Continuing Education Activity

Fragile X syndrome (FXS), or 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. 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, narrow face with a prominent jaw and forehead, hyperflexible fingers, and large ears. After puberty, enlarged testicles may be present in males.

This comprehensive review for healthcare professionals delves into the critical aspects of Fragile X syndrome (FXS), offering insights into its clinical presentation, diagnosis, and management. FXS, a leading cause of intellectual disability and autism spectrum disorder, often goes undiagnosed due to its diverse phenotypes and clinical overlap with other syndromes. The course emphasizes the importance of considering FXS in the differential diagnosis of intellectual disabilities and developmental impairments. Furthermore, it underscores the value of early diagnosis and intervention in enhancing patient outcomes and quality of life. The interprofessional healthcare team's role in managing patients with FXS is also highlighted, emphasizing a collaborative approach to improve patient care.

Objectives:

• Screen individuals for fragile X syndrome, especially those with intellectual disabilities, autism of unknown etiology, or ataxia and tremors in individuals older than 50 years.

• Differentiate fragile X syndrome from other intellectual and developmental disorders by recognizing specific physical features and considering fragile X syndrome as a potential diagnosis.

• Implement molecular genetic testing for FXS, utilizing polymerase chain reaction for CGG repeat measurement and Southern blot analysis for methylation status.

• Coordinate the various interprofessional team members and explain how their roles contribute to advancing the evaluation and treatment of fragile X syndrome and improving outcomes.

Introduction

Fragile X syndrome (FXS), also known as Martin-Bell syndrome in the past, 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.[1][2] 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, narrow face with a prominent jaw and forehead, hyperflexible fingers, and large ears. After puberty, enlarged testicles may be present in males.[3][4] About a third of these children have features of autism and delayed speech that are present from an early age. Hyperactivity and seizures are common.[5][3]

FXS testing should be a consideration in the differential diagnosis of any individual with intellectual disabilities, impaired development, or autism of unknown etiology.[6] In addition, all individuals older than 50 years with ataxia and tremors or females with premature ovarian insufficiency should be tested for this premutation.[4][7] Molecular genetic tests, rather than cytogenetics, are now used to diagnose FXS. The number of cytosine-guanine-guanine (CGG) repeats is measurable using polymerase chain reaction (PCR); methylation status is detected by Southern blot analysis. There is no cure for the disease, but early diagnosis and intervention can improve patients' and families' prognosis and quality of life and aid them in their future reproductive decisions.[4][7]

Unfortunately, clinicians frequently do not diagnose this condition due to several factors, including similar clinical features as other syndromes, various presenting phenotypes, and frequent absence of clinical features at birth. Therefore, FXS is underdiagnosed, leading to suboptimal management and patient outcomes.[8] This activity for healthcare professionals aims to enhance learners' competence in identifying the indications for diagnostic testing, selecting appropriate diagnostic tests, managing and counseling patients diagnosed with FXS, and fostering effective interprofessional teamwork to improve outcomes.

Etiology

FXS is an X-linked dominant condition with variable expressivity and reduced penetrance.[9] One reason is the differing number of CGG repeats in the FMR1 gene in affected individuals. Those without the disorder have 5 to 44 CGG repeats. However, individuals with abnormal alleles are classified according to their expanded number of CGG repetitions. Individuals with intermediate expansion have 45 to 54 CGG repeats, individuals with premutation expansion have 55 to 200 repeats, and those with a full mutation have >200 repeats.[7]

Furthermore, 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 phenotypic presentation than males, secondary to the protection provided by an additional unaffected X chromosome.[10][7] Consequently, patients with this condition can vary widely in their presentations.[5]

Epidemiology

FXS with a full mutation allele occurs in approximately 1 in 7000 males and 1 in 11,000 females; however, the exact frequency is unknown.[11] Female carrier status is estimated to be as high as 1 in 130 to 250 individuals, and the incidence of male carriers is about 1 in 250 to 800 individuals. However, it is essential to note that the carrier frequency can vary greatly based on the diagnostic testing used and the population of interest, with specific populations showing significantly higher or lower disease prevalence.[12][13][14] For instance, the prevalence in Columbian males is reported to be 1 in 20, which is 343 times higher than the rest of the world.[15]

