Fragile X syndrome (FXS) is a sex-linked disorder, and one of the most common genetic diseases in humans. Patients may experience mild learning disabilities and hyperactivity or severe mental impairment and autism.1 Studies show that FXS affects one in 4,000 females and one in 2,000 males of all ethnic groups and races.2 Thus, males are more frequently affected than females. In male infants, an estimated one in 1,000 live births has the FXS full mutation; for female births, the rate is one in 2,500.2 One in 259 women are carriers and can pass FXS to their children, whereas one in 800 men are thought to be carriers (transmitting males). The catch is that individuals with no signs of the condition can pass on the syndrome in a family. Also, some children with fragile X syndrome appear normal in infancy but develop typical physical and behavioral characteristics of the condition later in life. Approximately 80% to 90% of people with fragile X syndrome are not yet diagnosed.2
The cause of fragile X syndrome is not yet completely understood. However, in May of 1991 the gene responsible for the condition was identified. Called fragile X mental retardation 1 (FMR-1), this gene targets normal brain development. Interestingly, the FMR-1 gene can change in size as it is passed from generation to generation. Through the generations, the FMR-1 gene can increase in length as it is inherited, thus posing a greater risk of problems for the offspring of a person with FXS. This occurs in a small region of the gene, CGG, which undergoes repeated duplication. The outcome is DNA repeats that result in a longer gene. For patients affected with FXS, a defect in the FMR-1 gene causes it to shut down instead of producing the specific protein it encodes for--FMRP. This series of events is known as a full mutation. Patients who have no symptoms are known as carriers. In the case of carriers, a small defect known as a premutation occurs to the gene. Research has shown that people are usually carriers when they possess between 50 and 200 DNA repeats; individuals are fully affected when they possess over 200 DNA repeats.3, 4, 5
Mechanism of Inheritance: As a sex-linked disorder, fragile X syndrome has a pattern of inheritance (FIGURE 1) that lies within the sex chromosomes of an affected individual (specifically, on the X chromosome). The FMR-1 gene is located on the X chromosome. In the human body, females have two X chromosomes and males have one X and one Y chromosome. The number of X chromosomes determine whether a person is a female or a male. Females affected with FXS develop fewer--if any--characteristics of the disorder, since one of their X chromosomes has a normal, functioning gene. This tends to compensate for the other, nonfunctioning gene on their second X chromosome. The difference for males is that if their single X chromosome contains the nonfunctioning X chromosome-linked gene, they will be affected by FXS. The inheritance mechanisms of sex-linked syndromes allow for either parent, who may or may not experience symptoms, to pass the syndrome to their offspring.
All female carriers of fragile X are at risk of having children affected by FXS. There is a 50% chance that a female who is a carrier will pass the X chromosome with the fragile X mutation to each of her children. The major risk with a female carrier is when she has a son. A male offspring could inherit the mutated X chromosome, and in the majority of cases he will have FXS (possibility #3). When dealing with a father who is a carrier of the fragile X mutation (possibility #2), all of his daughters will be carriers, since he only gives his X chromosome to his daughters. On the other hand, sons of that carrier father are not at any risk for the fragile X mutation because they only receive the father's Y chromosome.
