's amazing and obviously they have a very personal experience with the disease in their case, but they know a lot about how this works, so I view them really as partners in trying to understand this. I don't really have a great go to analogy that explains this particular condition. Dr. Peter Todd:: There is sort of a difference in the way this disease presents, because of the difference in the way the gene behaves at different size repeats. Brenna: Absolutely. Just switching gears to focusing a little less on your clinical experience and more on your research. As someone who's focused on Fragile X Syndrome and associated Fragile X conditions, and you've said for about, I think about 25 years that you've worked on this, what has surprised you most? Dr. Peter Todd:: We've learned a lot about the biology of the brain and a lot about how certain elements in your DNA work through what we've, through Fragile X Syndrome and research on its associated diseases. I know you've heard a little bit about this from the genetic counselor earlier, but there is a ... when Fragile X Syndrome happens, you have a big repeat that causes the gene it's in to turn off. [inaudible 00:38:19] normally if your genes are DNA and they get transcribed into RNA, and then that RNA goes and gets translated into a protein. In Fragile X Syndrome, there's a big repeat that sits in the DNA and it turns that gene off, so you don't make any of the RNA or the protein. Dr. Peter Todd:: We've known that that's the loss of that protein that causes the disease. Obviously, if we could develop a way to make more of that protein, that would be really helpful. That would be potentially a cure. At the same time in Fragile X Tremor/Ataxia Syndrome or the ovarian insufficiency diseases, actually that is a big repeat but it doesn't get turned off, so you still do make the RNA, and now we know that that RNA can be a problem. It causes toxicity, it causes nerve cells to die. What that's led to is a lot of complexity in how you would approach this problem. If we turn that Fragile X gene back on, we figure out a way to do that. Dr. Peter Todd:: Now we have to deal with that big RNA repeat, and it's potential to cause toxicity. [inaudible 00:39:21] something we can solve, we have to build in a separate set of solutions for these problems. One of our goals has been to try and do that, to try and figure out ways to creatively prevent the toxicity of the repeat when it's RNA or [inaudible 00:39:35] made into proteins, and also to try and boost expression of this gene to get that Fragile X protein made enough to help people with these diseases. Brenna: It seems like a complex problem. Dr. Peter Todd:: It is. There's a lot of moving parts, but I think that when you're doing research, one of the reasons I think people do research on diseases and especially genetic diseases is, there's the goal to help people and then there's the fascinating nature of the research and what it teaches about brains, and genes and all of us more broadly. For me, all that complexity is very exciting, and it presents real problems that we can now try and solve. Our goal is to try and solve those difficult problems with the end goal of improving lives of people. Brenna: Yeah, for a lot of research before you can work on the solution you have to understand how the problem works and what's actually going on. It seems like there's been a lot of research for Fragile X Syndrome that has described what's actually going on, like you mentioned with the protein, or with the toxic RNA levels, but what's the missing stuff? Where are we at currently in terms of finding a cure? What is needed? Dr. Peter Todd:: I think we're getting a little bit ... we're getting closer, and there's more hope now than there was maybe in the past. I'll give you an example from another disease as where I think we're hoping to head. There's a disease, an early onset disease in kids called spinal muscular atrophy. New therapies are now available for this. There's gene therapy, a way in which to deliver the gene back into nerve cells, that's been FDA approved and is very effective in these kids. There's another technique that utilizes a small piece of RNA that goes in and actually helps correct a problem with splicing. Dr. Peter Todd:: To get to that solution required many years, 20 years of research and actually a really deep basic understanding of the biology of the gene and how it behaves. I think we now have that basis in Fragile X Syndrome, and we're all trying to figure out a way to take that information and convert it to something that we would actually be able to translate into patients. I think that the infrastructure is in place and the development is moving, but we're not quite there yet. We haven't found that perfect magic bullet and when we have it, it's going to take a little while to prove that it's the right one. But I remain hopeful that we will have therapies for this. Brenna: Well, thank you for spending time with us today talking to us not only about your experiences in clinic, but also your work as a researcher and what you think is coming down the pipeline. In closing, if you have one take home message that you could leave our listeners with about Fragile X Syndrome, what would that be? Dr. Peter Todd:: I guess my take home would be that people with Fragile X Syndrome and intellectual disability and disorders like this are really actually incredible