Continuing Education Activity

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). It accounts for about one-half of cases of X-linked intellectual disability 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. This activity reviews the cause, pathophysiology, and presentation of Fragile X syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Review the etiology of fragile X syndrome.
• Describe the history and physical exam findings when evaluating a patient with fragile X syndrome.
• Summarize the management options for patients with fragile X syndrome.
• Explain possible interprofessional team strategies for improving care coordination and communication to advance the evaluation and treatment of fragile X syndrome and improve outcomes.

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] Physical features include a long and narrow face with a prominent jaw, flexible fingers, large ears, and enlarged testicles in males.[3] These features usually become more apparent in older children.[3] 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.[4] There is no cure for the disease, but early diagnosis and intervention can improve the prognosis and quality of life for patients and families and aid them in future pregnancies.[3]

Etiology

Fragile X syndrome is 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 due to variability in X-inactivation.[6] Diagnosis is by molecular genetic testing, determining the number of CGG repeats in the FMR1 gene.[6] In those without the disorder, it is between five and 40 repeats. Individuals with 55 to 200 CGG repeats are considered to have a reputation, and their presentation can vary widely.[4] Individuals with greater than 200 CGG repeats have a full mutation (FM) for FXS.[4]

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, and the incidence of male carriers is about 1 in 250 to 800. However, it is essential to note that the carrier frequency can vary greatly based on the population of interest, with specific areas showing significantly higher[7][8], or lower[9] prevalence of the disease.

Pathophysiology

FXS is indirectly the result of the expansion of the cytosine-guanine-guanine (CGG) triplet repeat within the Fragile X mental retardation one gene (FMR1) located on the X chromosome.[10] This CGG expansion silences FMR1 expression resulting in an abolished or greatly diminished expression of the fragile X mental retardation protein (FMRP).[11] FMRP is a "master regulator"[12] and is necessary to develop neuronal connections (synapses) and some ovarian functions, and the lack of FMRP is the direct cause of FXS. Without FMRP, there is increased excitation of the neurons and diminished activity of GABA, which helps explain many symptoms of FXS, including seizures.

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. The expanded CGG triplets in the 5’-untranslated region of FMR1 are hypermethylated, resulting in a decreased expression of FMRP. Therefore, the methylation status of CGG triplets is a key factor for categorizing FXS; in other words, the greater the degree of methylation, the greater the deficit of FMRP. FMRP protein is expressed throughout the body, with specifically increased concentrations in the brain and the testes.[13][14] Numerous structures in the brain are affected, including decreased cerebellar size and volumes, cerebellar vermis hypoplasia, enlargement of the caudate, and lower activity in other brain areas.[4]

History and Physical

At birth, neonates with FXS 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.[15] There is often a significant delay in diagnosis given that the clinical signs often do not become obvious until later on in childhood[16], with the mean age of diagnosis being 32 months of life.[3] This delay means that families often have further pregnancies and children without being aware of the high likelihood of other children with the same syndrome.[17]

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. Delays occur in receptive and expressive language skills, with a more prominent delay in expressive language skills[18]. An estimated 30% to 60% of individuals with FXS have autism. Males with a full mutation will display a complete penetrance and likely display symptoms of FXS, while females with a full mutation display a penetrance of about 50% with symptoms ranging from mild to severe. The degree of intellectual disability in males with the full mutation is often moderate to severe, with an average IQ of 40.[3]  Attention-deficit/hyperactivity disorder (ADHD) is present in a significant majority (80%) of affected individuals, along with obsessive-compulsive behaviors, increased emotional lability, and aggressive behaviors.[3]

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
• Strabismus, refractive errors
• Pes planus
• Inguinal hernia
• 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
• Moderate 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.
• Chronic Otitis media
• Seizures

Premutation 

Many with premutation (55-200 CGG repeats) are undiagnosed, but studies have shown that males with premutation have a higher likelihood of developmental delays, seizures, and other related problems.[19] Those with the premutation are also at risk of developing Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) which presents with tremors and ataxia in the sixth decade of life[20]. Women with premutation are at risk for developing primary ovarian insufficiency.[21] In addition, the greater the number of CGG repeats in a female with the premutation, the greater the chance of expansion of a full mutation in the male offspring.[3]

Evaluation

Fragile X testing should be a consideration in the differential diagnosis of any individual with intellectual disabilities, impaired development, or autism of unknown etiology.[22] In addition, all individuals over 50 who have ataxia and tremor, or females with premature ovarian insufficiency should also be tested for the premutation.[3] 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 provides information relevant to FXS families concerning reproductive options. It is worth noting that testing only for CGG repeat numbers will not detect 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.[11]

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 are essential to target specific developmental differences. Early access to these specialists is essential for a better outcome. 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.21518720[3]

Mothers of a patient who has been diagnosed with FXS should also be evaluated since in the vast majority of cases, the mother is the carrier of the full mutation or the premutation.[3] This evaluation is important for future pregnancies, as well as for the mother's future health due to the sequelae of the premutation (as described above).

Treatment / Management

There is no cure for FXS.[23] Management includes speech therapy, behavioral therapy, sensory integration, occupational therapy, and special education. Early intervention is particularly important. Individuals with FXS in their families should consider genetic counseling to assess the likelihood of having a child that is affected. In many cases, a formal diagnosis of autism, ADHD, and other conditions that are associated with FXS often results in more timely access to services[24], and thus evaluating the patient for these associated conditions should be a priority.

Medications used for symptom-based treatment aim to minimize some 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 been 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 familiarity with both the particular drug and the FXS population.

Furthermore, it is essential to provide help and support to caregivers, as they bear a significant personal and economic burden. A significant portion of caregivers suffered injuries, required increased hours off from work, needed additional paid help around the house, and suffered from depression, stress and anxiety.[25]

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 for FXS, and a follow-up clinical trial is planned.[26][27]

Differential Diagnosis

Differential diagnoses to be considered in cases of suspected fragile X syndrome include:[28]

• Sotos syndrome
• Prader-Willi syndrome
• Klinefelter syndrome
• Rett Syndrome
• Trisomy 21

Prognosis

Most parents report that the quality of life in Fragile X Syndrome is good, with the lowest quality of life scores in cognitive functioning.[29] The prognosis depends on the extent and severity of comorbid conditions, ranging from mild to severe.  The presence of autism, in particular, presents a challenge long term quality of life and the ability to function independently.[30] It is important to note that while there is very little data for Fragile X Syndrome in particular, it is known that patients with intellectual disabilities have a higher mortality rate than the general population. 

Consultations

• Developmental-Pediatrics for evaluation of autism spectrum disorder
• Pediatric neurology in case of seizures
• Pediatric psychiatry for evaluation of mood disorders, ADHD, OCD
• Pediatric ophthalmology for evaluation of strabismus, nystagmus, ptosis, and refractive errors
• Pediatric orthopedic surgery for issues resulting from connective tissue dysplasia
• Pediatric surgery in case of inguinal hernias
• Audiology and pediatric otolaryngology in case of chronic otitis media
• Speech therapy
• Physical therapy
• Occupational therapy
• Genetic counseling

Enhancing Healthcare Team Outcomes

Clinicians (including specialists), nurses, and pharmacists should be aware of fragile X and work in a coordinated interprofessional team to manage the therapy of these patients and monitor for complications. This will improve clinical outcomes and family satisfaction. [Level 5]