What Is Fragile X?
Fragile X syndrome is also known as marker or Martin-Bell syndrome. It is a common cause of intellectual disability, mental retardation, and autism. It is named after Martin and Bell who investigated a family who had mental retardation in multiple male members in 1943. They were able to find the association of the cognitive disorders and unidentified mode of X-linked inheritance. This means that it is inherited in an X-linked dominant pattern.
In 1969, it was discovered that there is excessive genetic material on the X chromosome for males who are affected and for female carriers. Since then, gene mapping for this condition has been improving and the precise defect has been characterized. Due to the improvements and advances in molecular genetics, there is now reliable testing for the condition.
1. Statistics
In the United States, it has been estimated (conservatively) that fragile X syndrome affects about 1 in every 2,500 to 4,000 males and 1 in every 7,000 to 8,000 females. The female carrier status has been estimated to be as high as 1 in every 130 to 250 women while male carriers are estimated to be 1 in every 250 to 800 men. It is also estimated that fragile X syndrome affects as many as 10% of cases of undiagnosed mental retardation in males and 3% of undiagnosed mental retardation in females. While the exact frequency is unknown internationally, data collected from both Australia and England were found to be comparable to data from the United States.
2. Physical Appearance
Patients with fragile X syndrome tend to have a characteristic physical appearance where they have large protruding ears, a high arched palate, overcrowding of teeth, a long face, flat feet, soft skin, hyperextensible finger joints, clubfeet, single palmar crease, scoliosis, caved in or sunken chest (pectus excavatum), hypotonia (low muscle tone), hyperextensible thumbs, and postpubescent macroorchidism (having large testicles after puberty).
During childhood, there is also an early growth spurt but their adult height is often average. Patients also tend to be obese during their adolescent and early adulthood years. Strabismus is common while ptosis and nystagmus are occasionally present.
3. Intellectual Development
Those with fragile X syndrome may have an intelligence quotient (IQ) that ranges from normal to severe. In male patients with fragile X syndrome, the average IQ is estimated to be about 40 (if there is complete silencing of the FMR1 gene). Females are generally less affected and have an IQ that is borderline or normal but may experience learning difficulties.
The main challenges fragile X syndrome patients face are their visual spatial relationships, short-term memory, working memory, executive function, visual memory, verbal abilities, and mathematics. There is also some evidence that the IQ decreases with time in most cases. This is believed to be due to slowed intellectual development. In cases where the patient has both fragile X syndrome and autism, there is often a lower IQ and greater language deficit.
4. Social Interaction
In fragile X syndrome, patients often have social anxiety characterized by difficulty forming relationships with their peers, taking a prolonged time to initiate social interaction, gaze aversion, poor eye contact, and more. Social anxiety is present in up to 75% of male patients.
Affected individuals may also experience panic attacks in certain circumstances. In fragile X syndrome, it is believed that social anxiety may be attributed to their reduced ability to recognize a face. Those interested in interacting often have more empathy but may display withdrawal and anxiety when they are with unfamiliar people or places. Social anxiety in these patients can range from shyness to severe withdrawal (often due to coexisting fragile X syndrome and autism spectrum disorders).
5. Autism
In many patients, fragile X syndrome often coexists with autism. It has led to the screening for the FMR1 mutation whenever a child is diagnosed with autism. Among patients with fragile X syndrome, it is estimated that about 15% to 60% of these patients have concurrent autism spectrum disorder.
While fragile X syndrome patients often have difficulty forming a relationship with their peers, those with concurrent autism often have difficulties having a conversation even with those they are comfortable with. The best predictors of autism spectrum disorder among fragile X syndrome patients are avoidance and indifference. With both autism and fragile X present, there is often a lower IQ and greater language deficit. Animal models of fragile X were also observed to have autistic-like behaviors.
6. Neurology and Visual
Fragile X patients have a higher risk of seizures with rates ranging from 13% to 18%. Seizures in these patients tend to be partial, not frequent, and respond well to anti-seizure medications. Some patients with fragile X syndrome may also carry premutation alleles that put them at risk for the development of fragile X associated tremor/ataxia syndrome (FXTAS), which is a neurodegenerative disease.
This is usually seen in more than 50% of male carriers over the age of 70 years old. The tremor generally begins in the sixth decade of life with progression to coordination loss and cognitive decline. Fragile X patients may also have strabismus. Early recognition of this issue is important as management helps prevent amblyopia (lazy eye), which can have a great impact in the quality of life.
7. Mental Health
The majority of male patients and 30% of female patients with fragile X syndrome are estimated to have attention deficit hyperactivity disorder (ADHD). This means that these children are hyperactive, have short attention spans, and have difficulty dealing with large crowds and loud noises.
However, the disruptive behavior and hyperactivity usually decline with age. The inattentive symptoms will persist lifelong. These patients also tend to not only repeat the same phrase but will continuously talk about the same subject. Self-talking (talking to oneself with different pitches and tones) are also often observed. A minority will meet the criteria for obsessive compulsive disorder.
8. Memory and Fertility
In fragile X syndrome, male patients beginning at the age of 40 will progressively develop issues with their working memory, which involves the temporary storage while processing other information. In terms of fertility, approximately 20% of women who are fragile X premutation carriers are affected by fragile X-related primary ovarian insufficiency (FXPOI), which can be defined as having menopause before the age of 40.
This is generally seen in females who are premutation carriers instead of the full mutation. Although they may develop menopause-like symptoms, these individuals can potentially get pregnant as their ovaries may still occasionally release eggs that are viable. FXPOI is one of the issues caused by changes in the FMR1 gene.
9. Diagnosis
Patient history and examination can provide many clues to the possibility of fragile X syndrome. Imaging should be performed for patients with fragile X syndrome to evaluate if there is any scoliosis while echocardiography can be used to exclude any issues of the heart. Both karyotyping and DNA testing in combination are recommended for those suspected of fragile X syndrome.
Although a DNA test is sufficient, karyotyping can be used to help reveal other chromosomal anomalies. A polymerase chain reaction (PCR) and Southern blot test are 2 methods of genetic analysis that can be used to detect the FMR1 gene. Developmental evaluation by a physical, occupational, and speech and language therapist is also recommended to identify where the patient may need help. Ophthalmology and auditory examinations are also recommended.
10. Treatment and Management
Although there is no cure for fragile X syndrome, the main treatment and management goals are to improve quality of life and prevent potential complications. It generally includes behavioral therapy, speech therapy, special education, sensory integration occupational therapy, genetic counseling, and treatment of physical abnormalities.
Medications are for symptom-based treatments such as for ADHD, anxiety, depression, obsessive compulsive behaviors, mood disorders, and more. Medications used include antidepressants, antipsychotics, anticonvulsants, lithium, and metformin. Patient and family education is also crucial as a supportive home environment along with the cooperation of parents and siblings can greatly improve the outcome of the patient.
