Fragile X is the most common inherited cause of mental retardation. The condition is typically caused by a well-defined mutation at a specific locus of the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Approximately 85% of males and 50% of females who inherit the FMR1 mutation will demonstrate clinical features of the syndrome. Post-pubescent males with fragile X syndrome usually have distinct physical features, behavioral difficulties, and cognitive impairment. Females with fragile X syndrome tend to have more subtle symptoms.
Fragile X syndrome is an X-linked condition that doesn't follow a simple X-linked inheritance pattern. The normal sequence of the FMR1 gene was identified at Xq27.3 in 1991. The unique mutation that results in fragile X syndrome consists of an expanding region of a specific triplet of nitrogenous bases: cytosine, guanine, guanine (CGG) within the gene's deoxyribonucleic acid (DNA) sequence. Normally, FMR1 contains 6 to 50 sequential copies of the CGG triplet. When the number of CGG triplets expands to the range of 50 to 200 repeats, the region of DNA becomes unstable and is referred to as a premutation. A full mutation consists of over 200 CGG triplet repeats.
The full mutation typically causes abnormal methylation (methyl groups attach to components of the gene) of FMR1. Methylation inhibits gene transcription and thus protein production. The reduced or absent protein product (FNIRP) is responsible for the clinical features of fragile X syndrome. Approximately 15% to 20% of males with a full mutation don't have fragile X. This may be explained by either the ability of unmethylated portions (of their mutated FMR1) to be transcribed for eventual protein production, or that these males are mosaic for the FMR1 premutation. In asymptomatic mosaic males it's believed that the cells with a premutation can produce enough protein to compensate for the cells that contain a full mutation and consequently produce no protein.
Approximately 50% of females who inherit a full mutation from their mother have clinical features of fragile X syndrome. This is primarily due to the normal process of random X inactivation. At the time of meiosis, both X chromosomes must be activated. However, shortly after the zygote stage, an X chromosome is inactivated in every cell. Clinically measurable effects of the full FMR1 mutation will be more likely in relevant tissues or organs that have a disproportionate number of cells in which the normal X chromosome has been inactivated.
Males with a premutation don't have fragile X. They're considered unaffected or normal-transmitting males. Because males have only one X chromosome, all daughters of a transmitting male will inherit their father's X chromosome with the premutation. None of the male's sons will inherit the premutation because they inherit their father's Y chromosome rather than the X chromosome.
Females with the premutation don't have fragile X syndrome. However, the premutation can expand into the full mutation range (>200 CGG triplets) when it's transmitted from a premutation carrier mother to her offspring. This expansion can occur during or after maternal meiosis. Therefore, the following possibilities exist for every pregnancy of a mother with a premutation.
❑ A female conceptus receives the mother's X chromosome with the nonmutated FMR1 gene. She won't be affected with fragile X. None of her future offspring will be at risk for inheriting the syndrome from her.
❑ A male conceptus receives the mother's X with the nonmutated FMR1 gene. He won't be affected with fragile X. None of his future offspring will be at risk for inheriting the syndrome from him.
❑ A female conceptus receives the mother's X chromosome with the FMR1 premutation. She'll be a carrier like her mother but won't have fragile X syndrome. Her future offspring will be at risk for inheriting a full mutation from her.
❑ A male conceptus receives the mother's X with the FMR1 premutation. He won't be affected with fragile X. All of his future daughters but none of his future sons will inherit the premutation from him.
❑ A female conceptus receives the mother's X chromosome with the FMR1 gene whose premutation expanded into a full mutation during or after maternal meiosis. Depending on the outcome of random X inactivation, the daughter may have clinically definable fragile X syndrome. Her future offspring will be at risk for inheriting the full mutation and, thus, the syndrome from her.
❑ A male conceptus receives the mother's X chromosome with the FMR1 gene whose premutation has expanded into a full mutation during or after maternal meiosis. In 85% of cases, the son in this situation will have fragile X syndrome. Evidence indicates, however, that the FMR1 gene in the son's gametes will have the CGG triplet repeat within the premutation range, not the full mutation range like his somatic cells. Therefore, his future daughters wouldn't be expected to have fragile X syndrome.
It should be noted that most commonly the FMR1 status of a mother is subsequently determined after her son is clinically and later molecularly diagnosed with fragile X syndrome. Health care professionals need to be sensitive to the fact that the mother could either find out she's a carrier of a premutation or she has a full mutation. Consequently, not only will she learn her son's diagnosis but she, herself, could be diagnosed with fragile X if she has a full mutation and clinical symptoms.
