inherited movement disorders

Question 1

define what are the 4 types of movement disorders

Answer 1

-chorea
(wide variety of rapid, highly complex, jerky dyskinetic movements that appear well coordinated but are involuntary)

-ataxia
(loss of ability to coordinate muscle movement)

-dystonia
(characterised by abnormal movement with involuntary fast muscle spasms/ contractions leading to painful abnormal posturing)

-bradykinesia
(abnormal slow muscular movement)

Question 2

examples of inherited movement disorders from the 4 categories

Answer 2

chorea (Huntington’s disease)
ataxia (Friedreich’s ataxia )
dystonia (primary dystonia early onset)
bradykinesia (PD)

Question 3

what is Huntington’s disease and what are the clinical features as well as the order of symptom presentation, brain pathology? describe allele size for clinical presentation.

Answer 3

autosomal dominant condition, with an inherent genetic mutation within IT15/HTT gene—CAG triplet repeat expansion within exon 1 on chromosome 4 of this gene coding for H protein

neurological
(involuntary, well coordinated jerky and rapid movements)

cognitive decline (Later on in the progression of disease)

psychiatric
(anxiety, depression, and personality changes- can occur before onset.)

Person with Huntington disease on top row and comparison to normal brain.
White lines show the basal ganglia- the caudate and putamen.
In this disease – caudate especially shrinks and undergoes atrophy.
Generalised atrophy of brain volume too

order of presentation:
subtle changes before primary manifestation of this condition (prodromal)

allele size:
normal - 26 or fewer repeats (No clinical manifestation)

intermediate is 27–35 repeats, but there is a risk of transmission to next generation of the disease, causing a increase in likelihood that this repeat can expand

pathological - more than 36 repeats-reduced penetrance is 36-39 this is where you don’t have symptoms but may develop it later in life. (lower risk of developing diseases, usually at later stage of life)

Full penetrance - is more than 40 repeats

Question 4

what does CAG also code for? which gender increases expansion? what is anticipation and why does it usually occur and what increases the onset of H disease?

Answer 4

-glutamine (polyglutamine repeat of this protein- abnormal folding of glutamine, that can build up over time affecting neurons in caudate, putamen and leads to generalised atrophy)
-Huntington protein

paternal transmission/paternal germline is greater increasing expansion of repeats- the sperms replicative machinery has a greater tendency to add extra repeats during meiosis.

Anticipation – in the family tree you look at the generations and you see the age of onset is younger – normally the triplet of repat is getting better – bigger jumps with paternal transmission
occurs due to DNA repair/replication mechanism slips on repeats so it may add more than necessary
(the greater the repeats, the earlier the onset- or if you have less repeats/reduced penetrance will have later onset)

Question 5

what predictive testing can be done for H disease and why do some people do this? what are treatments

Answer 5

Genetic counselling looks at discussing the risk of transmission; therefore, it is important for parents to understand the concept of reduced penetrance and anticipation to make decisions regarding testing and family planning.

Blood tests are usually performed on second visits so during the first visit, they are asked reasons for wanting to undertake the test.

family members need to consider the likelihood of inheriting or passing on the disease, the potential for an increased number of repeats, and the implications for their or their children’s health.
however, ethical considerations need to be weighed out such that genetic status can impact one’s mental health.

no cure but treatment for symptoms

Huntington’s disease - treatment
♦ Chorea-olanzapine (dopamine D2 antagonist)
♦ Depression/Psychosis: antidepressants/antipsychotics
♦ Exercise, physiotherapy
◆ Good diet, high calorie as disease progresses

Question 6

what is friedreich’s ataxia, what is onset and clinical features, and what gene is implicated

Answer 6

it’s an autosomal recessive disorder

loss of ability to coordinate muscle movement

onset is 5-15

symptoms
-dysarthria (slurred speech)
-loss of balance
-muscle weakness

gene: FXN gene that codes for frataxin a mitochondrial protein, individuals with disease manifestation have 100-1000 GAA repeats
intronic GAA triplet repeat is not associated with anticipation (decrease risk of expansion as a result of transmission).
low levels of frataxin can lead to mitochondrial dysfunction, oxidative stress leading to damage to cells.

The progression of Friedreich’s ataxia is directly related to the length of the GAA repeat expansion: the longer the repeat, the earlier the onset of symptoms and the more severe the disease. However, unlike Huntington’s disease, Friedreich’s ataxia does not typically show anticipation, where symptoms start earlier and become more severe in successive generations. This difference is due to the nature of the genetic mutation

Question 7

what is primary dystonia’s early onset, and what are the onset, clinical features, and treatment

Answer 7

clinical features:
involuntary posturing of leg or arm
writer’s cramp
postural arm tremor

onset:
before 21 years

treatment:
Botulinum toxin
stereotactic surgery (DBS-electrode placement)