humans, and we should make sure we value them and do everything we can to help them independent of a cure or some fix that we hope to come up with. I think that most people who have a child with Fragile X Syndrome will speak to the many things they've learned from that child, the many improvements in the things they've seen in life that they would not have experienced prior. Dr. Peter Todd:: I guess I would say that we should all be working to think about improving the quality of lives for these people, but also recognizing that part of that is things we as a society and the community need to do to help them. Brenna: Thank you for sharing your knowledge and excitement with us, Dr. Todd. If you're interested in getting involved in Fragile X Syndrome research, you can go to fraxa.org to learn more. Our final guest is Gregg Harper, a former Mississippi State Representative. His son Livingston has Fragile X Syndrome. Gregg worked hard during his time in office to make sure that he advocated for this population. While he is now retired, his name lives on through the Greg and Livingston Harper Congressional Internship program for individuals with intellectual disabilities. Welcome, Gregg. Why don't you start out just introducing yourself? Gregg Harper: Sure. I'm Greg Harper, former member of Congress for the 3rd congressional district of Mississippi. Have been in Mississippi most of my life. Born in Jackson, Mississippi, my dad was a petroleum engineer so that meant we transferred often. For me from kindergarten through to 12th grade, I was in 10 different schools living in five different states. It was quiet a hop around, but Mississippi was always home and I've been back here for a long time. I'm blessed to have a great wife, Sydney and we have two children, Livingston, and Maggie. Maggie is now married and we have a grandchild, one so far. We're willing to accept more, if they'll get to work. Brenna: What is your involvement with the Fragile X Syndrome community? Gregg Harper: Well, our now adult son, Livingston, who is almost 31, has Fragile X Syndrome. That has been a part of our life since we got that diagnosis when he was almost four years old. We have lived with that and certainly lived with the consequences. Before he was four, we just didn't know what it was. We didn't have the correct diagnosis for a couple years. So that's how we've come to be a part of a very special community for us. Brenna: Yes. Speaking from your experience as a parent, and also as a former Congressman, what immediately comes to mind for you when you hear Fragile X Syndrome? Gregg Harper: Livingston. They're tied together and linked together. It's been a big part of our lives and so for us, whenever we think of that, it is our involvement in our life with Livingston and just how unique and special he is to have around. He's a real blessing to a lot of folks. Brenna: Yeah, so let's meet Livingston. Why don't you tell us a little bit about him? Gregg Harper: Sure. Livingston was our firstborn. We had lots of plans, and you have as parents for your children, particularly that firstborn. You're thinking, "Well, where are they going to go to school? What will they do? What will they be doing?" By the time Livingston was about probably less than two, we realized that he just wasn't meeting the milestones. He wasn't where, he was late to walk, late to talk, gross and fine motor skills issues and problems that showed us something wasn't right. Our pediatrician recognized that pretty early on. We went through a lot of tests but nobody tested for Fragile X Syndrome, because at that time, he was testing in a normal range on IQ. Gregg Harper: Nobody suggested that, we didn't know anything about it. But we were doing the right things, even though we didn't know that because he got even some early education issues, speech therapy, occupational therapy, the things you would have done had you had the correct diagnosis. Really we were just ... I certainly believe that God directs our paths and our next door neighbor at the time was an adoptive aunt to our kids, and she was head of all Special Education Programs for the county school systems. Went to a seminar with a breakout session on educating children with Fragile X and saw some video and her mouth fell open and came home and said, "I think this may be it." Gregg Harper: As a result, we had him tested and confirmed through that testing that he indeed had Fragile X Syndrome, and it was a life changer to know that. I'll have to say that as his parents, much of the literature on Fragile X Syndrome was, how should we say it? It was depressing. My wife and I threw it away and we said, "We're not going to worry about what he can't do. Let's focus on what he can do." That's how we began to move forward. We began to attend international Fragile X conferences which were held every two years. We went out to at that time Denver Children's Hospital, see Dr. Randi Hagerman and her team and to get him fully evaluated and come up with a plan. Gregg Harper: We begin to operate along those. Yes, the journey that we are still on was not the journey we had planned, but it's a great journey. It's just different than what we thought it might be. That's been our story with Livingston and he's ... Look, he's been great. If you told my wife, he's not going to be able to do X, Y, or Z, she pretty much said, "Well we'll show you." They said, "Well, he'll never ride a