Fragile X syndrome: A case for prenatal and carrier testing

The first time that you hear your baby cry, thousands of emotions flood your brain but the wait is finally over and he’s finally here. You thank your lucky stars that he is healthy and perfect. Fast-forward eight months: you are at story time and you notice that your son is the only one who cannot sit unassisted. Concerned, you take him to the family doctor, which is followed by a battery of tests to find out that he has fragile X syndrome. Fragile X syndrome is an inherited genetic disease and the likelihood of inheriting fragile X is second only to Down syndrome. Like Down syndrome, fragile X syndrome causes both developmental and mental impairment, but unlike Down syndrome, standard prenatal genetic tests do not look for fragile X.

Fragile X syndrome includes a group of disorders caused by genetic changes in one gene, FMR1. FMR1 encodes the protein FMRP1, which helps set up the cognitive pathways in the brain that involve memory, attention, judgement and knowledge. People with fragile X syndrome do not make enough FMRP1, so their brains do not develop properly. At birth, fragile X babies appear perfectly healthy and do not show signs of mental impairment until they are 6-8 months old. From that point onward, the symptoms become more obvious, as these babies take longer to develop skills like sitting, walking and speaking. The physical characteristics associated with fragile X (a long face, protruding ears, large head, prominent forehead and jaw) do not become noticeable until these children are much older.

The part of the FMR1 gene that is responsible for fragile X is known as a trinucleotide repeat region, which is simply a small part of the DNA that gets repeated multiple times. Normal individuals have 4-44 repeats, people with 55-200 repeats have what is called a ‘premutation’, and people with fragile X syndrome have more than 200 repeats. Once the repeat size goes over 200, the body stops making FMRP1. Women with premutations (55-200 repeats) can make eggs that have even more repeats and the children born from eggs with over 200 repeats develop fragile X syndrome. Parents with the premutation usually show no signs of fragile X syndrome and will typically not even know that they carry a disease gene that can be passed down to their children. Even though individuals who carry they premutation do not show signs of fragile X syndrome, as they grow older, they are at higher risk of developing other fragile X-associated diseases, including fragile X-associated tremor ataxia, which is a neurodegenerative disease.

Approximately 1 in 4000 boys and 1 in 8000 girls are born with fragile X syndrome every year. While this is not as frequent as the 1 in 800-1000 babies born with Down syndrome, the difference is that fragile X is usually inherited. Genetic tests can help parents find out if they carry premutations, which can be used to monitor children who are born with the premutations or to catch the children with fragile X syndrome early on. Early detection before the onset of developmental symptoms can allow for early intervention and treatment and provide the best outcomes for children affected with this syndrome. There is no cure for fragile X syndrome, but the developmental delays can be managed through supportive therapies, including speech, occupational and physical therapies, combined with drugs to target specific symptoms, such as autism and anxiety.

Fragile X syndrome is one of the most common diseases that cause mental impairment, and most children with this syndrome will need to be cared for throughout their lives. A simple genetic test can tell you if you are a premutation carrier. This is particularly important for women, because mothers with premutations have up to a 50% chance of having children with fragile X syndrome. The closer the premutation repeat size is to 200, the higher the chance of passing on fragile X. So, if you have a family history of either fragile X syndrome or unexplained intellectual or developmental disabilities, a simple genetic test might offer you peace of mind, whether you chose to have children or not. In a world where there is a choice for knowing the risk, making the choice to know may be more than half the battle.