Pathophysiology

FXS is indirectly the result of the expansion of the CGG triplet repeat within the fragile X mental retardation 1 gene (FMR1) located on the X chromosome, which silences FMR1 expression.[16] This CGG expansion is due to abolished or greatly diminished fragile X mental retardation protein (FMRP) and is the direct cause of FXS.[17][18] Point mutations or deletions may also be a cause of reduced functional FMRP.[18] FMRP is a master regulator that directs protein translation, impacting neuronal connections, synaptic plasticity, and ovarian functions.[19] Consequently, without FMRP, there is increased neuronal excitation and diminished gamma-aminobutyric acid activity, resulting in many FXS symptoms (eg, seizures and intellectual disability).[18]

The expanded CGG triplets in the 5' untranslated region of FMR1 are hypermethylated, resulting in a decreased FMRP. Therefore, the methylation status of CGG triplets is a key factor for categorizing FXS, meaning the greater the degree of methylation, the greater the FMRP deficit. The FMRP is expressed throughout the body, with increased concentrations in the brain and testes.[18][20] Therefore, numerous effects on brain structures may result, including decreased cerebellar size and volumes, cerebellar vermis hypoplasia, and caudate enlargement. Decreased activity in other brain areas also can occur.[5]

History and Physical

Newborns with FXS typically don't show initial clinical signs, with measurements like head circumference, weight, and height falling within the normal range. Physical and developmental symptoms usually become evident during early childhood.[3][21] Consequently, FXS diagnosis historically occurs only when symptoms arise, causing substantial delays in diagnosis at an average age of 32 months. This delay often leads families to have more children without knowing the high risk of having other children with the same syndrome.[22][4]

Clinical History

Upon presentation, a comprehensive history should be obtained, including past medical, birth, and family histories. The family history should contain a pedigree analysis of ≥3 generations and should particularly inquire about developmental delays, intellectual disabilities, premature ovarian failure, and fragile X-associated tremor/ataxia syndrome (FXTAS).[23][24] Intellectual disability is the primary clinical feature of FXS. Other common presenting symptoms include:

• Autistic behaviors (eg, hand flapping, performing repetitive tasks)
• Seizures
• Developmental delay
• Anxiety and depression
• Attention-deficit/hyperactivity disorder (ADHD) symptoms
• Sleep disturbance
• Aggression
• Poor eye contact[25]

Frequent otitis media and sinusitis infections are also common, resulting in conductive hearing problems, further contributing to developmental delays. Delays can occur in receptive and expressive language skills but are more significantly delayed in expressive language skills.[26] An estimated 90% of males and 17% of females with the FXS full mutation have autism.[27] Males with a full mutation will display a complete penetrance and are more likely to exhibit symptoms of FXS; 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.[4] ADHD is present in approximately 80% of affected individuals, along with obsessive-compulsive behaviors, increased emotional lability, and aggressive behaviors.[4]

Clinical Features

Following the collection of clinical history, clinicians should perform a thorough physical and neurological examination, particularly those presenting with intellectual disabilities.[3][21] Several characteristic FXS features may be found upon patient examination. For instance, an elongated, narrow face, broad forehead and philtrum, high-arched palate, and protruding ears are classic signs in a patient with FXS; pubertal macroorchidism is a specific hallmark of male FXS.[21][25] Prader–Willi phenotype is frequently observed, with patients having the same obesity, hyperphagia, and delayed puberty seen with the syndrome, though not caused by the same chromosomal deletion.[21] Other clinical features include:

• Dental crowding
• Strabismus
• Pes planus
• Inguinal hernia
• Hyperextensible finger joints and thumbs
• Hypotonia
• Moderate to profound cognitive impairment
• Chronic otitis media[25]

Individuals who are premutation carriers (ie, 55-200 CGG repeats) frequently have less severe cognitive deficits and are underdiagnosed; however, they have a high risk for developing FXTAS, presenting in the sixth decade of life with tremors, ataxia, and neuropsychiatric conditions. Males with premutation have a higher likelihood of developmental delays and seizures, while females who are premutation carriers commonly have associated primary ovarian insufficiency.[28][18][29] 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.[4] 

Individuals with FXS require evaluation by a geneticist and a specialist in neurodevelopment, such as a neurodevelopmental pediatrician. In many cases, a formal diagnosis of autism, ADHD, and other conditions associated with FXS often results in more timely access to services; thus, evaluating the patient for these associated conditions should be a priority.[30]

