Fragile X Syndrome (FXS) Flashcards
(38 cards)
What are the causes of intellectual disability?
*Infections (present at birth or occurring after birth; e.g. HIV,
rubella)
* Environmental (Deprivation syndrome)
* Chromosomal abnormalities (e.g. Down syndrome, fragile X
syndrome)
* Genetic abnormalities and inherited metabolic disorders
(Phenylketonuria)
* Metabolic (hypoglycemia from poorly regulated diabetes)
* Nutritional (Malnutrition)
* Toxic (substance abuse, lead poisoning)
* Fetal alcohol syndrome
* Trauma (before and after birth)
* Unexplained
What is Fragile X Syndrome?
- most common inherited form of mental retardation.
What is the prevalence of Fragile X Syndrome?
1 in every 3500 male and 1 in 4000-6000 female births.
What are the fragile sites on X chromosomes?
(1) FRAXA
- Chromosome band: Xq27.3
– Fragile X syndrome
– premature ovarian failure
(menopause before 40)
– late onset tremor/ataxia
syndrome (FXTAS), which
affect 1/3 of male carriers on
the age of onset of 50 years
– Macroorchidism
(2) FRAXE
- Chromosome band: Xq28
– mild mental retardation, rather
rare
What are the physical phenotypes of FXF symptoms?
- Long narrow face and
prominent ears
– Flat feet
– Macroorchidism (large testes
in male)
– Hyperextensible finger joints
– Hypotonia (low muscle tone)
– Cardiac abnormalities (mitral
valve prolapse and dilated
aortic root, may be related to
the connective tissue
abnormality in FXS)
What are the behavioural phenotypes of FXS symptoms?
- Strong reactions to changes in their environment that result sometimes in
aggressive outbursts
– Hand flapping and biting
– Speech and language difficulties
– Perseveration: inability to complete a sentence because of continuous repetition
of words at the end of a phrase
– Echolalia: speak in rapid bursts or repeat words
– Talking inappropriately and incessantly about one topic
– Shyness and anxiety
– Poor eye contact
– 80% of male and 40% of female FXS patients display hyperactivity and attention
deficiency
– 60% of male and 20% of female FXS patients have symptoms of autism
spectrum disorder (FXS is the most common known cause of autism)
What are the neurological phenotypes of FXS symptoms?
- Seizures
- Abnormal spine morphology
- Intellectual disability
What is an X-linked disease?
An X-linked disease is a condition caused by a mutation in a gene located on the X chromosome. Since males have only one X chromosome, if they inherit a faulty gene, they are more likely to show symptoms of the disease. Females have two X chromosomes, so they may be carriers (with one healthy and one faulty gene) and often do not show symptoms or have milder symptoms.
What is the Sherman Paradox?
The Sherman Paradox describes how Fragile X syndrome worsens with each generation — symptoms become more severe and appear at a younger age. This is due to anticipation, where the number of CGG repeats in the FMR1 gene expands in successive generations, increasing disease severity. Anticipation also occurs in other diseases like myotonic dystrophy and Huntington’s disease.
What type of mutation causes Fragile X Syndrome (FXS)?
Trinucleotide repeat expansion — a repeated CGG sequence in the FMR1 gene expands too much, causing the gene to be silenced.
Where is the FMR1 gene located and what does it do?
(1) Location: X chromosome, band Xq27.3
(2) FMR1 produces: FMRP (Fragile X Mental Retardation Protein), which is important for brain development and function.
Where are the CGG repeats located within the FMR1 gene?
Location: In the 5’ untranslated region (UTR) of exon 1 of the FMR1 gene.
What is the connection between CGG repeats and Fragile X Syndrome?
- Normal: Less than ~55 repeats
- Premutation: 55-200 repeats
- Full mutation (FXS): More than 200 CGG repeats
- Full mutation causes: Methylation of nearby CpG island and surrounding DNA, which silences FMR1, preventing FMRP production.
What is the role of the CpG island near the FMR1 gene?
(1) The CpG island is a region rich in CG dinucleotides before the CGG repeat.
(2) When CGG repeats expand past 200, both the CpG island and nearby DNA get methylated, turning off FMR1 expression.
How does silencing FMR1 cause Fragile X Syndrome?
(1) No FMRP is made.
(2) FMRP is essential for normal brain development, especially for synaptic function and plasticity.
(3) Without FMRP, intellectual disability, developmental delay, and other Fragile X symptoms occur.
How does Sherman Paradox relate to Fragile X Syndrome?
- Sherman Paradox refers to the increasing severity and earlier onset of Fragile X Syndrome in each generation.
- This happens because the CGG repeats expand more with each generation, leading to worse gene silencing and more severe symptoms — this is a classic example of anticipation.
How do CGG repeats change in male and female carriers of Fragile X Syndrome during transmission (spermatogenesis vs oogenesis)?
(1) Male Premutation Carrier:
During spermatogenesis (sperm production), CGG repeats tend to stay the same or decrease slightly.
Males with a premutation (55-200 repeats) usually pass on premutation alleles — they rarely expand to a full mutation (>200 repeats).
(2) Male Full Mutation Carrier:
Rare for males to pass on a full mutation to offspring because it tends to shrink in sperm.
Full mutation males are usually infertile or have reduced fertility.
(3) Female Premutation Carrier:
During oogenesis (egg production), premutations (55-200 repeats) are unstable and can expand into a full mutation (>200 repeats) when passed to offspring.
Risk of expansion depends on the size of the premutation — larger premutations are more likely to expand.
(4) Female Full Mutation Carrier:
Female carriers with a full mutation (>200 repeats) can pass on either a full mutation or sometimes a slightly smaller repeat size to offspring.
More instability in maternal transmission compared to paternal transmission.
Is the mechanism for CGG repeat amplification in Fragile X Syndrome fully understood?
No, the exact mechanism for CGG repeat amplification is unclear.
How do CGG repeats behave in male carriers of Fragile X Syndrome?
- Male premutation carriers (55-200 repeats) do not amplify to full mutation during sperm production.
- Male full mutation carriers (>200 repeats) typically do not pass on the full mutation — their sperm usually contains premutation-sized alleles.
- This means full mutations are unstable in sperm and can’t be maintained through spermatogenesis.
Can full-mutation males have normal daughters?
Yes, full-mutation males can have normal daughters, but these daughters typically only carry the premutation, not the full mutation.
How does this compare to Huntington’s disease in terms of repeat expansion through generations?
- In Huntington’s disease, sperm plays a key role in the expansion of CAG repeats.
- In Fragile X Syndrome, sperm does NOT amplify CGG repeats, and full mutations are unstable in sperm.
How do CGG repeats behave in female carriers of Fragile X Syndrome?
- Female premutation carriers (55-200 repeats) can experience expansion of CGG repeats during meiosis (egg production).
- This can lead to having affected children (with full mutation) or carrier children.
Who drives the amplification of CGG repeats across generations — males or females?
Females drive CGG amplification across generations — expansion occurs during oogenesis (egg formation), not spermatogenesis.
What are the repeat ranges for Huntington Disease?
(1) Normal: 10-26
(2) Premutation: 27-41
(3) Affected: 36 to 121.
