DNA testing in diagnosis of neurological disorders with loss of movement control Flashcards Preview

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Flashcards in DNA testing in diagnosis of neurological disorders with loss of movement control Deck (17):

as opposed to acquired neurodegenerative disorders (stroke, tumour, etc), some are [....].

A subset of these are caused by a genetic mechanism, [......]. These are characterized by an expansion of a segment of DNA within a specific gene, consisting of repeating units of 3 or more nucleotides in tandem.

For example: CAG CAG CAG CAG would be considered a [....] repeat.
CCTG CCTG CCTG CCTG would be considered a [....]

"unstable repeat expansions"

trinucleotide repeat. (most common)
tetranucleotide repeat.


below a certain threshold, there is a considered to be a normal or [stable] amount of repeats present in sperm/eggs and somatic cells, however beyond this threshold the repeats can be considered [....]



unstable repeat expansions are considered to be [....] mutations because the expansion size increases with each generation.

This phenomenon is called [...] and is usually associated with [....] onset, and/or [....] symptoms


earlier onset and greater severity of symptoms.


repeat expansion is thought to occur during DNA replication via [.....] in which the replicating strand detaches innapropriately from the template strand during replication by one repeat length.
---> newly synthesized strand contains an additional repeat

slipped mispairing.

NB: especially during meiosis


there are three classes of unstable repeat expansions:
1) non coding repeats causing a loss of protein function
-->leading to [.....]
this is the cause of [.....] disease.

2) non-coding repeats that confer novel properties on the RNA.---> leads to [.....]
this is the cause of [.....] disease.

3) repeats in a codon that confer novel properties on the affected protein-->results in [....]
this is the cause of [.....] disease.

1)impaired transcription of the affected gene
freiderich's ataxia

2)an RNA with a toxic gain-of-function
fragile x-associated tremor (FXTAS)

3) novel gain of function---production of modified protein ovverrides production of normal protein.
Huntington's Disease. Some spinal cerebellar ataxia's (SCA's)


clinical signs of huntington disease present variably based on progression:
early phase: clumsiness, irritability, disinhibition.
middle phase: [....]
late phase: [.....]

huntington's chorea, involuntary movements

rigidity, bradykinesia, dysphasia

NB: subtle prodromal disease signs to look out for: cognitive, behavioural, motor, brain imaging


the genetic basis of HD is in a [....] type unstable repeat expansion in the [....] gene.

The resultant HTT (huntingtin) protein (Poly-Q Huntingtin) exerts a toxic effect on the [....], especially in medium spiny neurons of the striatum.

Recall the striatum is the conglomerate of the: [......]

trinucleotide (CAG)
HTT (hungtington gene)

basal ganglia

caudate nucleus, putamen, and globus pallidum.


depending on number of repeats, the HTT gene show variable [....]. With increasing repeats, the [....] increases up to complete [.....].

the normal threshold for repeats is [....]. Full penetrance is at a threshold of [....].

CCG interruptions can [....] the effects of the CAG trinucleotide repeats.



26 or fewer repeats.
40 or more repeats is full penetrance of HTT gene.


gold standard for genetic testing of Huntington disease?

PCR "fragment analysis" on capillary electrophoresis and fluorescence detection.

NB: 36 or more repeats is the threshold for being considered 'affected' on this test.


how is Huntington Disease inherited?
age of onset?
main features?

-autosomal dominant.
-0.01% prev
-late-onset (4th-5th decade), although 5-10% acquire it before 20yrs old

-movement/motor disorder
-cognitive disorder
-psychiatric/emotional disorder

NB: Progressive neurodegeneration (10-15yrs btw diagnosis and death)


how are Spinocerebellar Ataxia's inherited?
age of onset?
main features?

-autosomal dominant.
-freq varies in diff populations (around 0.01%)
-late onset (generally)

main features:
-progressive degeneration of brain stem, cerebellum, spinocerebellar tracts (speech, eye movements, gait, hand coordination)

NB: +35 SCA's identified, 10 of these due to unstable repeat expansions


which gene is implicated in SCA1, SCA2, and SCA3? Why is SCA6 different?

In which SCA is a founder effect seen in australian aboriginals and portuguese?

ATXN1/2/3 is implicated in SCA1/2/3, respectively.

SCA6 involves a gene encoding a subunit of a calcium channel, CACNA1.-->problem arises when you have abnormal number of repeats,. producing a dominant negative effect.

SCA3 shows founder affect with indigenous aussies.


Gold standard for detecting SCA6?
threshold for normal repeats?

PCR with fragment analysis and electrophoresis.

4-18 repeats is normal. more than 19 is affected.


how is Friedrich's ataxia inherited?
age of onset?
main features?

-Autosomal recessive.
-0.002% prevalence (mostly indo-europeans)
-usually around puberty (typically


which gene is implicated in freidrich's ataxia? which chromosome? which intron?

the repeat causes abnormal DNA secondary structure or induces [...], resulting in reduced protein production.

this is a GAA trinucleotide repeat expansion in the FXN gene of chromosome 9, located within intron 1.


the normal protein product of the FXN gene is called, [....], and is responsible for transport of [....] into mitochondria. When it's defective it causes---->[....]

Fe (Iron)
mitochondrial iron accumulation, leading to oxidative damage.


how is FA detected?
what is the threshold for normal repeats?

electrophoresis. no ladder effect due to enormous amount of repeats.

5-33 repeats is normal.
affected range in 66-1700 repeats.

*34-65 uninterrupted repeats is considered premutation (mutable) range.