Fragile X Syndrome Flashcards
Fragile X is otherwise known as
FRAXA
Fragile Site, Folic Acid Type, Rare, Fra(x)
Fragile causes what type of disability in both males and females
intellectual disability from learning impairment to severe cognitive disability to intellectual disability. Its common in autism and ASD.
FRAXA mutation testing is common in which type of individuals
in males and female with developmental delays, mental disability and behavioural problems.
What are the physical features of fragile x
- Large ears
- long narrow faces with prominent forehead
- Mitral Valve prolapse
- Seizures
- Eye problems
What are the cognitive clinical features of fragile X
affects the brain development can lead to:
- Developmental delays
- Mental impairment
- learning disabilities
what is the prevalence of Fragile X in males and female
Males : 1 in 400
Females: 1 in 5000-8000
where is the fragile X site on the X chromosome
Xq27.3 (long arm of the X chromosome)
What is a major mutation causing fragile X
Mutation in the FMR1 gene (causes 99% of fragile X)
What does the FMR1 gene code for
FMRP (fragile x mental retardation protein)
what kind of mutation is the most common in the FMR1 gene causing fragile X
an expansion mutation
What repeat sequence is found in the expansion mutation of the FMR1 gene
CGG (region is in the 5 UTR of the FMR1 promoter)
What is the normal number of CGG repeats
about 30.
Describe the mechanism causing fragile X in the case of greater than 200 CGG repeats
Hyper-methylation of the cytosine of the CGG repeat.
Deactivation of the FMR1 gene
NO FMRP is produced
This results in fragile X.
Describe the normal number of repeats, include the number of repeats, the amount of mRNA produced, the level of FMRP produced and the resultant clinical phenotype.
Number of repeats: <45
mRNA produced: normal
FMRP produced: normal
clinical phenotype: normal
Describe the premutation number of repeats, include the number of repeats, the amount of mRNA produced, the level of FMRP produced and the resultant clinical phenotype.
Number of repeats: 55-200
mRNA produced: increased mRNA produced
FMRP produced: reduced
clinical phenotype: Premature ovarian failure, FXTAS
Describe the full mutation number of repeats, include the number of repeats, the amount of mRNA produced, the level of FMRP produced and the resultant clinical phenotype.
Number of repeats: >200
mRNA produced: reduced
FMRP produced: none produced
clinical phenotype: Fragile X syndrome (varies between males and females)
what is 45-55 repeats classed as
the intermediate allele
with the full mutation what is the chance of developing fragile X
All males will develop FXS
50% of females will develop fragile X.
those with 55-200 repeats are at risk of FXPOI and FXTAS, what is FXPOI
FXPOI: fragile x associated primary ovarian insufficiency.
- is a toxic RNA gain of function (in the premutation there is an increase in mRNA while a decrease in protein)
- Females with 55-200 mutations have a 21% risk of developing FXPOI
- Menopause before 40.
those with 55-200 repeats are at risk of FXPOI and FXTAS, what is FXTAS
FXTAS: fragile X associated tremor/ataxia syndrome.
- late onset neurodegenerative disorder that effects old adult carriers (usually over 55), the risk increases with age in those with the premutation
- there is an intention tremor and a cerebral gait ataxia.
- Occurs in 40% of males with the premutation and 8-16% of women with the premutation.
- occurs via a similar mechanism to FXPOI.
What laboratory tests are used to diagnose fragile syndrome
CGG repeat expansion via: PCR, southern blot, Repeat primed PCR and capillary separation. RT-PCR.
deletions: microarray MLPA (multiplex ligation-dependent probe amplification).
Future testing: next gen sequencing.
What is the gold standard of FXS lab tests
Southern Blot.
What is the function of the FMRP protein
repressor of target mRNA translocation at the neural synapses, shuttles target mRNA through dendrites and is important in the generation of synapses during the development.
