Case #4 Fragile X Syndrome Flashcards
HOw many people does FXS affect in US? (male vs female)?
Male: 1/2500-4000
Female: 1/7000-8000
Prevalance of female (heterozygous) carriers
1/130-250 in general population
Prevalence of male (heter) carriers
1/250-800
What % of previously undiagnosed mental retardeation in males and females, is due to FXS
males: 10%
female: 3%
Why doesn;t Betseys mother or father appear to nogt have FXS
If Betsey’s mther had the disease allele, it is possible that she did not exhibit any disease phenotye htat was readily identified; she had a premutation
She wouldn’t have been followed clinically
Genetic testing is expensive
Why is FXS have reduced penetrance in women?
b/c women carry an extra X chromosome
During development, X chromosomes are randly selected by cell to be inactivated which prevent Tx of almost the netire X chromosome.
THus, for almsot all x chromcomse gene,s mena nd women have about he same amt of expression.
FMR1 is subject to X inac in females
IF X inactivated
in X chrom carryign the disease allel is inactivated in disease-related tissues, thte ndividual is less likely to dispaly a fully recognizable phenotype.
A clinically unaffected mother may give birth to an affected daughter or oson
What are social implicatiosn of having disease for
chidlren wth FXS, esp boys, will need special educaitonal prodviers and cannot live independetly
is life expectancy diminsehd?
no.
NO end up life condquences are anticipated.
what is the role of genetic counselors
interpret tests thta re very complicated to clinician and patient
Explain costs and bnefits of genetic testing, and then prapproves tests with insurance complaines
explains what insureance will cover.
Continutity of care
What is FXS
oen of the most common causes of mental delays i males and speecy delays in in females
HOw many CGG repeats in premutaiton
55-200
How many CGG repeats in full mutation
> 200
waht is queationable repeats
45-54
Asymptomaitc females with 55-200 repeats have risk for….
twin pregnances
early failure of ovaries to produce vaible pregnancies
very early menoapuase
Males and females with 55-200 repeats are also at risk for FX….
Fragile X tremor/ataxia syndrome after age 50
symptoms: loss of balance, tremors, memory loss, mood swings, Parkinson-like symptoms, possibly demetnia
What other DIseases can be mistaken for
ADHD: imbalance in NT interactions that may result in inattentive and hyperactive impllsive symptoms of ADHD (need at least 6 symptoms )
Autism (seen in first 3 years of life)
Asperger’s syndoeme
Aphasia
few words
what idn of test to Dx FXS
Southern BLot
FXS inheritance
X-linked Dominant
Affected female inheritance
pass to 50% of children
Affected male inheritance
pass to 100% daughters
pass to 0% sons
most common form of intellectual instability in boys
What is the cytogenetics of FXS
CGG insertion into gene at Xq27.3 - called FMR1 gene
fucntion of FMR1 gene
not completely undersoot
RNA binding protein that is improtant in SYNAPTIC formation in brain
increase CGG repeats -> inc liklihood of expressivity
Diseases with CAG (glutaine) triplet repeat (4)
- Huntington’s Disease
- DRPLA (Denatorubropallidoluysim)
- Spinobulbar muscular atrophy
- # of spinocerebellar ataxis
Resut of CAG expanstion
formation of altered protein in affected individuatls
Non-poyglutamine triplet repeat
- FXS
- Friedriche’s Ataxia
- Myotonic Dystorphy
- 2 other spinocerebellar ataxia
What allele is causing FXS
CGG in “junk” region of X chromosome (5’UTR) of
Does not result in altered protein ,but expanded CGG makes X-chromosome MORE FRAGILE
Pre-mutaiton
55-200
Full mutation
> 200 CGG repeats
When full mutation –> FMR1 gene is turned off! no protein in is made
What happnes if protein synth of fmR1 turned off?
affects synaptic plasticity
Male vs Female with full mutaiton: symptoms
All males and 1/2 females: are affected with learning disabilties, anxiety disorders, and autistic-like behavior
Premutation frm maternal transmisttion
can be unstalbe
mothers with premutation can have affected chidlren
what determiens risk of premutation expanstion
depens on # of CGG repeats in maternal allele and other factors
What is expanstion risk
much greater in affected families
What is genetic anticipaition
condition becomes more severe and appears at an earlier age as disorder is passed from one generation to the next
i.e. expansion of CGG occurs in succeeding gnerations
What are other disorders with genetic ANTICIPATION
- Huntington’s Disease
- Kennedy Sydnrome
- Myotonic Dystorphy
What is genetic imprinting
Certain genes are expressed in a parent-of -ce…specific manner
phenotype ore sever when transimitted form mother than father
High CGG repeates and mental retardation
Most common preseting signs
Autistic-like behavior (hand flapping, avoidance of eye contact,0
- ADD/ ADHD
- IQ 35-70, decreased IQ with age
Age Dx usually mad
pre-school, elementary school
Physcial features
elongated face,
large ears
Macroorchidism (large testes)
Impulse control problems
Distractablity
Preservative Speech
Why do females have less severe symptoms
- one normal X chromosome due to X inactivation during development
Decrease PENETRANC wiht full mutaiton in FMR1
May not show learning disabilitys
may suffer social anxiety
May have fertility/premature ovarian failture
Comorbidity in females with premutation
Hypothyroidism and Fibromyalgia
Diagnosis
PCR
Southern Blot- look for CGG repeats in FMR1
Ethidium Bromide bindst o DNA after exposrue to UV
Translational research
Novartis Roche Seaside Therapeutics Afraxis GSK3 PDE4
Is life expectancy affected in pts with FXS?
no
What does ABMS
American Boards of Medical Specialities
What does ABMG
American Boards of MEidcal Genetics
