By Prof. Philippos Patsalis
Fragile X Syndrome (FXS) is the leading cause of inherited intellectual disability and the most commonly known cause of autism worldwide.
It is inherited in an X-linked dominant manner because the responsible gene is located on the X chromosome.
Therefore, one copy of the affected gene is enough to cause the condition in both males and females.
Almost all cases of FXS are due to a genetic change (mutation) in the FMR1 gene, where a DNA segment known as the CGG triplet is expanded.
Typically, this DNA segment is repeated from 5 to approximately 40 times.
If the CGG triplet is repeated between 55 to 200 times, individuals are carriers of premutation, an intermediate variation of the gene.
Even though they do not have FXS, some premutation carriers may experience certain symptoms.
If the CGG triplet is repeated more than 200 times, it results in full mutation and manifestation of symptoms.
In affected people, this mutation inactivates the FMR1 gene.
Consequently, the Fragile X Mental Retardation Protein (FMRP), which plays a crucial role in normal brain development, is either not produced or is dysfunctional.
FXS has been identified in all populations and ethnic groups, and its estimated prevalence in males is 1 in 7,000 and females 1 in 11,000.
Males are likely to be affected more severely than females because they have one X chromosome and one Y chromosome, while women have two X chromosomes.
The most common symptoms in males who have a full FMR1 gene mutation include moderate intellectual disability, delayed speech and language development, specific facial appearance such as long and narrow face, large ears, prominent jaw and forehead, and behavioural problems like hyperactivity, hand flapping, temper tantrums, seizures, and features of autism spectrum disorder.
Other characteristics in males include enlarged testicles (macroorchidism), malformed sperm and low sperm count, and connective tissue disorders like hyperflexible joints, hyperextensible fingers, thumbs, and wrists.
Some of these symptoms are hard to recognize in babies and young children but become more apparent with age.
Affected men will pass the mutated gene to their daughters and none of their sons, as they inherit the Y chromosome.
As females have two X chromosomes, the unaffected gene may produce certain amounts of the FMRP protein, and the condition may not manifest as severely as in males.
Females with the full FMR1 mutation may have mild intellectual disability and a milder presentation of the syndrome’s physical and behavioural features.
A small number of affected females have no apparent signs of the disorder.
This could be due to the X-inactivation mechanism.
This process randomly silences one of the two X chromosomes in females, explaining the variability seen in women who are carriers or affected by an X-linked disorder.
Affected women also have a 50% chance of passing the mutated gene to each offspring.
All their sons, who inherit the mutated gene, will have the FXS, and 50% of their daughters can be affected.
The FXS premutation is more common in the general population than the full mutation, and its estimated prevalence in males is 1 in 250-800 and females 1 in 130-260.
The high incidence indicates the critical role of carrier screening so that people are aware of their risks for infertility problems or having an affected child.
Carrier screening can detect the FXS full mutation and premutation and is recommended by The American College of Obstetricians and Gynecologists (ACOG) for women who are considering pregnancy or are currently pregnant and have a family history of Fragile X-related disorders or intellectual disability suggestive of FXS.
Most individuals with a premutation of the FMR1 gene are intellectually normal.
In some cases where the premutation causes lower levels of the FMRP protein, mild symptoms such as prominent ears may appear, or they may experience emotional disorders such as anxiety or depression. Some children with an FMR1 premutation may have learning disabilities or autism-like behaviour.
The premutation is also associated with an increased risk for two adult-onset disorders – the development of fragile X-associated tremor/ataxia syndrome (FXTAS) in both men and women, and an increased risk of women having premature ovarian failure, known as fragile X-associated primary ovarian insufficiency (FXPOI).
FXPOI occurs in approximately 1 in 4 female premutation carriers.
Through genetic testing such as carrier screening or infertility genetic testing, early detection can be critical for early interventions like oocyte harvesting and cryopreservation that can preserve fertility.
The FXS premutation can be passed silently through family generations before a child is born with the syndrome.
Women with premutation have a 50% chance of passing the mutated gene to each offspring. Furthermore, as the repeats can expand to more than 200 repeats in their oocytes, women with a premutation have an increased risk of having a child with FXS.
Contrastingly, the premutation in men does not expand to more than 200 repeats when passing the gene to their daughters, so each of them will inherit the permutation.
FXS may be indicated by some particular facial characteristics, although not all are recognizable at a young age.
For FXS diagnosis, molecular genetic testing is required to determine the number of CGG repeats in the FMR1 gene and must be requested by a genetic counsellor or a healthcare provider.
There is no specific treatment or a cure for the syndrome currently.
Still, support and management of the condition may improve the quality of life of affected individuals and their families.
These may include special education started at an earlier age, medications for behavioural issues and routine medical management of vision, hearing and heart problems.
The life expectancy of people with FXS is normal, and several affected individuals have an active lifestyle and good health.
FXS is one of many neurogenetic conditions that are believed to benefit from earlier identification and treatment.
The average age of diagnosis for a child with FXS is around three years old after developmental and intellectual delays are evident.
An earlier diagnosis, possibly through fetal or newborn screening, could potentially have neurodevelopmental benefits for the affected child.
At this time, an innovative program in the United States is offering voluntary newborn screening for FXS to evaluate the benefits of an early diagnosis and care management for affected children.
The writer is Chief Executive Director & Chief Medical Officer NIPD Genetics
Adventia and Rodinia genetic tests offered by NIPD Genetics can detect Fragile X Syndrome. To learn more, please visit www.nipd.com
The content is intended only for informational purposes and is not medical advice