DNA testing in diagnosis of neurological disorders Flashcards
(30 cards)
Describe the two broad mechanisms by which neurodegenerative disorders develop?
Acquired (eg. cerebrovascular disease, alcholism)
Inherited: unstable repeat expansions
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
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
Why are unstable repeat expansions referred to as dynamic?
Size of expansion changes
Describe the phenomenon of anticipation?
Expansion size increases in following generations
Usually associated with ealrier onset and greater severity of symptoms
Describe the mechanism by which expansion of repeats occurs?
Slipped mispairing
Which body system do unstable repeat expansions usually affect?
Neurological
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
Describe the general characteristics of neurodegenerative disorders caused by repeat expansions?
Loss of movement control
Late onset
Progressive
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
Describe the prevalence of HD?
1 in 10,000 to 20,000
Describe the onset of HD?
Late onset
Typically 40s-50s
Describe the major features/symptoms of HD?
Movement/motor disorder
Cognitive disorder
Psychiatric/emotional disorder
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
What is the expanded CAG huntingtin product referred to as?
polyQ-huntingtin
Where does polyQ-huntingtin exert its toxic effects?
Medium spiny neurons in striatum of basal ganglia
Describe the appearance of a HD brain on imaging?
Neurodegeneration
Initially starts in basal ganglia, but as disease progresses it spreads to whole brain
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?
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
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
How is HD clascially tested for?
PCR, gel electrophoresis and autoradiography
Describe the current method for HD testing?
PCR (fluorescent tagging), fragment analysis on capillary electrophoresis and fluoresence detection
Describe the major features and symptoms of spinal cerebellar ataxias?
Autosomal dominant
Phenotypic variation
Progressive degeneration of cerebellum, brain stem and spinocerebellar tracts
How are SCAs tested for?
Fragment analysis
