DNA testing in diagnosis of neurological disorders Flashcards Preview

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Flashcards in DNA testing in diagnosis of neurological disorders Deck (30):
1

Describe the two broad mechanisms by which neurodegenerative disorders develop?

Acquired (eg. cerebrovascular disease, alcholism)

Inherited: unstable repeat expansions 

2

What are unstable repeat expansions?

Expansion of a segment of DNA within a specific gene, which consists of repeating units of three or more nucleotides in tandem 

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3

What is the difference between naturally occuring repeat regions and repeat expansions?

Repeat expansion occurs when the number of repeats increases beyond a certain threshold > associated with a condition

 

4

Why are unstable repeat expansions referred to as dynamic?

Size of expansion changes

5

Describe the phenomenon of anticipation?

Expansion size increases in following generations

Usually associated with ealrier onset and greater severity of symptoms

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6

Describe the mechanism by which expansion of repeats occurs?

Slipped mispairing 

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7

Which body system do unstable repeat expansions usually affect?

Neurological

8

Describe the different ways in which unstable repeat expansions can affect a gene?

Non-coding repeats > loss of protein function > impaired transcription 

Non-coding repeats that confer novel properties on RNA > toxic ganin of function

Repeats in codon > novel properties on protein > novel gain of function 

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9

Describe the general characteristics of neurodegenerative disorders caused by repeat expansions?

Loss of movement control

Late onset

Progressive

10

Describe the genetics of Huntington disease?

Automsomal dominant 

CAG repeat expansion in HTT gene of chrm 4

Repeat in exon 1 - CAG codes for glutamine 

11

Describe the prevalence of HD?

1 in 10,000 to 20,000

12

Describe the onset of HD?

Late onset

Typically 40s-50s

13

Describe the major features/symptoms of HD?

Movement/motor disorder

Cognitive disorder

Psychiatric/emotional disorder

14

What is the normal role of the HTT gene?

Produces protein product - huntingtin

Seems to have roles in transcription

A lot we don't know about it 

15

What is the expanded CAG huntingtin product referred to as?

polyQ-huntingtin

16

Where does polyQ-huntingtin exert its toxic effects?

Medium spiny neurons in striatum of basal ganglia

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17

Describe the appearance of a HD brain on imaging?

Neurodegeneration

Initially starts in basal ganglia, but as disease progresses it spreads to whole brain

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18

Describe the basic molecular pathology of HD?

PolyQ-huntingtin is cleaved by caspases > generates N-terminal fragments with altered conformation > TOXIC 

Form aggregates and nuclear inclusions - may be protective?

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19

Describe the genotype/phenotype corrleation in HD?

Normal: <26 repeats

Normal, mutable (paternal transmission): 27-35 repeats

Zone of reduced penetrance: 36-39 repeats

Affected: >39 repeats 

20

Describe the effects of CCG interruptions in HD?

Don't code for glutamine > interrupt length of glutamine > can mitigate effects of CAG repeats and prevent onset of HD

21

How is HD clascially tested for?

PCR, gel electrophoresis and autoradiography 

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22

Describe the current method for HD testing?

PCR (fluorescent tagging), fragment analysis on capillary electrophoresis and fluoresence detection

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23

Describe the major features and symptoms of spinal cerebellar ataxias?

Autosomal dominant

Phenotypic variation

Progressive degeneration of cerebellum, brain stem and spinocerebellar tracts 

24

How are SCAs tested for?

Fragment analysis

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25

Describe the genetics of Freidreich ataxia?

Autosomal recessive 

GAA repeat expansion in FXN gene on chrm 9

Repeat location within intron 1

Causes abnormal DNA secondary structure > reduced protein (frataxin) production

26

Describe the main features/symptoms of Friedreich ataxia?

Progressive limb and gait ataxia

Cardiomyopathy

Diabetes mellitus

27

What is the general age of onset for FA?

Puberty 

28

Describe the pathogenesis of FA?

Repeat expasnion causes decreased frataxin production 

Causes mitochondrial iron accumulation > oxidative damage

29

Describe the FA genotype/phenotype correlation?

Normal: 5-33 repeats 

Affected: 66-1700

34-65: premutation range

30

How is FA tested for?

Standard PCR - can be used because we are dealing with large numbers of repeats 

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