Neurogenetic Disorders in Adults Flashcards
Of the following categories of genetic tests, which best describes the test for Huntington disease in a 20 yo asymptomatic individual whose father died of complications of HD?
A. Carrier
B. Diagnostic
C. Predictive
D. Susceptibility
A. Carrier: only done for AR conditions to see if someone is a carrier
B. Diagnostic: the pt is not symptomatic, so this is not diagnostic testing
C. Predictive
D. Susceptibility: done for complex/multifactorial disorders for which you think you are at risk; at risk, but doesn’t mean you will for-sure get it (unlike Huntington’s, which has near 100% penetrance)
What is the approach/classification of Neurogenetic disorders?
- Mental disorders
- Neurologic disorders
- Neuromuscular disorders
What are dementia conditions affecting young individuals? Old?
Young
- Alzheimer’s diseas
- Fronto-temporal dementia
Older
- Alzheimer disease
- Vascular dementia
- Lewy body dementia
What are genetic causes of Alzheimer’s?
- What percentage are familial vs. other causes
- Evidence for multifactorial
- Familial (25%)
- Multifactorial (75%): there is 25% chance of getting AD if there is a 1st degree relative (2.5x background risks)
- Syndromic (< 1%)
Which of the following is the best resource int he US for finding a lab which performs a given genetic test?
A. Gene clinics (genetests.org)
B. Genetic Alliance
C. National Institutes of Health Genome Browser
D. National Genetics and Education Developmental Center
E. Online Mendelian Inheritance in Man
A. Gene clinics (genetests.org)
B. Genetic Alliance
C. National Institutes of Health Genome Browser
D. National Genetics and Education Developmental Center
E. Online Mendelian Inheritance in Man
Describe the genetics behind early onset familial Alzheimer’s disease
- Age of onset
- Genetic cause
- Age < 65 yo
Single-gene disorder:
- AD3: PSEN1 (20-70%)
- AD1: APP (10-15%)
- AD4: PSEN2 (rare)
Describe the genetics behind late onset familial Alzheimer’s disease
- Age of onset
- Genetic cause
- Age > 65 yo
Susceptibility genes:
- APOE, variants: e2, e3, e4
- Not everyone with these will develop AD, but if you don’t have these on either allele, it is pretty protective
- Most common genotype is e4,e4
Early onset Alzheimer’s Disease is very common in older adults with _________. Why?
Down syndrome
- Increased risk is due to increased dosage of amyloid precursor protein (gene located on chr 21)
Recall the neurogenetic subclasses (mental, neurologic, neuromuscular): what falls under neurologic disorders?
- Basal ganglia disorders
- Ataxia
- Peripheral neuropathy
Describe the genetics of Parkinsons’ disease
- Multifactorial (due to decreased dopamine in substantia nigra)
- Most cases are sporadic
- 10-30% have family history
What is “young” for someone with Parkinson’s (and many cancer cases, etc.)
Young is < 50 yo
Describe the genetics behind autosomal dominant vs. recessive Parkinson’s disease
(recall that not all cases of Parkinson’s are considered genetic; family history is what makes us think of familial/genetic)
Autosomal dominant
- PARK 1
- Onset ~ 45 yrs
Autosomal recessive
- PARK2 (parkin), PINK1, DJ1
- Onset 20-40 yrs
(As general rule, AR diseases are more severe and present earlier than AD)
What is chorea? What conditions/disease is it seen in?
Chorea is a neurological disorder characterized by jerky involuntary movements affecting especially the shoulders, hips, and face.
- Seen in Huntington’s disease
Describe Huntington’s disease:
- Prevalence
- Peak age of onset
- Prognosis
- Classic triad
- Other signs/symptoms
- 1/10,000 Americans
- Peak onset in 3-4th decade
- Fatal
Classic triad:
- Movement disturbances
- Cognitive disturbances
- Psychiatric abnormalities
Signs/symptoms:
- C/F: psychiatric, depression, mood swings
- Cognitive: dementia
- Motor: chorea, bradykinesia
What is seen (genetically) in Venezuelan population with high prevalence of Huntington’s?
Founder effect
- One woman had HD and due to small community/”inbreeding” results in great prevalence
Describe the genetics of Huntington’s disease
- Genetic cause
- Inheritance pattern
- Penetrance patterns
- Disease correlates with what
- Triplet repeat expansion disorder: expansion of a segment of DNA that contains a repeat of 3 nucleotides; here CAG
- Autosomal dominant
Penetrance variation:
- 10-35 repeats: normal
- 27-35 repeats: pre-mutation
- 36-39 repeats: incomplete penetrance
- >40 repeats: HD
Inverse correlation with number of repeats and age of onset
Case 1: HD testing in a complicated family situation
- Mr. H is a 60y/o white veteran with a hx of seizures, TBI and 2 yr hx of dystonic movements involving the face and neck
- He is adopted
- Mother is ill and he is the only care-giver
- Depressed affect; no social support
- At follow up, there was no suicidal ideation now but there was 2 wks ago; he has many guns but no plans to use them
- Pt was stressed and frustrated b/c he cannot leave house and has to put mom on toilet every 10-15 min
- When asked if he will harm self, he says he died a long time ago in the Vietnam war
- Came in for another follow-up after mother had passed; had detailed counseling with geneticist and genetic counselor
- What should be considered?
Really think about how an asymptomatic individual can handle the news that they will have a fatal disease
- If depressed, be very careful
- In this case, the individual was not tested at initial genetics visit
- Was not tested at initial follow up (Vietnam war story, suicidal ideation)
- Was tested after mother died and after counseling
- After results, followed up in neurogenetics clinic; released from care
What are the psychological risks of testing (HD)?
Negative:
- Survivor’s guilt: why you and not me
- False sense of security (may contract for other causes)
Positive: stress/depression
Case 2: unusual results of HD
- 51y/o white male with features suggestive of HD that started 10 years ago
- Family history of HD in mother, brother, maternal uncle
- Testing sent by neurology in June 2010
- Seen by Genetics in Sept 2010: explained his results
- Allele 1: 41 repeats (normal is under 36 repeats)
- Allele 2: 38 repeats
- Patient has 6 children and 6 grandchildren
- Not in contact with eldest daughter
- Owns a gun
What is tricky here?
He’s in the grey zone; the triplets may expand in next generation
- All of his kids will pretty much develop Huntington’s (either allele can expand, and 1 will definitely be inherited)
- Never test children for Huntington’s disease; let them decide on their own; preserve child autonomy
What is anticipation?
Allele that passes from parent to child will expand
In Huntington’s disease, which parent more commonly exhibits anticipation?
In HD expansion is more likely from father to child
Triplet repeat disorders occur normally in groups of ____
Triplet repeat disorders occur normally in groups of 5-30 repeats
What is premutation? Anticipation?
In triplet repeat disorders:
- Premutation: expansion of the repeat but not disease-causing; associated with greater risk of expansion in the next generation
- Anticipation: symptoms become more severe or start earlier in the next generation
Hereditary ataxias involve what sings/symptoms?
- oor coordination of movements
- Gait is wide-based and unsteady
- Dysarthria is present