Fragile X Characteristics
Speech and language delays
Long, narrow face
Mitral valve prolapse
Short attention span
Shyness, social anxiety
Rapid, repetitive speech
Difficulty adjusting to change
Autistic-like features: hand-biting, -flapping
References 1, 7, 8, 9
Characteristics of Fragile X: Characteristics of fragile X syndrome can be divided into three categories: mental impairment, physical features and behavioral characteristics. However, not every case has a distinguishable characteristic from each category. Also, some cases do not appear to be associated with any characteristics (TABLE 1). A checklist of the major characteristics for fragile X has been developed to help diagnose children and adults with the disorder (TABLE 2). The checklist may be the first step for parents who are trying to solve the mystery as to why their child is experiencing cognitive and behavioral deficits. Studies have shown that 60% of males who had a score of 19 or higher and 45% of males with a score of 16 or higher had FXS.10
|Table 2 Fragile X Checklist
|Directions for the checklist are as follows: Give 2 points if the feature is present, 1 point if the feature was present in the past or is present to a borderline degree, and 0 points if the feature is absent. |
in the Past
|Short attention span
|Poor eye contact
|Sydney line or Simian creaseb,c
a. Perseverative speech is a continued repetition of words or phrases
b. Simian crease is a single horizontal crease on the palm instead of the usual two
c. Sydney line is a horizontal crease that goes from edge to edge across the palm
Source: Reference 10
More than 80% of male patients with fragile X develop at least one physical characteristic of FXS after puberty.1 Females on the other hand, do not develop most of the physical characteristics found in males, with the exception of large ears. Males and females also experience some differences with respect to mental impairment. For example, females perform well in reading and spelling but have difficulty with math. The majority of males with a full mutation, an estimated 70%, demonstrate some type of mental impairment (FIGURE 2). Approximately 30% of female patients with a full mutation develop some sort of mental impairment.3 Some male patients with FXS, however, achieve higher IQ scores than do other developmentally disabled children. Males process information in a simultaneous manner; therefore, learning skills that require sequential processing of information is difficult. Behavioral characteristics are slightly similar in both males and females. Some males experience attention-deficit hyperactivity disorders, speech disturbances, and autistic behaviors, and have poor eye contact. The same characteristics occur in females, but not at the same level of intensity, and in a smaller percentage of patients.
Before the early 90s, the only commercially available diagnostic test for FXS was a chromosomal test. Its cost was approximately $900 and it was not as accurate as the current diagnostic tests.2 The chromosomal test was not able to diagnose carrier individuals. In 1992 two DNA tests were developed that could detect both fully affected and carrier individuals. Southern blot analysis, which shows if the gene is a full mutation, was one test and the polymerase chain reaction (PCR), which can determine the actual size of the repeat section for premutation individuals, was the other test3 (FIGURE 3).
Both tests require a blood sample from the patient, which is then sent to the laboratory for analysis. DNA test results take several weeks compared to the chromosomal test, which takes a month to evaluate. The DNA tests are offered in many major medical centers in the U.S. for approximately $200 to $300.2
Prenatal Testing: Prenatal testing is available for any individual who chooses to be tested. Testing can be done as early as nine to 12 weeks in gestation. Kallinen et al reported that every 250th pregnant woman was a carrier of the fragile X mutation. In most cases the carrier female was unaware of the possibility of having an offspring who was fully affected with FXS.5 Three different testing methods are available on the market. The first is the chorionic villi sampling test, performed between the 9th and 11th week of pregnancy. The second is amniocentesis, performed between the 15th and 18th week. Last, the percutaneous umbilical blood sampling (PUBS) is performed between the 18th and 22nd week. The PUBS method is the most accurate but carries the greatest risk of miscarriage.7
Who Should Be Tested
Testing for FXS is recommended for those individuals who are suspected of having FXS. Testing should be done in the following groups:9
• Those of either sex with mental impairment, developmental delay, or autism.
• Those of either sex with ADHD and any characteristics of FXS.
• Those of either sex with a family member diagnosed with FXS.
• Those seeking reproductive counseling who have a family history of FXS or undiagnosed mental retardation.
• Mothers who know they are carriers of the fragile X mutation.
A list of laboratories that offer testing may be obtained by contacting the FXS foundation at (800) 688-8765.
Associated Medical Problems
Overall, children with FXS do not experience serious physical problems. However, they are more prone to certain medical problems in comparison to normal children. For example, an estimated 50% of these children often suffer from recurrent otitis media and require some sort of intervention either with antibiotics or polyethylene tube placement. Also, approximately 30%-50% of the children develop myopia and "lazy eye." In addition, orthopedic difficulties related to joint laxity and flat feet may occur. Various seizures are seen in 20% of males and 5% of females with the condition. Digestive disorders such as gastroesophageal reflux are also seen in individuals with FXS.4
Currently, there is no cure for fragile X syndrome, only the means to help relieve some of the symptoms and maximize the potential of each individual. Drug therapy has helped patients with anxiety, aggression, poor attention span and hyperactivity secondary to FXS. However, drug therapy is not the only treatment option. Speech, language, occupational and behavioral therapy as well as special education have been beneficial regarding the physical, cognitive and behavioral aspects of this syndrome. Since every individual with the fragile X mutation is affected differently, it is important to evaluate every case separately in order to establish an appropriate plan of management.
