Case #4 Fragile X Syndrome

Question 1

HOw many people does FXS affect in US? (male vs female)?

Answer 1

Male: 1/2500-4000

Female: 1/7000-8000

Question 2

Prevalance of female (heterozygous) carriers

Answer 2

1/130-250 in general population

Question 3

Prevalence of male (heter) carriers

Answer 3

1/250-800

Question 4

What % of previously undiagnosed mental retardeation in males and females, is due to FXS

Answer 4

males: 10%
female: 3%

Question 5

Why doesn;t Betseys mother or father appear to nogt have FXS

Answer 5

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

Question 6

Why is FXS have reduced penetrance in women?

Answer 6

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

Question 7

IF X inactivated

Answer 7

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

Question 8

What are social implicatiosn of having disease for

Answer 8

chidlren wth FXS, esp boys, will need special educaitonal prodviers and cannot live independetly

Question 9

is life expectancy diminsehd?

Answer 9

no.

NO end up life condquences are anticipated.

Question 10

what is the role of genetic counselors

Answer 10

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

Question 11

What is FXS

Answer 11

oen of the most common causes of mental delays i males and speecy delays in in females

Question 12

HOw many CGG repeats in premutaiton

Answer 12

55-200

Question 13

How many CGG repeats in full mutation

Answer 13

> 200

Question 14

waht is queationable repeats

Answer 14

45-54

Question 15

Asymptomaitc females with 55-200 repeats have risk for….

Answer 15

twin pregnances

early failure of ovaries to produce vaible pregnancies

very early menoapuase

Question 16

Males and females with 55-200 repeats are also at risk for FX….

Answer 16

Fragile X tremor/ataxia syndrome after age 50

symptoms: loss of balance, tremors, memory loss, mood swings, Parkinson-like symptoms, possibly demetnia

Question 17

What other DIseases can be mistaken for

Answer 17

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

Question 18

Aphasia

Answer 18

few words

Question 19

what idn of test to Dx FXS

Answer 19

Southern BLot

Question 20

FXS inheritance

Answer 20

X-linked Dominant

Question 21

Affected female inheritance

Answer 21

pass to 50% of children

Question 22

Affected male inheritance

Answer 22

pass to 100% daughters
pass to 0% sons

most common form of intellectual instability in boys

Question 23

What is the cytogenetics of FXS

Answer 23

CGG insertion into gene at Xq27.3 - called FMR1 gene

Question 24

fucntion of FMR1 gene

Answer 24

not completely undersoot

RNA binding protein that is improtant in SYNAPTIC formation in brain

increase CGG repeats -> inc liklihood of expressivity

Question 25

Diseases with CAG (glutaine) triplet repeat (4)

Answer 25

1. Huntington's Disease 2. DRPLA (Denatorubropallidoluysim) 3. Spinobulbar muscular atrophy 4. # of spinocerebellar ataxis

Question 26

Resut of CAG expanstion

Answer 26

formation of altered protein in affected individuatls

Question 27

Non-poyglutamine triplet repeat

Answer 27

1. FXS 2. Friedriche's Ataxia 3. Myotonic Dystorphy 4. 2 other spinocerebellar ataxia

Question 28

What allele is causing FXS

Answer 28

CGG in "junk" region of X chromosome (5'UTR) of Does not result in altered protein ,but expanded CGG makes X-chromosome MORE FRAGILE

Question 29

Pre-mutaiton

Answer 29

55-200

Question 30

Full mutation

Answer 30

>200 CGG repeats When full mutation --> FMR1 gene is turned off! no protein in is made

Question 31

What happnes if protein synth of fmR1 turned off?

Answer 31

affects synaptic plasticity

Question 32

Male vs Female with full mutaiton: symptoms

Answer 32

All males and 1/2 females: are affected with learning disabilties, anxiety disorders, and autistic-like behavior

Question 33

Premutation frm maternal transmisttion

Answer 33

can be unstalbe mothers with premutation can have affected chidlren

Question 34

what determiens risk of premutation expanstion

Answer 34

depens on # of CGG repeats in maternal allele and other factors

Question 35

What is expanstion risk

Answer 35

much greater in affected families

Question 36

What is genetic anticipaition

Answer 36

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

Question 37

What are other disorders with genetic ANTICIPATION

Answer 37

1. Huntington's Disease 2. Kennedy Sydnrome 3. Myotonic Dystorphy

Question 38

What is genetic imprinting

Answer 38

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

Question 39

Most common preseting signs

Answer 39

Autistic-like behavior (hand flapping, avoidance of eye contact,0 2. ADD/ ADHD 3. IQ 35-70, decreased IQ with age

Question 40

Age Dx usually mad

Answer 40

pre-school, elementary school

Question 41

Physcial features

Answer 41

elongated face, large ears Macroorchidism (large testes) Impulse control problems Distractablity Preservative Speech

Question 42

Why do females have less severe symptoms

Answer 42

1. 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

Question 43

Comorbidity in females with premutation

Answer 43

Hypothyroidism and Fibromyalgia

Question 44

Diagnosis

Answer 44

PCR Southern Blot- look for CGG repeats in FMR1 Ethidium Bromide bindst o DNA after exposrue to UV

Question 45

Translational research

Answer 45

``` Novartis Roche Seaside Therapeutics Afraxis GSK3 PDE4 ```

Question 46

Is life expectancy affected in pts with FXS?

Answer 46

no

Question 47

What does ABMS

Answer 47

American Boards of Medical Specialities

Question 48

What does ABMG

Answer 48

American Boards of MEidcal Genetics