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a_Genetics > 11/9- Neurogenetic Disorders in Adults > Flashcards

11/9- Neurogenetic Disorders in Adults Flashcards

1
Q

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

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)

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2
Q

What is the approach/classification of Neurogenetic disorders?

A
  • Mental disorders
  • Neurologic disorders
  • Neuromuscular disorders
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3
Q

What are dementia conditions affecting young individuals? Old?

A

Young

  • Alzheimer’s diseas
  • Fronto-temporal dementia

Older

  • Alzheimer disease
  • Vascular dementia
  • Lewy body dementia
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4
Q

What are genetic causes of Alzheimer’s?

  • What percentage are familial vs. other causes
  • Evidence for multifactorial
A
  • Familial (25%)
  • Multifactorial (75%): there is 25% chance of getting AD if there is a 1st degree relative (2.5x background risks)
  • Syndromic (< 1%)
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5
Q

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

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

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6
Q

Describe the genetics behind early onset familial Alzheimer’s disease

  • Age of onset
  • Genetic cause
A
  • Age < 65 yo

Single-gene disorder:

  • AD3: PSEN1 (20-70%)
  • AD1: APP (10-15%)
  • AD4: PSEN2 (rare)
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7
Q

Describe the genetics behind late onset familial Alzheimer’s disease

  • Age of onset
  • Genetic cause
A
  • 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
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8
Q

Early onset Alzheimer’s Disease is very common in older adults with _________. Why?

A

Down syndrome

  • Increased risk is due to increased dosage of amyloid precursor protein (gene located on chr 21)
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9
Q

Recall the neurogenetic subclasses (mental, neurologic, neuromuscular): what falls under neurologic disorders?

A
  • Basal ganglia disorders
  • Ataxia
  • Peripheral neuropathy
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10
Q

Describe the genetics of Parkinsons’ disease

A
  • Multifactorial (due to decreased dopamine in substantia nigra)
  • Most cases are sporadic
  • 10-30% have family history
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11
Q

What is “young” for someone with Parkinson’s (and many cancer cases, etc.)

A

Young is < 50 yo

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12
Q

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)

A

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)

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13
Q

What is chorea? What conditions/disease is it seen in?

A

Chorea is a neurological disorder characterized by jerky involuntary movements affecting especially the shoulders, hips, and face.

  • Seen in Huntington’s disease
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14
Q

Describe Huntington’s disease:

  • Prevalence
  • Peak age of onset
  • Prognosis
  • Classic triad
  • Other signs/symptoms
A
  • 1/10,000 Americans
  • Peak onset in 3-4th decade
  • Fatal

Classic triad:

  1. Movement disturbances
  2. Cognitive disturbances
  3. Psychiatric abnormalities

Signs/symptoms:

  • C/F: psychiatric, depression, mood swings
  • Cognitive: dementia
  • Motor: chorea, bradykinesia
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15
Q

What is seen (genetically) in Venezuelan population with high prevalence of Huntington’s?

A

Founder effect

  • One woman had HD and due to small community/”inbreeding” results in great prevalence
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16
Q

Describe the genetics of Huntington’s disease

  • Genetic cause
  • Inheritance pattern
  • Penetrance patterns
  • Disease correlates with what
A
  • 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

17
Q

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?
A

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
18
Q

What are the psychological risks of testing (HD)?

A

Negative:

  • Survivor’s guilt: why you and not me
  • False sense of security (may contract for other causes)

Positive: stress/depression

19
Q

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?

A

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
20
Q

What is anticipation?

A

Allele that passes from parent to child will expand

21
Q

In Huntington’s disease, which parent more commonly exhibits anticipation?

A

In HD expansion is more likely from father to child

22
Q

Triplet repeat disorders occur normally in groups of ____

A

Triplet repeat disorders occur normally in groups of 5-30 repeats

23
Q

What is premutation? Anticipation?

A

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
24
Q

Hereditary ataxias involve what sings/symptoms?

A
  • oor coordination of movements
  • Gait is wide-based and unsteady
  • Dysarthria is present
25
Q

What are inheritance patterns of hereditary ataxias?

A
  • AD
  • AR
  • X linked
  • Mitochondrial
26
Q

What falls under autosomal dominant form of hereditary ataxias?