To begin, it is important that a team of professionals get involved with the treatment plan of a patient. Nonpharmacological treatment options include an occupational and physical therapist, a speech and language pathologist, a special education teacher and a genetic counselor. Various strategies that these specialists have developed in order to help children or adults with FXS include the following: 3, 7
• Minimizing exposure to noise and odors may prevent excess stimulation.
• Music therapy may be soothing and calming.
• Structured daily activities help the individual learn to participate.
• Allowing an occupational therapist to work with the patient helps improve his or her response to formal education.
• Use of any type of visual device like a message board, calculator or pictures is helpful to increase memory capability.
• Emotional support and expression of feelings are helpful because the patient usually has a hard time with words.
A psychologist is needed to evaluate the condition of the patient with FXS to determine the need for pharmacological therapy.
Medical intervention (TABLE 3) is typically used to help control the behavioral characteristics that arise in patients with fragile X mutation. The first class of drugs are the central nervous system stimulants, such as methylphenidate (Ritalin), pemoline (Cylert) and dextroamphet-amine (Dexedrine). These drugs are used to treat the hyperactivity and attention problems associated with FXS. Hagerman reported that 80% of males with the full mutation experience hyperactivity and attention deficit whereas only 35% of females experience this behavior.11 These agents tend to improve hyperactivity and concentration ability in approximately 60% to 70% of school-aged children.3 Hagerman reports that stimulants are less effective in preschool children and during adolescence.10 These drugs have side effects such as poor appetite, increased blood pressure and heart rate, irritability and insomnia. Starting stimulants at low doses can help prevent the increase in irritability. If the side effects are not tolerated, then clonidine (Catapres) an alpha-2 agonist, or amantadine (Symmetrel) a dopaminergic agent, can be used. Catapres is available as a patch, which is an advantage for patients with compliance issues. A possible disadvantage is that the patch needs to be changed every five to seven days to ensure continuous blood levels are achieved.3 The literature states that Catapres is beneficial in approximately 60%-80% of children with severe hyperactivity.11 Patients receiving clonidine should be monitored for sedation. They also should receive a baseline EKG since this medication may prolong cardiac conduction. Another advantage of the patch is that it causes less sedation than the tablet formulation, although a disadvantage is the potential to cause irritation to the skin.3, 9, 10, 11
|Table 3 Medication Overview
for Fragile X Syndrome
|This table lists various medications discussed in this article, as well as some additional agents used in the symptomatic treatment of patients with fragile X syndrome. |
||Commonly used psychostimulant NOTE: poor appetite and irritability |
||Commonly used psychostimulant NOTE: poor appetite and irritability|
||Long acting psychostimulant NOTE: poor appetite and irritability |
||SSRI used to treat a wide range of mood, anxiety impulse control disorders and attention problems NOTE: decrease weight and insomnia|
||SSRI: same as Prozac NOTE: no effect on appetite or sleep|
||SSRI: same as Prozac NOTE: increase weight and sedation|
||SSRI: same as Prozac|
||Serotonin and norepinephrine re-uptake inhibition; spectrum of activity similar to SSRIs, but may be useful in treatment-resistant cases|
||Major sedation, used to treat sleep disorders; also helpful for decreasing agitation in some cases|
||Less sedating derivative of trazodone|
||Ineffective for anxiety, used for ADHD, lack of sedation, cardiovascular effects and cognitive impairment; high seizure risk|
||Serotonin re-uptake inhibition; spectrum of activity similar to SSRIs and Effexor|
||Tricyclic antidepressant; used in ADHD and anxiety disorders NOTE: elevates heart rate and blood pressure|
||Same as the prior agent NOTE: elevates heart rate and blood pressure|
||Same as the prior agent NOTE: elevates heart rate and blood pressure |
||Brief Description |
||Centrally acting alpha-2 agonist, used for hyperactivity NOTE: sedation and prolonged cardiac conduction |
||Commonly used to treat bipolar illness: moderately effective in treating aggression|
||Anticonvulsant and mood stabilizer used for behavior disorders in the neuropsychiatric population|
||Same as the prior agent NOTE: increase weight, hair thinning and stomach aches|
||Some anti-obsessional, antidepressant and anti-aggressive activity NOTE: less sedating |
||Benzodiazepine and anticonvulsant, weak mood stabilizing and anti-obsessionaleffects NOTE: sedation|
|Source: Reference 14 |
Antidepressants may be prescribed to alleviate mood swings, temper tantrums and aggression. The antidepressant used most frequently is fluoxetine (Prozac) a selective serotonin reuptake inhibitor (SSRI). Other SSRIs, including sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox) and citalopram (Celexa), are also used. It is important to note that not all SSRIs have the same side effect profile and this class of medication may take three to four weeks before improvement is seen. Therefore, counseling with this drug therapy is important. Counseling during this period also ensures that possible suicidal ideation is monitored.
