Fragile X syndrome and genetics
Fragile X syndrome is a genetic condition that is the most common inherited form of intellectual disability, affecting approximately 1 in 1,500 males and 1 in 2,500 females. It is associated with mutations in the FMR1 gene located on the X chromosome, leading to a repeat of the CGG triplet sequence that disrupts normal gene function. The inheritance pattern is unique; males with the affected X chromosome exhibit symptoms, while females may be carriers with milder or no symptoms unless both X chromosomes are affected. Symptoms in affected individuals can include moderate to severe intellectual disability, distinctive physical features, and behavioral issues such as hyperactivity or autism.
Diagnosis is often based on physical and behavioral assessments, supplemented by genetic testing for the CGG repeat mutation in the FMR1 gene. While there is no cure, therapies and educational support can help manage symptoms and improve quality of life. For families with a history of Fragile X syndrome, genetic counseling is advisable to understand risks for future children. This condition highlights the complexities of genetic inheritance and the need for support in affected individuals and their families.
Fragile X syndrome and genetics
DEFINITION Sex chromosomes, the chromosomes X and Y, determine sex; the presence of two X chromosomes codes for females and an X chromosome paired with a Y chromosome codes for males. These chromosomes are received from an individual’s parents, each of whom contributes one sex chromosome to their offspring. In 1969, geneticists studied a family of four mentally challenged brothers who had X chromosomes whose tips appeared to be detached from the rest of the chromosome. It is now recognized that this fragile site occurs in the vicinity of the FMR1 gene. There are more than fifty intellectual disability-related disorders associated with the X chromosome, but their frequencies are rare. Fragile X syndrome is the most common inherited form of mental retardation, affecting an estimated 1 in 1,500 males and 1 in 2,500 females.
Risk Factors
Individuals who have family members (especially male relatives) with fragile X syndrome are at risk for the condition.
Etiology and Genetics
In males, any abnormal gene on the X chromosome is expressed because males have only one X chromosome. In females, two copies of the fragile X chromosome must be present for them to be affected. This is the classic pattern for X-linked, or sex-linked, traits (traits whose genes are located on the X chromosome.)
The pattern of inheritance for fragile X is unusual. Fragile X syndrome increases in severity through successive generations. This is explained by a worsening of the defect in theFMR1gene as it is passed from mothers to sons. Since males contribute the Y chromosome to their sons, fathers do not pass the fragile X gene to their sons. They will, however, contribute their X chromosome to their daughters. Because these daughters also receive an X chromosome from their mothers, they generally appear normal or only mildly affected. It is only when these daughters have a son that the condition is expressed.
An explanation for this increasing severity through generations was discovered by analyzing the DNA sequence of the FMR1 gene. The molecules composing DNA are adenine (A), thymine (T), cytosine (C), and guanine (G) and are referred to collectively as “bases.” In fragile X syndrome, a sequence in which the three bases CGG are repeated over and over was found. The repetitive sequence is found in normal copies of the FMR1 gene, but in individuals with fragile X syndrome, there are many times more copies of the CGG triplet. The longer repetitive sequence in the FMR1 gene prevents it from being expressed. Individuals not having the fragile X syndrome have a working FMR1 gene.
Symptoms
Males affected with fragile X syndrome have moderate to severe intellectual disability and show distinctive facial features, including a long and narrow face, large and protruding ears, and a prominent jaw. Additional features include velvet-like skin, hyperextensible finger joints, and double-jointed thumbs. These features are generally not observed until maturity. Prior to puberty, the only symptoms a child may have are delayed developmental milestones, such as sitting, walking, and talking. Children with fragile X syndrome may also display an abnormal temperament marked by tantrums, hyperactivity, or autism.
A striking feature of most adult males with fragile X syndrome is an enlarged testicular volume (macroorchidism). This enlargement is not a result of testosterone levels, which are normal. Men with fragile X syndrome are fertile, and offspring have been documented, but those with significant intellectual disability rarely reproduce.
The intelligence quotient (IQ) of the majority of affected males is in the moderate to severely low range. Only a few affected males have IQs above seventy-five. Males with fragile X syndrome frequently show delayed speech development and language difficulties. Repetitive speech patterns may also be present.
Screening and Diagnosis
Fragile X syndrome is often evident from an individual’s appearance, intelligence, and behavior. External signs may include a large head circumference in babies, oversized testes in males during puberty, mental retardation, and subtle differences in facial characteristics. For females, the only external sign of the condition may be excessive shyness. Fragile X can be diagnosed with a polymerase chain reaction (PCR), a test that looks for the triplet repeat mutation in the FMR1gene.
Treatment and Therapy
There is no specific treatment for people with fragile X syndrome, but there are a variety of ways to minimize the symptoms. Affected individuals can receive special education and training, as well as speech, physical, occupational, and behavioral therapies to address the educational, physical, social, emotional, language, and sensory problems associated with the condition.
Prevention and Outcomes
There currently is no cure for fragile X syndrome, but various educational and treatment programs are available to alleviate or eliminate its symptoms. Individuals with a family history of the syndrome may wish to seek genetic counseling before deciding to have a child.
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