Definition, prevalence, symptoms and treatment of Fragile X are provided by Elisabeth Fernell.
Fragile X syndrome is caused by a change (mutation) in a gene on the X chromosome’s long arm (Xq27.3). The gene is called fragile X mental retardation 1 (FMR-1). The syndrome is the most common hereditary cause of mental retardation and is passed on through X-linked recessive inheritance. Diagnosis is made through DNA-analysis of blood samples. The gene change causes a trinucleotide sequence, three genetic nucleotide bases, CGG, to be repeated too many times. Generally, this sequence is repeated in the gene between 5 and 44 times. If a person has an FMR1-gene with 55-200 CGG-triplets, a so-called premutation is present.
In cases of a full mutation, i.e. when the number of repeats of the nucleotide sequence surpasses 200, the gene is turned off. Normally the gene encodes a protein that is important for the neurons’ connection points (synapses). When the gene is turned off, that specific protein cannot be formed.
In cases of a premutation there is some production of the protein and the ones who have a premutation therefore do not get equally pronounced symptoms compared to someone with a full mutation. Men and women with a premutation are considered genetic carriers of Fragile X syndrome. However, a premutation is unstable, and may increase in size when it is transferred from mother to child. Hence, children of women with a premutation may get Fragile X syndrome. Children with a full mutation of the gene in question may have inherited the mutation from the mother, who may be a carrier of a premutation or have a full mutation themselves. Boys who have inherited a full mutation get Fragile X syndrome, but girls with a full mutation do not always get the syndrome, since they have two X chromosomes, i.e. the other X chromosome has a normally functioning gene. Daughters of fathers with premutation become premutation carriers, whose children in turn risk getting the syndrome, while a premutation cannot be inherited from father to son.
In girls and women with full mutation the symptomatic presentation is quite varied – some are clinically symptom-free, some have mild symptoms, while still others may have severe symptoms including mental retardation. Mild symptoms in girls may include learning difficulties and particular problems with anxiety/worrying. The vast majority of boys with Fragile X syndrome, as well as some girls, suffer from mental retardation, in many cases severe and in other cases milder. The presence of concurrent concentration difficulties/stamina problems in combination with overactivity/impulsiveness (ADHD) is very common, and autism spectrum disorders, especially in boys, are also common. Epilepsy also occurs at an increased rate.
The prevalence rate of Fragile X syndrome has been estimated at around 1 in 4000 live births for boys and around 1 in 6000 live births for girls.
Two conditions called FXTAS and FXPOI have been described in premutation carriers. FXTAS refers to a Fragile X-associated tremor/ataxia syndrome, which has primarily been described in older men with premutation but also in women. FXPOI refers to premature ovarian insufficiency with premature menopause. In cases of FXTAS, neuropathy and autonomous dysfunction may also be present, as may different neuropsychiatric symptoms with impaired cognitive ability, especially ones concerning executive functions. Autoimmune diseases, such as MS and hypothyroidism, have also recently been shown to occur at an increased rate in premutation carriers.
Treatment of Fragile X syndrome includes habilitation efforts with medical, psychological/neuropsychological, pedagogic and social/supportive measures.
Currently ongoing studies are testing treatment directed at the disorder that arises as a result of the genetic change. The protein that cannot be formed is, among other things, supposed to inhibit glutamate receptors in the brain’s synapses. When these receptors are not inhibited, an excess of glutamate is released, which is harmful to the brain. In currently ongoing studies, patients are given a drug that inhibits glutamate receptors, a glutamate antagonist, thereby preventing the release of harmful proteins. Such studies are being performed and evaluated at GNC and at Karolinska University Hospital, among other places.