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Med Gen Neuro > Genetics of Neurodegenerative Diseases > Flashcards

Genetics of Neurodegenerative Diseases Flashcards

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1
Q

What is the trinuclotide repeat present in Huntington disease? And what does it code for?

A
  • CAG
  • encoding for glutamine
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2
Q

Which gene is effected in Huntington disease?

A

HTT

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3
Q

In which category of diesease does Huntington disease fall?

A

polyglutamine diseases

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4
Q

What is the mean age of onset for Huntington disease? What is the range?

A

mean: 30-50
range: 2-85

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5
Q

Huntington Disease

What is the mean duration of disease?

A

17-20 years

this describes the time from symptom onset to death

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6
Q

What is the mechanism of disease for Huntington disease?

A
  • CAG repeat in HTT gene encodes a polyglutamine stretch in the Huntington protein
  • Huntington protein i expressed early in development and is critical for life
  • expansion of polyglutamine makes the Huntington protein prone to misfold and then aggregate leading to neuronal loss
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7
Q

What is the mean CAG repeat length in a normal chromosome? In an HD chromosome?

A

normal ~ 18
HD ~ 42

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8
Q

At what CAG repeat size is an individual affected?

A

36

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9
Q

Does the trinucleotide repeat expand with paternal or maternal transmission in HD?

A

paternal

maternal expansion is possible but but less likely and the expansion is smaller

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10
Q

HD

What is the CAG repeat size of a normal allele?

A

≤ 26

Risk of expansion in this repeat size is essentially zero, but there is one case report of 26 –> 44, so upper end of normal may have some instability

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11
Q

HD

What number of CAG repeats is present in an intermediate allele?

A

27-35 CAG repeats

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12
Q

HD

What are the risks for someone with an allele with an intermediate number of CAG repeats?

A
  • no personal risk for HD
  • risk for HD in offspring

There have been reports of HD symptoms in intermediate allele carriers though.

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13
Q

HD

What factors contribute to risk of expansion in offspring for a carrier of an intermediate number of CAG repeats?

A
  1. repeat size: larger intermediate alleles more likely to expand
  2. sex of carrier: more liekly to expand in paternal transmission

34-35 CAG repeat allele in a male is highest risk

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14
Q

HD

How frequent are intermediate alleles in the general population?

A

1 in 50

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15
Q

HD

What is the number of CAG repeats in an allele that is considered ‘reduced penetrance’?

A

36-39 CAG repeats

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16
Q

What do we know about personal risk for HD for individuals with an allele with CAG repeats in the ‘reduced penetrance’ range?

36-39 CAG repeats = reduced penetrance range

A
  • may or may not develop sympotoms of HD
  • there is data to correlate current age and number of repeats with likelihood of developing symptoms at a certain age in the future
  • eg: 40 yo w/ 39 repeats = 52% chance of developing symptoms by 70

reduced peentrance genes have been observed at high frequency in gen pop

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17
Q

Number of CAG repeats to be full penetrance

A

40+

full penetrance = will cause HD in lifetime

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18
Q

Number of CAG repeats for juvenile onset HD

A

60+

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19
Q

Age of onset of HD to be juvenile onset? Symptoms?

A
  • <20 yo
  • epilepsy & Parkinsonism
20
Q

Effect of homozygosity in HD alleles?

A
  • similar age of onset to heterozygotes
  • accelerated rate of disease
21
Q

Loss of interruption variants result in loss of CAA interruption. Results in CAG repeat lengthening by 2. This is associated with what?

A
  • increased somatic instability
  • higher frequency of repeat expansions in sperm
22
Q

Reduced penetrance HD allele with loss of interruption (LOI) variant effect?

A

reduced penetrance HD allele individuals presented with symptoms 29 years earlier than anticipated

23
Q

Inheritance pattern of hereditary ataxia/spinocerebellar ataxia

A

autosomal dominant

24
Q

heredtiary ataxia when adult onset and AD is AKA

A

spinocerebellar ataxia

25
Q

Age of onset for hereditary ataxia/spinocerebellar ataxia?

A

adult

over 35 different types

26
Q

AR ataxias age of onset

A

childhood

27
Q

most common cause of hereditary ataxia

A

nucleotide repeat disorders

28
Q

hereditary ataxia

anticipation occurs in both mat and pat transmission, but is gene dependent

A
  • SCA1, SCA2, SCA3, SCA7, Friedreich Ataxia, CANVAS = pat
  • SCA8 & FXTAS = mat

but at least some of there are AR?

29
Q

SCA6 characteristics

A
  • adult onset
  • slowly progressive cerebellar ataxia
  • dysarthria (difficulty speaking due to muscles)
  • nystagmus (repetative, uncontrolled eye movements)
  • age of onset: 19-73
  • near full penetrance
  • no anticipation
  • CAG repeat expansion in CACNA1A gene
30
Q

sequence variants in CACNA1A cause

A
  • epilepsy
  • episodic ataxia
  • hemiplegic migraines

CACNA1A-related disorders (does not cause SCA6 like CAG repeat expansion in this gene does)

31
Q

FGF14-related ataxia (SCA27B)

A
  • GAA repeat expansion
  • normal: 6-249 repeats
  • reducaed penetrance: 250-300 repeats
  • pathogenic: >300 repeats
  • transmission: expansions = mat, contractions = pat
32
Q

Hereditary Ataxia can soemtimes be treated with replacement therapy if due to

A
  1. Vit E Deficiency
  2. Coenzyme Q10 Deficiency
33
Q

About 5-10% of Parkinsons Disease is monogenic . Can be AD, AR, rarely XL.Age of onset for AD vs AR?

A
  • AD = >50 yo
  • AR = <40 yo
34
Q

Recurrence risk for first degree relatives of someone with idiopathic Parkinson’s

A

two fold (8%)

35
Q

AD Parkinson’s genes

A
  • LRRK2
  • GBA
  • SNCA
  • VPS35
36
Q

AR Parkinson Disease genes

A
  • PRKN
  • PINK1
  • DJ1/PARK7

when AR = childhood onset, when AD = adult onset PD

37
Q

AD Parkinson Disease
* penetrance?

A
  • variable
  • age dependent
  • ethnicity based
38
Q

GBA variants cause

A
  • elevated risk for Parkinson Disease
  • AR = Gaucher disease
39
Q

Juvenile onset PD clinical presentation and genes

A
  • autosomal recessive
  • DJ1, PINK1, PRKN
  • dystonia, spasticity, dementia

hetero = adult onset PD

40
Q

Percentage of Alzheimer Disease that is famial (3+ affected) vs non-familial

A
  • familal = 25%
  • non-familial = 75%
41
Q

How many affected family mmebers to be considerd history of familial AD?

A

3 or more

42
Q

Lecanemab (leqembi) is a medication for AD. Why is APOE testing beneficial for patients with AD regarding this medicaiton?

A
  • APOE e4 allele associated with increased risk for harmful side effects such as brain bleeds and swelling
  • homozygous e4 highest risk
43
Q

APOE e4 allele and AD

A

hetero and homozygous increased risk for AD by 20-35%

44
Q

What percentage of those with FTD have familial FTD?

A

30%

45
Q

Gene associated with FTD

A

C9orf72
* hexonucleotide repeat (G4C2)
* causes FTD, ALS, or FTD-ALS
* full penetrance by 80
* short disease duration compared to GRN & MAPT
GRN & MAPT
* high penetrance
* onset ranges 30-87

Med Gen Neuro (5 decks)

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