Introduction

Fragile X syndrome (FXS), also called Martin-Bell syndrome, is a non-Mendelian trinucleotide repeat disorder. FXS is the most prevalent inherited cause of mild to severe intellectual disability and the most common monogenic cause of autism spectrum disorder (ASD).[1][2] It accounts for about one-half of cases of X-linked mental retardation and is the most common cause of mental impairment after trisomy 21 physical features include a long and narrow face with a prominent jaw, flexible fingers, large ears, and enlarged testicles in males. These features usually become more apparent in older children. About a third of these children have features of autism and delayed speech that is present from an early age. Hyperactivity and seizures are common. FXS is indirectly the result of the expansion of the cysteine-guanine-guanine (CGG) triplet repeat within the Fragile X mental retardation one gene (FMR1) located on the X chromosome.[3] This CGG expansion silences FMR1 expression resulting in an abolished or greatly diminished expression of the fragile X mental retardation protein (FMRP).[4] FMRP is necessary for the development of neuronal connections (synapses) and some ovarian functions. The lack of FMRP is the direct cause of FXS. Diagnosis is by molecular genetic testing, which determines the number of CGG repeats in the FMR1 gene. Normally, it is between five and 40 repeats. Individuals with 55 to 200 repeats have an FMR1 gene premutation (PM) and usually (but not always) have a normal intellect. Individuals with greater than 200 CGG repeats have a full mutation (FM) for FXS. Testing for PM carriers (by an FMR1 DNA test) allows for genetic counseling. Prenatal testing for FXS is an option often provided to women with a premutation or a full mutation.

Etiology

Fragile X syndrome is considered to be an X-linked dominant condition with variable expressivity and reduced penetrance.[5] However, due to X-inactivation in females and genetic anticipation, the inheritance of FXS does not follow standard X-linked dominant inheritance. Females with full FMR1 mutations have a milder phenotype than males as a result of variability in X-inactivation.

The expanded CGG triplets in the 5’-untranslated region of FMR1 are hypermethylated, resulting in a decreased expression of FMRP. The methylation status of CGG triplets is, therefore, a key factor for categorizing FXS; in other words, the greater the degree of methylation, the greater the deficit of FMRP. A molecular consequence of reduced FMRP is the hyperacti­vation the extracellular-signal-regulated kinase (ERK) sign­aling pathways as well as the mammalian target of rapamycin complex 1 (mTORC1).

Epidemiology

Fragile X syndrome occurs in about 1 in 4000 males and 1 in 8000 females. The exact frequency is, however, unknown. Female carrier status is estimated to be as high as 1 in 130 to 250 population, and the incidence of male carriers is about 1 in 250 to 800 population. Life expectancy is lower than in the general population.

History and Physical

At birth, FXS neonates often exhibit no clinical signs of FXS with most parameters (e.g., head circumference, weight, and height) in the normal range. In early childhood FXS, physical and developmental features become more apparent, including developmental delays, psychomotor delays, intellectual disabilities, and a long face with prominent ears and flat feet[6]. Pubertal macroorchidism development in males is a hallmark of male FXS. Frequent bouts of otitis media and sinusitis are often present. Otitis media can cause conductive hearing problems, further contributing to developmental delays. Poor expressive language skills are common. An estimated 30% to 60% of individuals with FXS have autism. Males with a full mutation will display a complete penetrance and will likely display symptoms of FXS, while females with a full mutation display a penetrance of about 50% with symptoms ranging from mild to severe.

Signs include:

• Long face with long palpebral fissures as well as a broad philtrum
• Prominent forehead and protruding ears with soft cartilage
• High-arched palate and dental crowding
• Hyperextensible finger joints and thumbs
• Postpubertal macroorchidism
• Hypotonia
• Biting, hand flapping, poor eye contact, language disorders from cluttered speech to complete lack of speech depending on phenotype severity
• Mild to profound intellectual disability
• Some have a Prader–Willi syndrome (PWS) phenotype with obesity, hyperphagia, and hypogonadism, but lack the characteristic hypotonia and feeding problems in infancy.

Evaluation

Fragile X testing should be a consideration in the differential diagnosis of any individual with a family history of FXS, intellectual disabilities, impaired development, or autism of unknown etiology.  Molecular genetics, rather than cytogenetics, are now used to diagnose FXS. The number of CGG repeats is measurable using the polymerase chain reaction (PCR) and methylation status by Southern blot analysis. Measuring the number of CGG repeats on the X chromosome permits accurate FXS risk assessment and also provides information relevant to FXS families concerning reproductive options. It is worth noting that testing only for CGG repeat numbers will not detect the less than 1% of FXS caused by FMR1 missense mutations or deletions. Both sequencing of the FMR1 gene and direct measurement of the FMRP protein level would be useful for detecting potential “nonCGG repeat” causes of FXS.[4]

Prenatal testing for FXS can be accomplished by PCR using DNA from chorionic villi or amniocytes. Prenatal detection of FXS can promote early intervention and help with family planning decisions. Due to its complex mode of inheritance and long-term health implications, genetic counseling is especially important.

Individuals with FXS require evaluation by a geneticist and a specialist in neurodevelopment such as a neurodevelopmental pediatrician. Specialists in occupational therapy, speech therapy, and behavioral therapy may also be appropriate to target specific developmental differences. Psychiatry evaluation may be helpful if there are symptoms of mood disorders, self-injurious behavior, depression, or specific phobias, all of which have been reported in higher frequency in FXS.

Treatment / Management

There no cure for FXS.[7] Management includes speech therapy, behavioral therapy, sensory integration, occupational therapy, and special education. Early intervention is particularly important. Individuals with FXS in their family should consider genetic counseling to assess the likelihood of having a child that is affected.

Medications used for symptom-based treatment aim to minimize some of the behavioral and mental health challenges associated with FXS. Stimulants may target hyperactivity, impulsivity, and attention issues. Antidepressants may treat anxiety, obsessive-compulsive behaviors, and mood disorders, and antipsychotics are an option if self-injurious or aggressive behaviors are present. Anticonvulsants help to control seizures. Drugs targeting the mGluR5 (metabotropic glutamate receptors) linked with synaptic plasticity have demonstrated to be particularly beneficial. Adverse effects specific to the FXS population may occur with most of the agents listed above. Therefore, medication management is best done by practitioners with familiarity both with the particular drug and the FXS population.

Understanding the molecular mechanisms for FXS could provide valuable insights into potential therapies. As mentioned above, FXS is associated with increased activation of the ERK and mTORC1 pathways, which are both inhibited by metformin, a drug widely used to treat type 2 diabetes. Promising behavioral and biochemical results in an FXS animal model (FMR1 knockout mice) suggest that metformin could be a potential therapy of FXS, and a follow-up clinical trial is being planned.[8][9]

Differential Diagnosis

Differential diagnoses to be considered in cases of suspected fragile X syndrome include[10]:

• Sotos syndrome
• Prader-Willi syndrome
• Klinefelter syndrome

Enhancing Healthcare Team Outcomes

Clinicians (including specialists), nurses, and pharmacists should be aware of fragile X and work in a coordinated team to manage the therapy of these patients and monitor for complications.