Evaluation

Diagnostic Studies

FXS may be clinically suspected after characteristic symptoms become apparent. However, clinicians should consider FXS in the differential diagnosis of any individual with intellectual disabilities, impaired development, or autism of unknown etiology. Diagnostic studies are indicated to obtain confirmation of FXS.[6] Additionally, all individuals older than 50 years with ataxia and tremors or females with premature ovarian insufficiency should be tested for the premutation.[4]

Molecular genetics, rather than cytogenetics, are now used to diagnose FXS. Initial PCR testing is recommended, which measures the number of CGG repeats. Southern blot may then be performed to confirm the diagnosis by analyzing the methylation status.[15] 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. Clinicians should know that limiting testing to only CGG repeat numbers will miss less than 1% of FXS caused by FMR1 missense mutations or microdeletions. Therefore, if PCR and Southern blot testing do not confirm suspected FXS, more comprehensive sequencing for the FMR1 gene (eg, whole genome sequencing) and directly measuring the FMRP level assist in capturing potential FXS due to etiologies other than expanding CGG repeats.[17][7][15]

In patients with intellectual disabilities with an unknown cause, other diagnostic studies should be considered to exclude differential diagnoses, including chromosomal microarray and metabolic testing (eg, serum total homocysteine, urine organic acids, glycosaminoglycans, oligosaccharides, purines, and pyrimidines.[23] Further evaluation with a brain MRI is recommended in children with an abnormal physical examination (eg, microcephaly and macrocephaly) or neurologic examination (eg, focal motor findings, extrapyramidal signs, or focal seizures).[23]

Diagnostic Studies for Associated Conditions

As patients grow older, secondary conditions develop and become more apparent. As a result, additional diagnostic studies to assess for these FXS-associated conditions are frequently indicated, including electroencephalograms to evaluate possible seizure activity, sleep studies to assess obstructive sleep apnea symptoms, or imaging studies to diagnose urinary tract abnormalities (eg, vesicoureteral reflux or ureteral dilation).[4]

Prenatal Testing

Testing for premutation or full mutation carriers with an FMR1 DNA test allows for genetic counseling and family planning. Clinicians should offer prenatal testing for FXS to men and women with a previous child or family history of FXS.[4] Parents with a personal or family history of or a child with an intellectual disability of unknown etiology should also be offered prenatal testing.[4] Some societies also recommend clinicians offer women with premature ovarian failure testing. This evaluation is vital for future pregnancies and possible sequelae. 

Prenatal testing for FXS can be accomplished by PCR using parental DNA or fetal DNA obtained through chorionic villous sampling or amniocentesis. 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 critical.[4][15]

Treatment / Management

Supportive Therapies

There is no cure for FXS; therefore, management primarily involves symptomatic treatment, including speech therapy, behavioral therapy, sensory integration, occupational therapy, and special education.[15][3] Early interventions for most FXS-associated conditions are crucial for better outcomes. For instance, nutritional counseling to mitigate the risk of obesity in patients with FXS is recommended. Psychiatric counseling can be beneficial if someone exhibits mood disorders, self-injurious behavior, depression, or specific phobias, as these issues tend to occur more frequently in individuals with FXS.[4]

Furthermore, it is essential to help and support caregivers, as they bear a significant personal and economic burden. A substantial 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.[31] Furthermore, providing occupational therapy and tailored training for individuals affected by the condition can help them achieve greater independence, improve their self-care skills, and receive vocational training.[15] 

Pharmacologic Therapies

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 (eg, bupropion, buspirone, or selective serotonin and norepinephrine reuptake inhibitors) may treat anxiety, obsessive-compulsive behaviors, and mood disorders. However, these antidepressants are more often used in adult patients than children. Atypical antipsychotics (eg, aripiprazole and risperidone) are frequently used if self-injurious or aggressive behaviors occur.[15] Anticonvulsants help to control seizures. Drugs targeting the 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 abovementioned agents. Therefore, medication management is best done by the practitioner's familiarity with the drug and the FXS population.[15]

