Fragile X syndrome


Most common cause of inherited mental retardation.

The most frequent form of inherited intellectual impairment, with a prevalence between one in 4000 and one in 6000 males.

The prevalence in females is approximately 1/2 of that in males.

Carrier rate is approximately 1 in 750 men and one in 250 women.

Mutations in the Fragile X mental retardation 1 (FMR1) gene may cause multiple disorders that can occur through a lifespan and includes: fragile X. syndrome, and premature menopause, known as primary ovarian insufficiency, late onset neurodegenerative disorders, fragile X.-associated trauma/ataxia syndrome.

It is caused by a change in a gene called FMR1, as a small part of the gene code is repeated on a fragile area of the X.

FMR1 gene, among other genes, can lead to disease through trinucleotide expansions.

FMR1 CGG expansions ( greater than 200 CGG repeats) may result in the absence of protein space (FMRP) which is important for synapse function.

In carriers of smaller, premutation alleles of 55-200 CGG repeats, a disease process with increased expression and RNA toxicity occurs.

Individuals carrying a full mutation form of the FMR1 gene may have intellectual and developmental abnormalities, which can include psychiatric and emotional diseases that may manifest even individuals with normal IQ level.

Males and females can both be affected, but because males have only one X chromosome, a single fragile X is likely to affect them more.

Most fragile-X males have large testes, big ears, narrow faces, and sensory processing disorders that result in learning disabilities.

Autism is seen in the majority of cases with fragile X. syndrome.

Shyness, social anxiety, and autistic behavior is common in girls with the full mutation of the FMR1 gene.

Majority of children with the pre-mutation have normal mental capacity, but they may have developmental problems with attention and social communication in boys (Farzin F).

Approximately 3% of boys with special needs have fragile X syndrome.

Caused by absent or decreased levels of fragile X  mental retardation protein (FMRT) gene.

The FMR1  loss of function mutation gene is located on Xq27.3.

More than 99% of cases or related to the loss of function caused by an unstable expansion of a trinucleotide (CGG)  repeat at the  5′  untranslated region.

Fewer than 1% of cases  are related to deletions, point mutations, or missense  mutations in the FMR1 The one gene.

X-linked recessive disease with variable expression and incomplete penetrance.

Mutations in a single gene fragile X mental retardation 1 (FMR1) cause a number of disorders occurring throughout the entire life span.

FMR1 mutations cause heritable form of intellectual disability, fragile X syndrome, and premature menopause.

The most frequent form of inherited intellectual impairment, with a prevalence between one in 4000 and one in 6000 males.

Mutations of FMR1 cause late onset neurodegenerative disorders, fragile X-associated tremor/ataxia syndrome (FXTAS).

30% of all carrier women are affected.

A fragile site or gap exists at the end of the long arm of the X-chromosome in the lymphocytes of affected patients when grown in a folate deficient medium.

Carrier mothers typically have a 30-40% chance of giving birth to a retarded male and a 15-20% chance of having a retarded daughter.

Frequently a maternal family history of having a mentally retarded or learning disabled relative.

Classic findings include: long face, prominent jaw, post-pubertal macroochidism, large prominent ears, high arched plate, flattened nasal bridge, micro or microcephaly, hypertelorism, epicanthal folds, simian palm creases, vertical sole creases, long philtrum, hemangioma and hyperextensible joints.

Classic physical findings appear in children as young as 2-3 years of age but usually are apparent by 8-12 years of age.

Young children may present with developmental delay, speech delay, impaired attention span, discipline problems, autistic behaviors, poor motor coordination, persistence of drooling and hypotonia.

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