Fragile X Syndrome Fragile, Not Broken

-Divya Samat,
Intern
K.J.Somaiya Medical College

Recently, I heard the story of a mother who got pregnant after 9 years of trying to conceive and multiple IVF trials. Her infant son, Varun soon began to display signs of developmental delay and intellectual disability. Physicians at the time diagnosed this as ‘autism’ and it was this condition for which he received treatment for 10 years. His mother, a special educator herself, never felt that the diagnosis fit his affectionate and sociable nature. It wasn’t until Varun was 10 that his parents came across an article published by the Fragile X Society India and much to their surprise, identified many of the characteristics in Varun. They got in touch with the Chairperson, Mrs. Kedia who after listening to their story advised they get tested for this genetic mutation. So at age 10, Varun was finally diagnosed with Fragile X Syndrome. His mother too got tested and it was found that she was a premutation carrier, likely having Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) which explained the infertility. The tears shed that day were not of remorse or despair but of happiness at finally having found the answer that had evaded their family for 19 years.

Do you know what is the most common inherited cause of intellectual disability? Or the only single gene mutation known to cause autism? It is Fragile X Syndrome. It is not unlikely that you have never heard this term before or read it in a list of causes or mentioned as an option in an MCQ. I will be the first to admit that I didn’t know much about the condition when I started writing this article. However, after days of research and reading, watching videos and listening to families’ experiences, I feel like I am in a comfortable place to write this article. The days of listening to personal stories, the victories and the struggles as well changed my perspective about this condition and that is what I hope to do for you through this article.  

Fragile X syndrome is an X-linked dominant disorder with reduced penetrance, and is associated with intellectual and emotional disabilities ranging from learning problems to intellectual disability and mood instability to autism. 1 in 5000 children are affected which accounts for approximately 4,00,000 children in India alone. It passes silently down through generations until a child is affected with the full mutation-Fragile X Syndrome. 1 in every 151 women and 1 in every 468 men are permutation carriers of fragile X. The lack of awareness about the condition is shocking not only due to the sheer prevalence of the condition or the fact that it is often misdiagnosed as autism but because of the short and long term implications a timely and accurate diagnosis could have on the child and his family. A correct diagnosis would not only ensure early intervention and targeted therapies for the child but also help the family make informed decisions regarding their reproductive options. 

So, What Causes Fragile X Syndrome?

Fragile X syndrome (FXS) is a genetic disorder caused by changes in a gene called the fragile X mental retardation 1 (FMR1) gene located on the X chromosome. There is a place in the FMR1 gene where the DNA pattern of the chemical letters, CGG, is repeated over and over again. Most people have less than 45 repeats. Having more than 200 repeats causes the FMR1 gene to “turn off” so that it can’t make FMRP (Fragile X Mental Retardation Protein). FMRP is essential for brain development, mainly synaptic transmission, synaptic plasticity, learning, and regulation of anxiety. The lack of the FMR protein in the brain leads to FXS. 

Inheritance Patterns of FXS

Normal (5 to 44 Repeats) 

Most people have about 5 to 44 repeats of the letters CGG in their FMR1 genes. 

Intermediate (45 to 54 Repeats)

People who have an intermediate number of repeats do not have FXS. However, they may have a slightly higher chance of having some symptoms.

Premutation (55 to 200 Repeats) 

People who have a premutation might have another fragile X-associated disorder and related concerns. In addition, they can have children with a premutation or full mutation (FXS).

● With each pregnancy, women have a 50% chance of passing the premutation or full mutation on to their child. The more CGG repeats the mother has, the more likely her child will have full mutation fragile X.

● Men will have daughters with a premutation, but sons will not be affected. 

Fragile X Associated Disorders include the following: 

1) Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

FXPOI is a cause of infertility and early menopauseamong adult women. Women who have a premutation are at higher risk for primary ovarian insufficiency and are at higher risk for having children who have FXS.

2) Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

FXTAS is a disorder of the nervous system that can cause intentional tremors, balance problems, frequent falls, neuropathy, autonomic dysfunction, cognitive decline, and dementia, which may progressively worsen over time.

3) Fragile X-Associated Neuropsychiatric Disorders (FXAND)

For many years, she has believed that carriers of a Fragile X premutation are at risk for a variety of mental health and medical problems due to the premutation itself including anxiety, depression, attention deficit hyperactivity disorder (ADHD), chronic pain, fibromyalgia, chronic fatigue, sleep disturbances, and autoimmune problems.

Full Mutation (FXS): More than 200 Repeats

People with a full mutation have FXS. 

How do you identify a child who might have FXS? 

Because the disorder is X-linked, females are generally much more mildly affected than males. It is important to know that it is a spectrum disorder and one may not see all symptoms always. 

Signs that a child might have FXS include:

• Developmental delays
• Learning disabilities
• Autism/ Austistic traits
• Intellectual disability

The behavioural phenotype may be helpful in suggesting the diagnosis of FXS. Autistic-like features are common and include hand flapping, hand biting, gaze avoidance, tactile defensiveness, and hyperarousal to sensory stimuli. These features – along with impaired social skills, such as socio-emotional reciprocity – are expressed with varying degrees in children with FXS and may be indicative of a concurrent diagnosis of autism spectrum disorder. 

Fragile X Syndrome often occurs with other conditions.Some of these conditions include anxiety, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, depression, difficult peer relationships, intellectual disabilities, and learning disorders. Anxiety interferes with the learning and behaviours of children with Fragile X.

Children with Fragile X are often very social and friendly. They have excellent imitation skills, strong visual memory/long-term memory and a wonderful sense of humor.  