bike." Well he learned to ride a bike. He'll probably never jump off of a diving board. Well, he jumped off a diving board and swam really good. Those things we pushed him to do and then he did very well. Has always been in music and choirs and sing very well, great pitch. Gregg Harper: Also he wanted to go to college like his buddies, and so we're very thankful to Mississippi State University started a program called the Access Program. Livingston was one of the first two students to graduate from that and had an incredible experience. We'd probably still be there if [inaudible 00:49:23] keep paying tuition [inaudible 00:49:24]. It was a great time for him. He's worked at a local restaurant now for a little over five years, and he's very happy. Brenna: Thinking of how much you've seen in the 30 years with Livingston, how have you seen things change in the Fragile X community or in the information that's given to families? Gregg Harper: I think that the awareness is greater now, that a lot of physicians maybe pediatricians that have been practicing for a while were very familiar with it. I believe that there's a greater awareness of the condition. There's more testing that's being done. If you have unexplained ... somebody that's MR that you don't have a real explanation for that, it's at least a rule out test. There are a lot of ... for us our misdiagnosis when he was two was that he had mild cerebral palsy and was a near miss on autism. Both of those were incorrect. Sometimes as a parent, you just have to keep digging and searching. Gregg Harper: I do think that the communication is better to do more as far as treatment and therapies that are out there. Those continue to improve as research is being done as we speak. Brenna: Absolutely. Switching more to your advocacy side, you've spoken of you and your wife and your attitude of, "We're going to show them. We're going to do everything that we can. Livingston is going to do anything he wants to do." During your 10 years in office, you've worked on a number of initiatives to help individuals with Fragile X Syndrome. What's been one of your proudest accomplishments? Gregg Harper: Well, certainly being the only member who was a parent of a child with Fragile X Syndrome, we were very close to the group that came up for National Fragile X Advocacy Day. For 10 years, every year I gave them to start their advocacy day on Capitol Hill, we started with a tour of the House floor in the Capitol, just to get them in the mood and that sense of excitement. Just those relationships mattered a great deal. But certainly for us seeing my son want to work, want to ... We've always had to live in the so called "normal world". Gregg Harper: I was on the Committee on House Administration from the very beginning, and that's the committee that has oversight or jurisdiction over the intern program, which was for regular college students who wanted to come spend a semester or a summer working on The Hill, but there was nothing there for students with intellectual disabilities, so I started one. We started it as a pilot program with five or six students from George Mason University's Mason LIFE program. From there, that pilot program was very successful. It's now been a permanent program of now for well over actually like 11 years now, and over 250 House and Senate offices have now participated, the House and Senate, of course. Gregg Harper: What we've seen there is that's an ongoing program. In fact, the demand is greater than the supply of the students. Sometimes an office may want to have a student from Mason LIFE for that program, but they may have to wait a semester because they're not enough to go around to meet that. But here's what that does, not only does it improve the life skills and the confidence. and these social skills of these students with special needs, it also changes the minds and the hearts of the staffers who maybe have never been around anybody like that. Gregg Harper: As we look forward, those are going to be the ones that will be running companies 20 years from now and hiring people, and we want them to look to see the value of what those individuals can do, and how they can do real work, fulltime work for fulltime pay, and we want them to be considering them. I think that's a big step. For Livingston and me, one of the greatest honors ever in December of 2018, they had a reception honoring me retiring, with all of the Mason Life students, a lot of House members and Senate members and staffers. Gregg Harper: We were in the Rayburn Room. It was full, just off the House floor, and Rodney Davis from Illinois was emceeing it and he said, "Livingstone, come up here and stand next to me, and Gregg you come stand next to Livingstone," and he announced to the full room. He said "I want everybody to know that from this day forward, this program will forevermore be called the Gregg and Livingstone Harper congressional intern program for students with intellectual disabilities. That made everything that I've done being away from my family, the sacrifices that members do make made everything worthwhile. Gregg Harper: Just in that moment, and to have him there with me. It doesn't get any better than that. Brenna: That sounds amazing, not only to have your son but then to have so many individuals who participated in that internship program with you there to celebrate you, and I think as someone who was not part of the