Fragile X syndrome, the most common cause of inherited intellectual disability and autism spectrum disorders (ASD), is associated with a variety of physical features and behavioral and developmental symptoms, such as impaired learning, memory, sensory processing, and social skills, as well as anxiety, self-harming behavior, and seizures.
Genetic cause of fragile X
Fragile X is caused by mutations in the fragile X mental retardation 1 (FMR1) gene, located in the X chromosome (one of the sex chromosomes; the other being the Y chromosome).
This gene provides the instructions to produce the FMRP protein, which controls the production of several proteins at synapses — the site of near contact between nerve cells that allows them to communicate.
In some individuals, FMRP deficiency leads to the excessive production of different proteins at synapses, affecting synaptic plasticity (their ability to strengthen or weaken in response to information) and overall nerve cell communication.
While the mechanisms by which this deficiency causes fragile X are not fully understood, previous studies suggested an association with higher-than-normal activation of mGluR5, a specific receptor of the neurotransmitter glutamate, at synapses.
Neurotransmitters are key molecules in nerve cell communication, and glutamate is involved in brain functions that include learning and memory.
Nearly all cases of fragile X syndrome are caused by excessive repeats of three nucleotides — CGG — in the FMR1 gene. Nucleotides are the building blocks of DNA, in which the C stands for cytosine and G for guanine.
Normally, this CGG segment is repeated from 5 to about 40 times. The presence of 55 to 200 CGG repeats is classified as a premutation, and more than 200 repeats are considered a full mutation, leading to fragile X. The highly expanded CGG segment prevents the FMR1 gene from producing a normal FMRP protein.
While people carrying a FMR1 premutation, classified as premutation carriers, do not develop the disease, they are at risk of developing late-onset fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI).
FXTAS, characterized by progressive uncoordinated walking, low-frequency tremors, parkinsonism, and nerve damage, affects men more frequently and severely than women.
Among premutation carriers, about 40–75% of men and 8–16% of women develop this disorder. The chances of having it also increase with age in men carrying the premutation.
FXPOI comprises a wide spectrum of impaired ovarian function before age 40, which may be evident as irregular or absent menstrual cycles, infertility, and other menopause symptoms. About 20% of women carrying the premutation will develop FXPOI.
Notably, neither FXTAS nor FXPOI are thought to be caused by FRMP deficiency, but rather overproduction of the abnormally long FMR1’s messenger RNA, the intermediate molecule derived from DNA that guides protein production. The buildup of this abnormally long molecule is thought to be toxic to cells.
Premutation carriers may also show milder symptoms of fragile X.
In rare and ultra-rare cases, fragile X may also be caused by a partial or complete deletion of the FMR1 gene, or by a mutation in a single DNA nucleotide, both resulting in an absent or defective FMRP protein.
Inheritance of fragile X
Fragile X is inherited in a X-linked dominant manner, meaning that both males and females only have to inherit one mutated version of the FMR1 gene in the X chromosome to develop the disease.
Since men only have one X chromosome (inherited from the mother), those who inherit the mutated gene will have more severe disease. In women — who have two X chromosomes, one from the mother and one from the father — a healthy gene copy can compensate for the mutated copy to a certain extent.
The FMR1 premutation can expand to more than 200 CGG repeats (full mutation) in cells that develop into eggs, meaning that women carrying the premutation have up to a 50% chance of passing the mutated gene to their children. These children will either be carriers of the disorder or have fragile X syndrome.
Men who carry the premutation will pass the intact mutation to all their daughters (who will be carriers) but not to a son, because boys receive an Y sex chromosome from their fathers, instead of an X chromosome.
Last updated: April 7, 2021
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