Fragile X Syndrome

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • Most common cause of inherited intellectual disability (ID)
  • Caused by mutations in the FMR1 gene on chromosome Xq27.3, causing loss of function of fragile X mental retardation protein (FMRP) that is essential for neurocognitive development

EPIDEMIOLOGY

  • Affects ~1 in 7,000 males and ~1 in 11,000 females
  • Carrier prevalence in females for FMR1 premutation is 1:291 and for intermediate allele(s) is 1:143.

RISK FACTORS

Genetics

  • Caused by loss-of-function mutations in the FMR1 gene on chromosome Xq27.3
  • Fragile X syndrome is inherited in an X-linked manner.
  • >99% of affected individuals have a trinucleotide (CGG) repeat expansion (>200 repeats) within the 5′ untranslated region of the FMR1 gene that causes hypermethylation and subsequent silencing of the 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 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 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 intellectual quotient [IQ] of 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

GENERAL PREVENTION

  • Prenatal diagnosis by chorionic villus sampling (~10 to 12 weeks’ gestation) or amniocentesis (~16 to 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.

PATHOPHYSIOLOGY

Residual FMRP 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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