  • Presentation age
  • Clinical features
A

Spinocerebellar ataxia (SCA)

  • Most likely diagnostic group for adult cerebellar ataxia
  • Overlapping clinical features with 25+ subtypes
27
Q

What falls under autosomal recessive form of hereditary ataxias?

  • Associated with what conditions/disease
  • Presentation age
A

Friedrich ataxia

  • Most common of AR ataxias
  • HOCM, DM association
  • Usually presents in childhood, but some may present in adulthood
28
Q

What falls under X linked form of hereditary ataxias?

A

FXTAS (fragile x tremor/ataxia syndrome)

29
Q

What is FXTAS?

  • What causes it
A

Fragile X tremor/ataxia syndrome

  • Premutation in FMR1
  • Caused by CGG trinucleotide repeats (55-200 repeats)
  • Most common cause of intellectual disability in males (?)
30
Q

What falls under mitochondrial form of hereditary ataxias?

A
  • MERRF: Myoclonic Epilepsy with Ragged Red Fibers
  • NARP: Neuropathy, Ataxia, and Retinitis Pigmentosa

Note if deafness or DM are present with ataxia

31
Q

What is Charcot Marie Tooth?

  • Prevalence
  • Aka
  • Genetic causes
  • Age of onset
A

Most frequent heritable disorder of the peripheral nervous system (1/3300): 20% of individuals presenting to neuromuscular clincis

  • Also known as Hereditary Motor and Sensory Neuropathies (HMSN)
  • HMSN 1: most frequent heritable neuropathy
  • CMT exhibits genetic heterogeneity (AD, AR, XLR; 40 diff genes)
  • CMT1: PMP22 duplication
  • HNP (hereditary neuropathy with pressure palsies): PMP22 deletion
  • Thus PMP22 gene is seen to be dose-dependent
  • Onset is 5-20 years
32
Q

__________ are the most frequent cause of slowly progressing weakness in the distal extremities

A

Heritable neuropathies are the most frequent cause of slowly progressing weakness in the distal extremities

33
Q

Signs and symptoms of CMT?

A
  • Distal weakness and atrophy (feet and/or hands)
  • Mild to moderate sensory loss
  • Pes cavus
  • Absent DTRs
  • Neuropathy can be painless/painful
34
Q

Case

  • 40y/o Caucasian woman complains of spasms of her fingers making it difficult for her to work as a phlebotomist for past 4 years
  • Needs to massage fingers to relieve spasm
  • Stumbles while walking and climbing stairs
  • Spasm of tongue muscles making it difficult to talk
  • Difficulty swallowing
  • Facial symmetry, normal reflexes
  • Grip myotonia +
  • Percussion myotonia +

Diagnosis?

A

Myotonic dystrophy

35
Q

What is Myotonic Dystrophy?

  • Prevalence
  • Signs/symptoms
  • Other organs affected
  • Presentation
  • Classes
A
  • 1/20,000
  • Muscle weakness and myotonia (slow relaxation of the muscles after contraction) which progresses slowly over time
  • Myopathic facies
  • Eyes, heart, and brain can also be affected
  • Exhibits variable presentation, even within families
  • Mild, classical, or congenital (severity of symptoms; age of onset)
36
Q

Describe the genetics underlying Myotonic dystrophy

  • Subtypes
A

Autosomal dominant; due to CTG repeat

  • Normal: 5-37
  • Premutation (no Sx but children at risk): 38-49
  • Mild: 50-150
  • Classical: 100-1000
  • Congenital: > 1000
37
Q

Which of the following disorders is not caused by a trinucleotide repeat expansion?

A. Myotonic dystrophy

B. Huntington disease

C. Fragile X

D. Parkinson disease

A

A. Myotonic dystrophy

B. Huntington disease

C. Fragile X

D. Parkinson disease

38
Q

A 60 yo man wants to know his risk to get Alzheimer disease so that he can plan his end-of-life care. He does not have any family history of AD. Which of the following tests would you recommend for him?

A. PARKIN gene test

B. ApoE genotyping

C. APP gene test

D. CAG repeat analysis

A

A. PARKIN gene test

B. ApoE genotyping - because he has no family history of disease; no reason to suspect early onset/familial Parkinson’s disease

C. APP gene test

D. CAG repeat analysis

a_Genetics (18 decks)

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