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

[edit] Fragile X Syndrome

[edit] 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

[edit] 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; there may 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

[edit] 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.

[edit] 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").
  • Normal: n < 50 repeats promoter unmethylated
  • Premutation: n ~ 50-200 promoter unmethylated
    • “Premutation” alleles are slightly expanded; the gene can still be transcribed but is potentially unstable and may expand further (e.g., to full mutation) in next generation.
  • Full mutation: n > 200 promoter methylated
    • “Full mutation” alleles have large expansions, are not transcribed, and cause Fragile- X syndrome.

• As the repeat expands disease is caused by a loss of FMR1 function.
  • 50-69 repeats: <20% chance of expansion
  • 70-70 repeats: 39%
  • 80-89 repeats: 76%
  • 90-99 repeats: 89%
  • 99-> repeats: 99%

• Normal transmitting male (NTM): have the premutation but not the syndrome.
• Unaffected female: can be heterozygous for full mutation.
  • Females who are heterozygotes for a full mutation and normal allele may or may not develop the syndrome: 50% have mental retardation.
  • Therefore, this disorder is not cleanly recessive or dominant.
• Affected male: has the full mutation and the syndrome.
  • Affected males (with Fragile X syndrome) generally do not reproduce.
• Expansions from premutation to full mutation are usually NOT inherited from fathers.
  • There may be selection against passage of large alleles through the male germ line.
• Affected female: Heterozygous for full mutation and normal allele

• 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.

[edit] Pathogenesis

• The pathogenic mechanism is a “loss of function” of the fmr1 gene or its gene product FMRP.
  • Recall that FMRP is expressed in neurons as well as oligodendrocytes (myelin producing cells of CNS).
  • Recall that FMRP is involved with the transport of mRNA of other genes.
• A similar syndrome can be caused by rare FMR1 point mutations (mutant protein).

• 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

• Repeats in the fmr1 gene are found in the 5' untranslated region.
  • Recall that Muscular Dystrophy occurs by a 3' UTR repeat.

[edit] 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.

• The premutation state is not completely innocuous!:
  • Women (with the premutation) are at 3-4 fold increase for premature ovarian failure and early menopause.
  • Men over 50 (with the premutation) are at risk (1 of 4) for "Fragile X associated tremor / ataxia syndrome (FXTAS)".
    • FXTAS (Fragile X associated tremor / ataxia syndrome) 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?

[edit] Diagnosis

[edit] Treatment

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers