DNA Testing in Diagnosis of Neurological Disorders with Loss of Movement Control Flashcards
What is an unstable repeat expansion?
an expansion of a segment of DNA within a specific gene where a particular unit is repeated, most commonly a trinucleotide sequence
Why are unstable repeat expansions called dynamic mutations?
because the mutation can increase and decrease in size and is not fixed for every cell in the body
What does the number of repeats correlate with?
disease severity and age of onset
What is the mechanism of unstable repeat expansions?
the region of DNA already has a repeat sequence which means the replicative mechanism can slip along the DNA as it reads it which can result of looping out of the DNA which would result in expansion of the repeat
What type of disorders are primarily caused by unstable repeat expansions?
neurological disorders e.g. Huntington’s, Fragile X syndrome, myotonic dystrophy and Freidrich ataxia
What are the 3 possible effects of an unstable repeat expansion?
loss of protein production or novel RNA properties if the expansion is in a non coding region, and novel protein properties if the expansion is in a coding region
What are the clinical features of a neurodegenerative disorder caused by repeat expansions?
generally late onset, symptoms worsen over time, characterised by loss of movement control
What is the inheritance for Huntington’s disease?
autosomal dominant
What is the prevalence of Huntington’s disease?
1 in 10,000-20,000
What are the main clinical features of Huntington’s disease?
motor disorder, cognitive disorder, psychiatric disorder
What is the repeat expansion in Huntington’s disease?
CAG repeat coding for glutamine in HTT gene on chromosome 4
What is the role of the protein product huntingtin?
regulating transcription, intracellular transport, signalling and metabolism and reducing apoptosis
Where does the expanded product of huntingtin protein (polyQ-huntingtin) first show effects?
in the medium spiny neurons in the striatum of the basal ganglia
What can be seen on a brain scan of a patient with Huntington’s disease?
atrophy initially of the striatum but eventually the whole brain - can see enlarged ventricles
Why is the polyQ-huntingtin protein toxic?
because it is cleaved by caspases into glutamine rich fragments which are toxic and can form aggregates and nuclear inclusions
How many CAG repeats are required for 100% penetrance of Huntington’s?
40 or more
How many CAG repeats are normal in the HTT gene?
26 or less
How is Huntington’s disease tested for?
gel electrophoresis or fragment analysis to see the size of the fragments
What are spinocerebellar ataxias?
progressive degeneration of cerebellum, brain stem and spinocerebellar tracts - some of which are due to unstable repeat expansions
What is Freidrich ataxia?
a progressive limb and gait ataxia due to an unstable repeat expansion - also causes cardiomyopathy and diabetes mellitus
What is the inheritance of Freidreich ataxia?
autosomal recessive
What is the prevalence of Freidreich ataxia?
2-4 in 100,000
What is the repeat expansion in Friedreich ataxia?
GAA repeat expansion in intron 1 of FXN gene on chromosome 9
What is the effect of the repeat expansion in Freidrich ataxia?
reduced protein production which leads to mitochondrial iron accumulation leading to oxidative damage
What is the normal number of repeats in the FXN gene?
5-33
What is the number of repeats in the FXN gene which will cause Freidrich ataxia?
66 to 1700