Fragile X syndrome is estimated to occur in about 1 in 1,500 males and 1 in 2,500 females. It has been reported in almost all races and ethnic populations.
Small children may have relatively few identifiable physical characteristics; behavioral or learning difficulties may be the initial presenting features.
Many adult male patients display a prominent jaw and forehead and a head circumference exceeding the 90th percentile. A long, narrow face with long or large ears that may be posteriorly rotated can be a helpful finding at all ages. Connective tissue abnormalities — including hyperextension of the fingers, a floppy mitral valve (in 80% of adults), and mild to severe pectus excavatum — have also been reported. Unusually large testes, found in most affected males after puberty, are an important identifying factor of the disorder.
The average IQ of a person with fragile X syndrome is comparable to that of a person with Down syndrome; however, the behavioral characteristics are quite different. Hyperactivity, speech difficulties, language delay, and autistic-like behaviors may be attributed to other disorders, such as attention deficit hyperactivity disorder, and thus delay the diagnosis.
Approximately 50% of females with the FMR1 full mutation will have clinical symptoms, although the degree of severity and number of symptoms vary widely among females with fragile X syndrome. Those who are symptomatic typically have a much milder clinical presentation than males due to having an unaffected X chromosome in addition to the one with an FMR1 full mutation. Some degree of cognitive impairment is usually present in symptomatic females. Learning disabilities — math difficulties, language deficits, and attentional problems — are most common. Some females can have IQ scores in the mental retardation range. Although affected females can have autistic-like features, excessive shyness or social anxiety are the more common behavioral symptoms. Prominent ears and the connective tissue manifestations may be as significant as in males. Although males with the FMR1 permutation are asymptomatic, some female carriers of an FMR1 premutation can have associated symptoms. These symptoms include significantly earlier menopause and a low normal performance IQ.
A specific genetic test (polymerase chain reaction) can also be performed to diagnose this disease. This test looks for an expanded mutation (called a triplet repeat) in the FRAXA gene.
Before identification of the FMR1 mutation, a special cytogenetic (chromosome) blood test was used to microscopically detect the fragile site on the long arm of the affected X chromosome. It's now common knowledge that a full FMR1 mutation doesn't always result in a cytogenetically detectable fragile site. Therefore, chromosome analysis alone can provide false-negative results. Chromosome analysis still has utility together with FMR1 mutation analysis when performing a genetic evaluation on a male with mental retardation of unknown etiology.
In addition to diagnosing fragile X syndrome, genetic testing can determine whether the mother of a diagnosed individual is a carrier of the FMR1 premutation or has a full mutation. This information can be used for preconceptional genetic counseling by a trained professional and prenatal testing if the woman so chooses. FMR1 mutation analysis can also be subsequently performed on at-risk family members. It should be noted, however, that communication of genetic test results to at-risk family members constitutes a breech of patient confidentiality and privacy unless prior written permission to communicate results has been obtained from the previously tested patients.
Fragile X syndrome has no known cure. Treatment is aimed at controlling individual symptoms. Surgery may be needed to repair a defective mitral valve.
❑ Individuals who have been identified as carriers may experience guilt and grief; provide support to help the carrier and family members accept the diagnosis.
❑ Parents of an affected child may need help to deal with their grief over unmet expectations for the child; refer them for appropriate counseling if necessary.
❑ Refer the family (and possibly the extended family) to a professional trained in genetics to discuss the diagnosis, testing, and the risk of recurrence in future offspring.
❑ Recurrent otitis media is common. To maximize the affected child's potential for language development, early diagnosis and aggressive treatment of otitis media are essential.
❑ Throughout childhood, assess and refer the patient and his family for history of seizure activity.
❑ Assess and refer for hyperactivity, attention deficit, or both.
❑ The patient and his family can contact the National Fragile X Foundation for additional information and support.
Review other book chapters online related to X Chromosome Disorders:
Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
|
More About This Book:
Title: Professional Guide to Diseases (Eighth Edition) Authors: Springhouse Publisher: Lippincott Williams & Wilkins Copyright: 2005 ISBN: 1-58255-370-X 
|
|
What do you think about the features of this website? Take our user survey and have your say:
Next articles:
Tools & Services:
Medical Articles:
Search Specialists by State and City
By using this site you agree to our Terms of Use. Information provided on this site is for informational purposes only; it is not intended as a substitute for advice from your own medical team. The information on this site is not to be used for diagnosing or treating any health concerns you may have - please contact your physician or health care professional for all your medical needs. Please see our Terms of Use.
Copyright © 2009 Health Grades Inc. All rights reserved.