Understanding the molecular mechanisms for FXS could provide valuable insights into potential therapies. FXS is associated with increased activation of the ERK and mTORC1 pathways, both inhibited by metformin, a drug widely used to treat type 2 diabetes. Promising behavioral and biochemical results in an FXS animal model (ie, Fmr1 knockout mice) suggest that metformin could be a potential therapy for FXS, and a follow-up clinical trial is planned.[32][33] Transdermal cannabidiol has been shown in recent studies to reduce hyperactivity, social avoidance, and general anxiety in children, though further research is still needed.[15] Clinicians may also consider thyroid replacement in patients with hypothyroidism or beta-blockers to treat tremors.[19]

Reproductive Considerations

Individuals with FXS in their families should consider genetic counseling to assess the likelihood of having a child who is affected. Prenatal detection of FXS can promote early intervention and help with family planning decisions. Due to its complex mode of inheritance, long-term health implications, and significant caregiver responsibilities, genetic counseling is critical. Males of reproductive age with full mutations are infertile; male premutation carriers typically have normal fertility. However, females who have full mutations are fertile, and female premutation carriers often have impaired fertility due to premature ovarian insufficiency, which frequently occurs.[4][15]

Differential Diagnosis

Differential diagnoses to be considered in cases of suspected FXS include:[34]

• Sotos syndrome
• Prader-Willi syndrome
• Klinefelter syndrome
• Rett syndrome
• Trisomy 21
• Metabolic disorder
• Autism

Prognosis

Early interventions, such as medications and supportive therapies, improve the quality of life for patients diagnosed with FXS.[15] Most parents report that the quality of life in FXS is good, with lower scores observed in those with reduced cognitive functioning.[35] The prognosis depends on the extent and severity of associated conditions, ranging from mild to severe. Autism, in particular, can challenge a patient's long-term quality of life and independence. Typically, the life expectancy of individuals with FXS is similar to that of the general population. However, it's worth noting that individuals with intellectual disabilities have a higher mortality rate than the general population.[15][36]

Complications

Individuals with FXS may experience a range of associated conditions, including strabismus and refractive errors in their vision and inguinal hernias, and they often present with moderate to profound intellectual disabilities. Chronic otitis media and seizures are also frequently observed in individuals with this condition. These comorbidities require close monitoring and appropriate medical attention to provide comprehensive care for those affected by FXS.

Consultations

Individuals with FXS should undergo a comprehensive evaluation, typically conducted by a geneticist and a neurodevelopmental specialist, such as a neurodevelopmental pediatrician. Access to occupational, speech, and behavioral therapy specialists is crucial to address specific developmental abnormalities, and early intervention is essential for a more favorable outcome. It's also important to consider psychiatric evaluation if symptoms are related to mood disorders, self-injurious behavior, depression, or specific phobias, as these are more frequently reported in individuals with FXS.[4]

Other consultations that may be needed include assessments by pediatric neurologists for seizure evaluation, pediatric ophthalmologists for issues related to strabismus, nystagmus, ptosis, and refractive errors, pediatric orthopedic surgeons for concerns stemming from connective tissue dysplasia, pediatric surgeons for the evaluation of inguinal hernias, as well as audiology and pediatric otolaryngology for cases of chronic otitis media. Genetic counseling is also a valuable component of the overall care for individuals with FXS.

Deterrence and Patient Education

Numerous pediatric experts support the idea of universal newborn screening for FXS; however, its actual implementation faces obstacles, including cost considerations, the lack of long-term follow-up, and limited treatment options.[3] In managing FXS, educating parents or caregivers is of paramount importance. They need to understand the progression of the disease and its potential complications. Furthermore, parents should be informed about the risks FXS poses to future children and guidance on genetic testing to aid informed decision-making. It is also essential to inform patients about their risk of experiencing premature ovarian failure or developing FXS-associated tremor/ataxia syndrome.

Enhancing Healthcare Team Outcomes

Optimal diagnosis and management of FXS requires the coordinated efforts of several different clinicians. Individuals with FXS require evaluation by a geneticist and a specialist in neurodevelopment, such as a neurodevelopmental pediatrician. Occupational, speech, and behavioral therapy specialists are all essential to address specific developmental abnormalities. Additionally, 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. Early access and follow-up with these specialists are crucial for better outcomes. There is no cure for FXS currently. Therefore, management primarily involves symptomatic treatment and coordination of care with various clinicians, nurses, and other health professionals, including pharmacists, lab technicians, and counselors, to help mitigate the risk of any FXS-associated conditions.