FRAGILE X SYNDROME

Scientific background

Fragile X syndrome is the most common monogenic inherited cause of intellectual disability. In contrast to other diseases with X-linked recessive inheritance, fragile X syndrome shows healthy male carriers, and in some of the female patients, symptoms are as severe as in males. The incidence of affected males is estimated to be 1:5164 according to a 2009 study.

The cause of fragile X syndrome is a CGG triplet repeat expansion in the non-translated 5′ region of the FMR1 gene on the long arm of the X chromosome. The most frequent normal alleles in the general population have a length of 29-30 CGG repeats. Alleles in the range of 45 to 54 repeats are defined as gray zone alleles (EMQN ring trials). Some instability is already present at this repeat count, regardless of the sex of the carrier; however, expansion to a full mutation in one generation has not yet been observed in this range.

Alleles with 55 to 200 CGG repeats are referred to as premutation. In females, the inheritance of premutations is unstable, usually leading to an extension of more than 200 triplets (full mutation) when they are passed on to the next generation. Above this length, methylation of cytosine residues of the repeat and adjacent regulatory elements occurs, ultimately leading to inhibition of transcription and consequent failure of the FMR1 gene product. In males, the premutation is stable when passed on to the next generation. Mothers of children with a full mutation are obligate carriers with either a premutation or a full mutation. The risk of recurrence is up to 50% for affected children depending on the sex or the length of the premutation in the mother.

In the presence of the full mutation, the developmental delay is first noticeable in childhood and usually affects speech more than motor skills. The children often have slightly abnormal measurements for body length and head circumference. Occasionally, symptoms of connective tissue weakness such as hyperextensible joints and muscle hypotonia are present. Hyperactivity and autistic behaviors are characteristic features. Apart from rather large ears, other phenotype features, such as an elongated face and prominent chin, are not very pronounced in childhood but characterize adults with fragile X syndrome. Postpubertal macroorchidism is often seen in males. Female carriers of the full mutation can show variable symptoms ranging from an inconspicuous phenotype (about 30%) to intellectual disability of a severity similar to that seen in males. About 20% of premutation carriers have premature menopause (fragile X associated primary ovarian insufficiency, FXPOI). In older premutation carriers, particularly males, more than 30% show a progressive neurological disease pattern consisting of intention tremor, gait ataxia, parkinsonism, autonomic dysfunction, and dementia, which is called fragile X tremor/ataxia syndrome (FXTAS).

References

Mila et al. 2018, Clin Genet 93:197 / Hall et al. 2018, Handb Clin Neurol 147:377 / Hagermann et al. 2017, Nat Rev Dis Primers 3:17065 / Pugin et al. 2017, Neurologia 32:241 / Biancalana et al. 2015, Eur J Hum Genet 23:417 / Spath et al. 2010, Am J Med Genet A 152A:387 / Leitlinien zur molekulargenetischen Diagnostik: Fragiles-X und Fragiles-X assoziiertes Tremor/Ataxie Syndrom 2009, medgen 21 / Rost et Klein 2005, J Lab Med 29:152 / Nolin et al. 2003, Am J Hum Genet 72:454 / Oostra et al. 2001, Clin Genet 60:399 / Oostra et al. 1993, J Med Genet 30:410

Fragile X Syndrome: the leading cause of inherited intellectual disability and the most common known cause of autism

Fragile X Syndrome (FXS) is the leading cause of inherited intellectual disability and the most commonly known cause of autism worldwide. Fragile X syndrome is inherited in an X-linked dominant manner because the responsible gene is located on the X chromosome, and 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 is 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 the manifestation of symptoms. In affected people, this mutation inactivates the FMR1 gene and 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 in 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 appearances such as a long and narrow face, large ears, prominent jaw and forehead, and behavioral problems like hyperactivity, hand flapping, temper tantrums, seizures and features of autism spectrum disorder. Other male characteristics 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 a mild intellectual disability and a milder presentation of the syndrome’s physical and behavioral features. A small number of affected females have no apparent signs of the disorder. This could be due to the X-inactivation mechanism, a process that randomly silences one of the two X chromosomes in females, which explains 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 in 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 of 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 behavior. 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, and early detection, through genetic testing such as carrier screening or infertility genetic testing, 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 counselor or a healthcare provider. There is no specific treatment or a cure for the syndrome currently, but 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 behavioral 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. Currently, the average age of diagnosis for a child with FXS is around 3 years old, which is 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 of America is offering voluntary newborn screening for FXS in an effort to evaluate the benefits of an early diagnosis and care management for affected children.

World Fragile X Day is celebrated on July 22 to raise public awareness about FXS and educate healthcare providers, teachers, and policymakers about their role in supporting people with FXS. The goal of this day is to celebrate remarkable individuals facing FXS and remind ourselves that there is still a lot of work to be done through pioneering research, gene therapy, and new medications which can advance the care and clinical management of people with FXS.

Adventia and Rodinia genetic tests can detect Fragile X Syndrome. Adventia is an expanded carrier screening test for any individual or couple who wishes to know whether they are a carrier of a genetic disease. Rodinia screens for mutations associated with infertility in individuals and couples with difficulty conceiving and maintaining a pregnancy. Genetic results, possible next steps, and clinical management should always be discussed with your healthcare provider. 

The content is intended only for informational purposes and should not be perceived as medical advice.

Compiled using information from:

• National Fragile X Foundation
• FRAXA Research Foundation
• National Organization for Rare Disorders
• National Human Genome Research Institute
• Center for Disease Control and Prevention
• The American College of Obstetricians and Gynecologists (ACOG)

References

• Okoniewski, Katherine C et al. “Early Identification of Fragile X Syndrome through Expanded Newborn Screening.” Brain sciences vol. 9,1 4. 3 Jan. 2019, doi:10.3390/brainsci9010004
• Man, Limor et al. “Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations.” Frontiers in molecular neuroscience vol. 10 290. 12 Sep. 2017, doi:10.3389/fnmol.2017.00290
• Bartholomay, Kristi L et al. “Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings.” Brain sciences vol. 9,1 11. 12 Jan. 2019, doi:10.3390/brainsci9010011

Last updated in 2021