Fragile X Syndrome
- Most common cause of inherited intellectual disability (ID)
- Caused by mutations in the FMR1 gene on chromosome Xq27.3
- Affects ~1 in 4,000 to 6,000 males; prevalence in females is ~1/2 than in males.
- Carrier prevalence in females for FMR1 premutation is 1:382 and for intermediate allele(s) is 1:143.
- Caused by loss-of-function mutations in the FMR1 gene on chromosome Xq27.3
- >99% of affected individuals have a trinucleotide (CGG) repeat expansion (>200 repeats) within the 5′ untranslated region of the FMR1 gene.
- Repeat size categories (based on guidelines from the American College of Medical Genetics):
- Normal number of repeats: 5 to 44
- Intermediate (“gray zone”): 45 to 54
- Premutation: 55 to 200
- Full mutation: >200
- Other FMR1 gene mutations may rarely occur (<1% cases).
- Fragile X syndrome is inherited in an X-linked manner.
- Fragile X is a CGG trinucleotide repeat disorder that shows anticipation, in which the phenotype can be more severe in subsequent generations due to an expansion in the number of CGG repeats.
- Expansion only may occur in the germline of mothers who carry a premutation range repeat allele of FMR1.
- Expansion does not always occur in offspring of female premutation carriers. In general, the larger the number of CGG repeats (>50), the higher the probability that expansion to a full mutation will occur.
- A male with a premutation will pass on the premutation to 100% of his daughters and none of his sons.
- Females with a full mutation are typically less severely affected than males because their second FMR1 allele is typically normal and, assuming random X-inactivation occurs, produces variable amounts of fragile X mental retardation protein (FMRP).
- Males with mosaicism for the FMR1 full mutation (some cells with the full mutation and other cells with the premutation) are generally less severely affected (average IQ 60) relative to males with the full mutation in all the cells.
- Patients with larger chromosomal deletions involving FMR1 and other nearby genes typically have a more severe phenotype
- Prenatal diagnosis by chorionic villus sampling (~10–12 weeks’ gestation) or amniocentesis (~16–20 weeks’ gestation) is possible for at-risk pregnancies.
- Preimplantation genetic diagnosis in the setting of in vitro fertilization is possible for at-risk couples when a familial FMR1 mutation is known.
Residual FMRP protein levels directly correlate with the severity of fragile X syndrome manifestations:
- Absence of FMRP results in characteristic craniofacial, neurologic, and connective tissue abnormalities.
- Decreased FMRP levels may cause long-term depression of hippocampal synaptic transmission via specific glutamate receptors, with resulting behavioral and neuronal phenotypes.
Commonly Associated Conditions
Other FMR1-related disorders include fragile X–associated tremor/ataxia syndrome (FXTAS) and premature ovarian insufficiency (POI):
- FXTAS can be seen in older (age >50 years) male and female premutation carriers. Clinical features include intention tremors, abnormal gait with frequent falling, cerebral atrophy, and memory deficits.
- POI can be seen in 20–25% of female premutation carriers, with menopause occurring prior to age 40 years.
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