Physical features include a long, narrow face, large forehead, prominent ears, prominent jawline, joint hypermobility, hypotonia and flat feet. The facial characteristics can be subtle and may become more apparent with increasing age.

Individuals with FXS usually do not have significant medical issues. Recurrent otitis media and recurrent sinusitis are common during childhood. Joint laxity with hyperextensibility finger joints and pes planus (flat feet) may be present and usually improve with age. Gastroesophageal reflux disease occurs in a third of young infants with FXS. Seizures and EEG findings consistent with epilepsy are another common feature of FXS during childhood. Life expectancy is not affected in people with FXS. 

Making a Diagnosis of FXS 

A common myth is that there is no value in making a diagnosis of FXS if there is no cure. Although currently there is no cure for FXS, there are important supportive treatments that can be applied once the diagnosis is known. Moreover, a diagnosis can be helpful as it provides a reason for a child’s intellectual disabilities and behavior problems. This allows the caregivers to learn more about the disorder and manage care so that the child can reach his or her full potential. It also enables families to receive counseling for family planning. 

There are three general circumstances in which Fragile X testing should be considered:

● Clinical symptoms that suggest Fragile X syndrome, FXTAS, or FXPOI. .

● Family or personal history of a Fragile X genetics and inheritance (i.e., carrier).

● A family history of FXS, FXTAS, intellectual or learning disabilities or autism of unknown cause, or infertility.

The testing procedure encompasses two complementary analyses. PCR with primers flanking the repeat is used to determine the number of CGG repeats and a Southern blot of genomic DNA is used to determine the methylation status and to gauge the size of full mutations, which are often resistant to PCR amplification. The combination of Southern blot and PCR for the detection of fragile X-associated mutations has a sensitivity of 99%.

If a positive FXS test is discovered, the proband and family should be referred for genetic counseling and cascade testing of family members at risk of carrying a full mutation or premutation. Premutation carriers should be counseled regarding their risks of passing a full mutation onto their children, and they should also be counseled of their own risks of POF and/or FXTAS. Prenatal diagnosis for full mutations can be performed on either chorionic villus or amniocentesis samples and have proven to be reliable.

Management of FXS 

Although currently there is no cure for FXS, there are supportive treatments such as educational and therapeutic approaches tailored to the individual, screening for and treatment of medical issues, and behavioral treatment methods. Psychopharmacologic intervention should be combined with other supportive strategies, including speech therapy, sensory integration occupational therapy, individualized educational plans, and tailored behavioural interventions to maximize functioning.

Some researchers believe that many of the behavioural problems observed are secondary to problems with hyperarousal to sensory stimuli and structuring the environment of the affected individual such that they are comfortable with their surroundings is one approach to alleviating this issue. Another approach is the use of α2-adrenergic agonists, which are thought to dampen the response to sensory input to the brain. Selective serotonin reuptake inhibitors (SSRIs) are quite commonly used to treat mood disorder, anxiety, and obsessive-compulsive behaviours associated with FXS. Reports of improvement in mood stabilization, attention, and academic performance have been noted with the atypical antipsychotic aripiprazole. Future clinical trials involving mGluR5 antagonists and AMPA receptor signaling may potentially provide a targeted treatment of FXS in alleviating the core psychiatric and neurologic symptoms.

Environmental variables such as parenting ability, parental expectations of child behavior, organization of the home, emotional climate, and enrichments in the home may influence an individual’s development of adaptive behaviors, cognitive abilities, and behavioral symptoms. 

Strengths and Strategies for Fragile X Syndrome

● Excellent visual memory: Keep all the learning as visual as possible. Visual timers, visual schedules, sight reading and visual based educational programs 

● Keep it contextual: Children with FXS are need based learners. Try to incorporate what the child likes in the learning process. 

● Imitation Skills- Children with Fragile X are excellent imitators. Use this trait to teach and reinforce routines, ADL skills and academics

● Indirect Teaching: They learn a lot by watching others. Use the third person dialect to get your way around children with Fragile X 

● Excellent Long Term Memory: Very often children with Fragile X demonstrate information that has not been taught. They are often learning more than you teach them. 

● Social interaction: Instead of asking questions, let them complete sentences. Do not force eye contact as this may be a trigger for anxiety.

● Praise and celebrate every victory of the child

Finding Support

Having a diagnosis of a rare condition is very challenging and families often need a road map. Having support and community resources can help increase confidence in managing FXS, enhance quality of life, and assist in meeting the needs of all family members. It might be helpful for parents of children with FXS to talk with one another as one parent might have learned how to address some of the same concerns another parent has. Often, parents of children with special needs can give advice about good resources for these children.

Varun loves spending his time painting, making caricatures and baking. He is an artist, baker and entrepreneur as well, selling his bakery items and creative products. Not only that, he loves imparting knowledge and conducts workshops on baking and doodling. He is diligent, compassionate, hardworking and loves to learn new things. He proves that the sky’s the limit and you won’t ever know if you don’t try. This was all possible due to the correct diagnosis and targeted therapies. However, there are many children who aren’t as lucky. They remain undiagnosed and untreated for FXS and the number is growing. After all, we are talking about a condition which is rare and a country with a large population.

July 2021 is World Fragile X Awareness Month. Although current therapies for FXS are aimed at symptom management, it is hoped that future molecular therapies will be directed at preventing the development of some of the symptoms of FXS.Early diagnosis will be key to making these therapies more effective, and there are efforts to implement new-born or infant screening for FXS. Spreading awareness is the first step in guiding early diagnosis and intervention. Clinicians too should play an active role by addressing parental concerns and considering the diagnosis of FXS in any infant or toddler with developmental delays. 

References