Prozac usually causes a decrease in weight following initiation of treatment and causes insomnia whereas Paxil usually increases weight and causes sedation. In comparison, Zoloft has no major effect on appetite or sleep. There are some similarities in that all SSRIs cause some level of dizziness and sexual dysfunction.
The tricyclic antidepressants are used as alternative medication for treating hyperactivity and attention problems. Patients receiving agents like imipramine (Tofranil) and desipramine (Norpramin) should be monitored for an increase in outburst behavior and cardiac arrhythmias due to elevated heart rate and blood pressure.3, 10, 12
Valproic acid (Depakote) and carbamazepine (Tegretol) are anticonvulsants used if seizures are present in addition to severe mood instability. Weight gain, hair thinning, stomach aches and appetite changes are side effects of Depakote. If taken after a meal, the stomach upset can be avoided. Electrolytes, liver function tests and complete blood counts are monitored routinely during Depakote therapy. Lithium (Lithobid), a psychotherapeutic medication, is used to control the temper tantrums, but it, too, requires the same monitoring parameters as the prior agents.
Atypical antipsychotics are an alternative class of drugs used in treating the severe tantrums or mania that a patient may experience. Olanzapine (Zyprexa) and risperidone (Risperdal) are two of these agents found to be effective, but they are not used as frequently because they may produce weight gain due to increasing appetite. Sedation, akathesia, orthostatic hypotension and a low risk of tardive dyskinesia are other possible side effects.3, 9, 10
Many children and adolescents with FXS show anxiety over changes in their environment. As a result, these individuals experience many emotional outbursts and panic attacks. Another class of drugs--anxiolytics--is used to help control the anxiety. Diazepam (Valium) and alprazolam (Xanax) are benzodiazepines found to be helpful. The disadvantage with this subclass of drugs is that they have the potential to be addictive and the withdrawal process may be a problem for some patients. Also, sedation is a very common side effect for patients who receive these medications. Sedation sometimes requires that the drugs to be given at lower doses and on an as-needed basis. An alternative agent, buspirone (Buspar), classified as a nonbenzodiazepine, is less sedating and nonaddictive. 3, 13
Last, 10-50 mg/d of folic acid is currently under investigation to evaluate its effectiveness in managing hyperactivity. Its mechanism of action is not clearly established; however, the advantage is that it can be used in young children who cannot receive stimulants. The disadvantage is that it has shown to be a weak psychostimulant, and there is still much data needed to adequately characterize its effectiveness. Some reports indicate that folate may increase the risk of seizures. Therefore, it is advised to avoid this treatment if seizures are not controlled. If patients are given folic acid as high as 250 mg/d and 1000 mg/d, thorough monitoring is needed. Laboratory monitoring parameters include complete blood count (CBC), serum glutamic oxaloacetic transaminase (SGOT), blood urea nitrogen (BUN), creatinine, urine analysis, folate, B6 and zinc serum concentrations. In addition, the patient should be informed that improvements in behavior or attention might not begin until the second month of therapy.10
Fragile X syndrome is one of the most common causes of genetically inherited mental impairment. The symptoms vary according to each individual regarding what characteristics will prevail. For some individuals, signs of the condition are nonexistent but for others the physical, behavioral and mental changes are great. As researchers strive to uncover more of the etiology of the syndrome, much has already been established. The discovery of the FMR-1 gene in 1991 has facilitated knowledge as to why FXS may occur. Understanding the inheritance patterns and the development of the new DNA tests has been beneficial for couples who are thinking of starting a family. Treatment options are available for maximizing the potential of each affected individual. Speech, language, occupational and behavioral therapy may improve patients' ability to function, and also modify the physical, cognitive and behavioral aspects of this syndrome. Medical interventions with CNS stimulants, antidepressants, anticonvulsants, psychotherapeutic agents, anxiolytics and folic acid have produced health benefits in the form of reduced hyperactivity, temper tantrums, attention problems, mood swings, aggression, seizures and anxiety.
