22.11 NS: DNA testing

Question 1

What are some inherited neurodegenerative disorders with loss of movement control caused by?

Answer 1

Unstable repeat expansions (repeating units of three or more nucleotides adjacent to each other)

e.g. CAG, CAG, CAG

Question 2

Where do repeat expansions come from?

Answer 2

Naturally occuring

Below threshold: stable in sperm/eggs and somatic cells

Above threshold: unstable in sperm/eggs and/or somatic cells

Question 3

What do unstable repeat expansions have in common?

Answer 3

Dynamic mutations

Expansion size increases in subsequent generations (anticipation)

Anticipation associated with earlier onset and/or more severe symptoms

Question 4

What is the mechanism of expansion?

Answer 4

Slipped mispairing

Question 5

What is the:
Inheritance pattern
and location in gene for…
Huntingons and Friedreich ataxia?

Answer 5

Huntington: AD, coding region (repeats in a codon, proteins get certain properties)

FA: AR, intron (non coding repeats, loss of function)

Question 6

What is the prevalence, age of onset and features of HD?

Answer 6

1:10,000-20,000

Late onset

Movement/motor/cognitive/emotional/psychiatric disorder

Progressive neurodegeneration

Question 7

What are pre-disease, early, middle and late features of HD?

Answer 7

Pre-disease: subtle cognitive/behvioural/motor/brain imaging signs

Early: clumsiness, agitation, abnormal eye movements, depression

Middle: tics, balance/gait problems, weakness, weightloss, emotional disturbances

Late: rigidity, bradykinesia, catatonic

Question 8

What is the genetic basis of HD

Answer 8

CAG repeat expansion in HTT gene on chromosome 4

CAG codes for glutamine, toxic effect esp. in medium spiny neurons

Question 9

What is the patholgy of HD?

Answer 9

Progressive degeneration, loss of medium spiny neurons in striatum (BG)

See massive brain atrophy

Question 10

What is the phenotype/genotype?

Answer 10

Normal: 40

Question 11

How do we test for HD?

Answer 11

PCR, fragment analysis

Question 12

What are the genetics, prevalence, age of onset and main features of cerebellar ataxias?

Answer 12

AD
Frequency various throughout populations
Late onset
Progressive degeneration of cerebellum, brainstem and spinocerebelar tracts

(35 described, 10 due to unstable repeat expansions)

Question 13

What occurs in SCA6?

Answer 13

A different calcium channel alpha subunit

Normal: 4-18rpts
Affected: >19 rpts

Question 14

What is the genetics, prevalence, carrier frequency, age of onset and main features of Friedreich ataxia?

Answer 14

AR
2-4: 100,000
Carrier frequency: 1/60 and 1/100 (Indo-Europeans)
Onset: puberty
Features: Progressive limb and gait ataxia, cardiomyopathy, diabetes

Question 15

What is the pathology of FA?

Answer 15

GAA repeat in FXN gene (chromosome 9). Repeat in intron 1, switches off gene expression reducing protein production

Causes an iron overload in the heart

Question 16

What is the phenotype/genotype correlation in FA?

Answer 16

Normal: 5-33 rpts
Affected: 66-1700 rpts