internship, but I would definitely say thank you for all of your hard work and your advocacy on The Hill. Gregg Harper: Well it was a joy and the students that we worked with just meant so much, but there's more to be done. One of those things would be to think about the program, the access program that Livingston went to at Mississippi State University. What we'd like to see in the future is maybe in the summer, to allow students from some of those other post-secondary education programs around the country, to send a student to be a part of the summer program, where they can go work on Capitol Hill where they'll expand it beyond just those at Mason LIFE, at George Mason. Those are things that I think we can look at for the future. Then one of those ... Gregg Harper: When I became Chairman of the Committee on House Administration, in January of 2017, one of the first things I did is I said to my staff, "Look, we've got the slot. We've got the money in our budget, you find me the best recent graduate from George Mason University. We're going to hire them fulltime to work here." We hired a young man who still works fulltime on The Hill doing great work, and that's the type of life change experience we want to see for some of these students. It changed his family's life. Brenna: Outside of your own advocacy, you're also a member of the National Fragile X Foundation's advocacy team. What's your best advice for families who maybe are trying to get involved in advocacy or just joining the community in general? Gregg Harper: Well, certainly being a part of that great group, we're always going to be about raising awareness and building those relationships with those policymakers. You can do that on a national level by coming up for the advocacy day that they have each spring. That's an important part of it. You can do it locally, because every United States senator and member of the House have local district offices. You can be involved there. You can let them meet your child that has Fragile X, let them know why the funding and research initiatives are so important, and then reach out to the Fragile X community. Gregg Harper: The website is fragilex.org. You can get lots of great information there and just begin to be a part of it. I think that's very [inaudible 00:57:09]. Brenna: With your connection to this group and the community, are there any upcoming events that you'd like to highlight for us? Gregg Harper: Right now, there is an ongoing deal with the 17th International Fragile X Conference, which by the time listeners are hearing this that may be over with, but you can still access it because it's being done virtually. You can access on demand by going to that, signing up for the program. It'll not only give you all of the great topics that are going to be discussed, but also upcoming seminars that will be done, that will be included in that as well. I think you can go back and access these programs for up to six months if you register. Very educational, talking about therapy, about research, about different initiatives that are out there. Gregg Harper: Certainly, I'll be doing an advocacy portion on that as well if you want more [inaudible 00:58:05]. Brenna: That sounds fantastic. Thank you again for spending time with us today Mr. Harper. In closing, what would be your best advice for someone who's diagnosed with Fragile X Syndrome, or maybe you have a loved one who is diagnosed? Gregg Harper: Certainly, there's an initial shock that you go through, that you realize that things are going to be different. There's some comfort in knowing you actually have a definitive answer for what a problem may be. But then after that, you just have to pick yourself up and you do you have to trust ... Certainly we have a lot of trust that God will direct our paths and guide us in those things. I think that's an important area as well. I'll just say, "Don't ever give up," and don't do what we did, which is sometimes put a ceiling on our child's ability and think, "Well, he can't do that." Gregg Harper: There are many things that if we just get out of the way he could do. We've had to learn and relearn that from time to time, because they can do great things. Livingston has gotten to be friends with some special people in the great Singing Policeman the tenor, Daniel Rodriguez, Livingston got to sing with him. He came to Mississippi and sang with Livingston on stage with a choir in a packed auditorium and just ... It's just an amazing thing to get to do. The key thing is never give up on your child. Always push them and love, but just know they can do a lot more and if the parent will just get out of the way a little bit. Brenna: Thank you Gregg for taking the time to speak with us today. Your story and Livingston's story is one of faith and hope. If you are interested in getting involved in advocacy work or looking to connect with other families, you can go to fragilex.org. Today we had the chance to hear from four amazing experts in Fragile X Syndrome, but it is only just the beginning. We have taken all of today's information and included it in a free downloadable guide. You can get your free copy by going to rare disease.com/fragilex. We would love to connect with you. If you need to talk to someone, we're standing by. Go to rare disease.com/help. We're waiting for you. Rare Disease Connection is a production of Aspect Health and raredisease.com. Thanks for joining us.