Fragile-X Syndrome

From Iusmgenetics

Contents 1 Fragile X Syndrome 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

Fragile X Syndrome

General background information

• Called "Fragile X" because in a certain subset the conditions are right for an end of the X chromosome to fall off.
• 1 / 1250 males
• 1 / 2000 females
• All ethnic groups

Mode of inheritance

• Not clearly dominant or recessive
  • Unusual: some obligate carrier males have a normal phenotype (normal transmitting males, NTM)
  • An example is that females heterozygous for full mutation and normal allele may or may not manifest the disease.
• Fathers do not usually pass on large repeats; ther emay be some sort of selection against pass of large alleles through the germ line.
  • This is similar to myotonic dystrophy.
• Mothers are usually the source of expansive repeat alleles

Single important gene

• The fmr1 gene is expressed in neurons and oligodendrocytes.
  • Recall that oligodendrocytes are the myelin producing cells of the CNS.
• FMR1 is involved in the transport of mRNA of other genes.

Etiology

• CGG triplet repeat expansion in the 5' UTR of exon 1 of fmr1 gene.
  • We describe the expansion as small ("premutation)" or large ("full mutation").
• As the repeat expands disease is caused by a loss of FMR1 function.
• Fragile X syndrome demonstrates germline AND somatic instability such that the pt may be mosaic in terms of number of repeats in the UTR of exon 1.
• As the repeat increases in size, the risk of expansion increases.
• Sometimes CGG repeats are interrupted by AGG repeats; interrupted repeats are less likely to expand.

• It should be noted that a syndrome similar to Fragile X can be produced via particular point mutations of fmr1.

Pathogenesis

• Fragile-X syndrome manifests according to the number of CGG repeats in the fmr1 gene:
  • Normal: < 50 repeats, promotor is unmethylated
  • Premutation: 50-200 repeats, promoter is unmethylated
    • Can be transcribed but is unstable and may expand in the next generation.
  • Full mutation: > 200 repeats, promotor is methylated
    • Not transcribed

Phenotypic information

• Mental retardation:
  • Males: moderate; 3-6%
  • Females: mild
• Behavioral problems: hyperactivity, tantrums, autistic features
• Physical findings:
  • Before pubery: large head
  • After pubery: prominent ears / jaw / forehead
  • Macroorchidism
    • Those will the full mutation usually do not reproduce.

• Premutation phenotypes:
  • Women are at 3-4 fold increase for premature ovarian failure and early menopause.
  • Men over 50 are at risk (1 of 4) for "Fragile X associated tremor / ataxia syndrome (FXTAS)".
    • May also be seen in some females
  • Up to 25% of premutation carriers may have mild cognitive and / or behavioral deficits.
  • Perhaps this premutation state of disease is due to an RNA gain of negative function?

Diagnosis

Treatment

Recent research

5 important facts

Not to be confused with

Questions and answers