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Fragile X syndrome

Fragile X syndrome (FXS), also called Martin-Bell syndrome or marker X syndrome, is a genetic condition associated with a mutation in the X chromosome or sex chromosome. It is the most common monogenic (single-gene) cause of inherited intellectual disability- autism spectrum disorder (ASD), as well as the second most common cause of mental impairment.

FXS is caused by a mutation within the fragile X mental retardation (FMR1) gene located on the X chromosome, which involves an expansion of the cysteine-guanine-guanine (CGG) nucleotide triplet repeats in the DNA structural sequence. Normal individuals carry approximately 5 to 40 CGG repeats within the FMR1 gene, while individuals who are carriers for FXS (premutation) have 55 to 200 CGG repeats and individuals with FXS (fully mutated) carry more than 200 CGG repeats.

This CGG expansion silences FMR1 expression resulting in deficiency or absence of the expression of the fragile X mental retardation protein (FMRP), which plays a crucial part in the establishment and maintenance of connections between cells in the brain and nervous system, as well as some ovarian functions. The prevalence of FXS with a full mutation is estimated to be 1 in 4000 in males and 1 in 8000 in females, where females are often observed to present milder symptoms than males. However, the incidence of females who are carriers of the altered gene appears to be about four times that of males (1 in 130 to 250 population in case of females and 1 in 250 to 800 population in males).

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Symptoms

Patients with fragile X syndrome present with the following symptoms:

  • Elongated facial features with the increase in length of palpebral fissures (area between the two open eyelids), and a broad philtrum (the vertical groove between the base of the nose and the border of the upper lip).

  • Protruding forehead and ears also have soft cartilage.

  • High-vaulted palate along with dental crowding.

  • Hyperextensible finger joints, flexible flat feet, and scoliosis (a sideways curvature of the spine that most often is diagnosed in adolescents).

  • Macroorchidism (a condition with enlarged testicles) occurs after puberty.

  • Hypotonia (weak muscle tone).

  • Speech deformity from cluttered speech to complete lack of speech depending on phenotype severity.

  • Eye problems, including strabismus (inability to focus both eyes on an object), hyperopia (far-sightedness), and astigmatism (defect in the eyes resulting in distorted image formation).

  • Mild to severe intellectual disability.

  • Prader–Willi syndrome (PWS) phenotype in some cases with obesity, hyperphagia (excessive eating from increased appetite), and hypogonadism (failure of the gonads to function properly).

  • Signs of anxiety, attention deficit hyperactivity disorder, impulsivity, autism, mood instability, depression, and aggression.

Diagnosis

Evaluation of a suspected case of FXS is done by a geneticist and a specialist in neurodevelopment, such as a neurodevelopmental pediatrician. Fragile X testing should be taken into consideration during the diagnosis of any individual with a family history of FXS, intellectual disabilities, impaired development, or autism.

Diagnosis of fragile X syndrome requires DNA from blood, amniotic fluid, or other tissues. Prenatal testing for FXS is done by polymerase chain reaction (PCR)  by taking a DNA sample from the cells of the placenta or by taking a sample of the amniotic fluid. The PCR measures the number of CGG repeats and the Southern blot analysis checks the methylation status of the FMR1 gene. By using specific primers for the FMR1 gene, the PCR allows the amplification of the region that contains the CGG repeat and, thus helps to identify individuals with an expanded FMR1 allele both in the premutation and in the full mutation range. The Southern blot analysis measures the FMRP protein level and determines the methylation status of the gene. Sequencing of the FMR1 gene is necessary in less than 1% of the cases where the disease is caused by FMR1 missense mutations and not by CGG repeat numbers.

Management

FXS has no cure. The goal is to manage the symptoms and early intervention is of utmost importance. FXS management includes:

  • Special education to help with learning 

  • Speech and language therapy

  • Occupational therapy to help with daily tasks

  • Behavioral therapy and sensory integration.

 

Symptomatic medications used in FXS include psychostimulants, antidepressants, antipsychotics, and anticonvulsants to take care of behavioral and mental health challenges. Currently, there are no Food and Drug Administration (FDA)–approved therapies for FXS. Also, the off-label usage of certain drugs to manage disease symptoms has undesirable side effects. Since 30% to 60% of FXS cases are found to develop autism hence it is particularly important to take into account certain drugs that help in relieving symptoms of autism spectrum disorder (ASD). 

The cannabis plant has a profound effect on social behavior. N-palmitoylethanolamine (an endocannabinoid, found to be lower in ASD) was found to be effective in combination with risperidone for reducing irritability symptoms in children with ASD. As 10–30% of people with ASD suffer from comorbid epilepsy, it is also necessary to manage this condition. An emerging phytotherapeutic called epidiolex, which is a cannabidiol (CBD) compound, has been recently approved by the US FDA to treat severe forms of epilepsy. FXS should be diagnosed indiscriminately and need prompt management.

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