Pharmacists can play an important role in educating patients about the various medical interventions and what patients can expect when taking these medications. Encouraging patients to continue therapy with pharmacological and nonpharmacological means as well as guiding them to the appropriate support groups can help to optimize patient outcomes. Pharmacists can also monitor patients' progress and remind them of the necessary monitoring. Fragile X syndrome is a lifelong struggle for these patients and their caregivers, but successful management techniques are available. The dedicated concern and intervention of pharmacists and other healthcare professionals can help increase awareness of and patient education on fragile X syndrome.
The following resources provide additional information on fragile X syndrome and the latest research developments, related conditions and patient support.
The National Fragile X Foundation
PO Box 190488
San Francisco, CA 94119-0488
800-688-8765, Fax: 510-763-6223
Various literature on the possible medication
usage for Fragile X Syndrome. Available at:
FRAXA Research Foundation
45 Pleasant Street, Newburyport, MA 01950
National Society of Genetic Counselors
Guidelines on the identification and evaluation
of Fragile X Syndrome.
Available at: http://www.guideline.gov
National Society of Genetic Counselors
233 Canterbury Drive, Wallingford, PA 19086-7608 http://www.nsgc.org
Fragile X Research Foundation of Canada
905-453-9366, Fax: 905-453-0095
Arizona Fragile X Resource Group
602-954-7975. Fax: 602-954-4629
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2. FRAXA Research Foundation Home Page [resource on World Wide Web]. URL: http://www.fraxa.org. Available from Internet. Accessed 2001 November 20.
3. National Fragile X Foundation Home Page [resource on World Wide Web]. URL: http://www.FragileX.org. Available from Internet. Accessed 2001 August 11.
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5. Kallinen J, Heinonen S, et al. Prenatal diagnosis of fragile X syndrome and the risk of expansion of a premutation. Clin Genet. 2000 Aug; 58(2):111-115.
6. Kumar V, Cotran R, Robbins S, et al. Chapter 7: Genetic and Pediatric Diseases. In: Basic Pathology. 6th ed. Philadelphia: WB Saunders; 1997:176-190; 197-199; 207-209.
7. National Institute of Child Health and Human Development Home Page [resource on World Wide Web]. URL: http://www.nichd.nih.gov. Available from Internet. Accessed 2001 August 11.
8. Stoll C. Problems in the diagnosis of fragile X syndrome in young children are still present. Am J Med Genet. 2001; (100):110-115.
9. The task of identifying children with this complex disorder and coordinating their care often falls to the primary care physician. Patient Care. 1997 Sept:147-162.
10. Hagerman R. J. Medical Follow-up and Pharmacotherapy. In: Fragile X Syndrome: Diagnosis, Treatment, and Research. 2nd ed. The John Hopkins University Press, Baltimore; 1996:63; 292-298; 304-306.
11. Hagerman, RJ. Fragile X: Treatment of Hyperactivity. Pediatrics. 1997; (99):753. Letter.
12. Kando JC. Depressive Disorders. In: Pharmacology: A Pathophysiologic Approach., 4th ed. Dipiro, JT, Talbert, RL, GC, et al. Appleton & Lange., Stamford, CT. 1999:Chapter 65.
13. Kirkwood CK. Anxiety. In: Pharmacotherapy: A Pathophysiologic Approach., 4th ed. Dipiro, JT, Talbert, RL GC, et al. Appleton & Lange., Stamford, CT. 1999:Chapter 67.
14. Tranfaglia M.R. A medication guide for fragile X syndrome. Version 3.1. FRAXA Research Foundation, West Newbury, MA; 2000:25-26.