Fragile X Syndrome Latest Facts: Symptoms, Diagnosis, and Treatment

What is Fragile X Syndrome?

Fragile X syndrome is a genetic disorder characterized by a moderate degree of intellectual disability. It is caused by a mutation in a gene located on the X chromosome, which makes the X chromosome appear constricted under the microscope; hence the condition was termed Fragile X syndrome. In affected children, Intelligence Quotient (IQ) is invariably below 55 in a male child while only about 70 % of affected females have an intellectual disability. The frequency of Fragile X Syndrome is variable in males and females, affecting 1 in every 4000 live male births, and 1 in every 8000 live female births.

Child With Fragile X Syndrome. Image courtesy of Peter Saxon

What Causes Fragile X Syndrome?

Within the X chromosome, there is a gene called the Fragile X Mental Retardation 1 (FMR1) gene. In healthy people, this gene consists of about 29-30 trinucleotide repeats of CGG in its 5 prime regions. In Fragile X Syndrome, a mutation in the FMR1 gene results in the expansion of the FMR1 gene to greater than 200 CGG trinucleotide repeats. This high number of CGG trinucleotide repeats causes methylation of both the trinucleotide repeat expansion and promoter site at Xq27.3, which in turn results in the FMR1 gene silencing.

FMR1 gene expresses FMRP protein, which is found in high concentrations within the central nervous system and the male gonads. FMRP has been implicated to be responsible for mRNA transportation to nerve synapses. Any abnormality in this transportation can disrupt the normal functioning of the synapses and impair both learning and memory. Furthermore, FMRP also has some effect on dopamine transportation in the brain cortex, which may be the culprit behind some of the symptoms seen in Fragile X syndrome such as attention deficit hyperactivity disorder. Symptoms of anxiety seen in patients with Fragile X syndrome are thought to be due to the decrease in the regulation of GABA pathways, which predominantly plays an inhibitory role in the brain.

Due to the location of the mutation, Fragile X syndrome is an X-linked dominant disorder with highly variable disease expression and penetrance. Males are affected more severely than females. This phenotype variability between genders is due to the presence of two X chromosomes in females, and the uncertainty in the X-inactivation, as either the mutated or the non-mutated X chromosome, can be inactivated in females.

Symptoms and Signs of Fragile X Syndrome

Children born with Fragile X Syndrome appear normal at birth. Characteristic symptoms and signs of Fragile X Syndrome only become apparent at puberty. Although intellectual disability is the most noticeable sign of disease, an affected child also displays a set of physical features that are classically seen in Fragile X Syndrome. Adolescent children display characteristic physical signs such as a long face with large protruding ears, large testis, muscle hypotonia, hyperextensible joints of the finger, and flat feet. Children with Fragile X Syndrome are also susceptible to ophthalmologic problems such as strabismus and amblyopia.

Furthermore, affected children also display atypical social behaviors such as avoidance of eye contact, shy nature, problems with memorization, and difficulty remembering faces. Difficulties with clear speech or stuttering may also be seen, and most children with Fragile X Syndrome also display characteristic symptoms of Autism. A major reason for repeated visits to the physician in Fragile X Syndrome children is recurrent episodes of middle ear infection, and sinusitis prior to the onset of puberty.

One-fifth of affected females may have early onset menopause due to ovarian insufficiency associated with X chromosome mutation. Females have a milder phenotype of Fragile X Syndrome in comparison to males, and may, therefore, have relatively milder symptoms. The average IQ in males with Fragile X Syndrome is about 40, whereas affected females may have a normal or near-normal borderline IQ.

Diagnosis of Fragile X Syndrome

Prenatal diagnosis can be done via amniocentesis or sampling of chorionic villus while the fetus is in the uterus. The sample is examined by the Polymerase Chain Reaction to determine the number of CGG repeats in the FMR gene of the X chromosome. Gene sequencing can be done in patients with deletions or missense mutations of the FMR gene in whom the PCR test cannot be used to test the trinucleotide expansion.

Management

As with all genetic disorders, there is no cure for Fragile X Syndrome. Management for this condition is chiefly focused on improving speech, behavior, and sociality by speech therapy, occupational therapy, behavioral therapy, physical exercises, and special education. Pharmacological therapy can be given for patients with anxiety, mood disorders, and ADHD such as anti-depressants, antipsychotics, and anticonvulsants, and anxiety medications.

Long-term Outlook

Life expectancy is lower than average in people diagnosed with Fragile X Syndrome. But more importantly, patients may have life-long difficulties due to social, behavioral, cognitive, and psychological issues. Males with Fragile X Syndrome who live beyond the age of 40 may have worsening memory problems, increased difficulty in performing daily activities, and deterioration in speech.