Huntington's Disease Flashcards
Who discovered Huntingtons disease?
‘chorea’
Recognised as an inherited disorder in 1872 when a 22-year-old American doctor, George Huntington, wrote a paper called: On Chorea.
give three basic principles of huntingtons inheritance
- Everyone with the mutated gene will get HD - it is autosomal dominant
- Probability of each offspring inheriting the affected gene is 50% - it is inherited
- Inheritance is independent of gender.
what is huntingtons disease?
A neurodegenerative disease, caused by the aggregation of the huntingtin (HTT) protein in the human brain nerve cells. It is inherited from a persons parent in an autosomal dominant pattern
what does chorea mean in latin and greek?
‘dances’
involuntary/ uncontrollable movements/ mulscle jerks and twitches
there has been an _ in prevalence of huntingtons over the past two decades
increase
there has been an _ in prevalence of huntingtons over the past two decades
increase
what regions of the world have the highest prevalence of HD
America, Australia & most European & Western countries:
(10.6-13.7:100,000)
what regions of the world have the lowest prevalence of HD?
Asia & Africa (0.5:100,000 in Japan & China)
where is the huntingtin gene located
on chromosome 4
everyone has the HTT gene, but only those that ________________ will develop HD and pass it on to their children
when was the HTT gene identified?
1983
when did a predictive test for the faulty HTT gene become available?
1993
what does CAG code for?
Glutamine
how many CAG repeats are in a normal HTT gene?
10-35
how many CAG repeats are in a normal HTT gene?
10-35
how many CAG repeats are in a faulty HTT gene that causes HD?
36 or more
the length of the tail comes down to what?
how many copies of the CAG repeats there are
why can a higher number of CAG repeats potentially lead to huntington develoment in future generations
CAG repeats are prone to errors at DNA replication, so number of repeats likely increases over generation/time due to replication in the germinal line
having an increased number of repeats increasese chance of a mutation occurring in them
why can a child inherit more repeats than their parent had?
CAG repeats are prone to induce errors at DNA replication, so number of repeats likely increases over generations/time due to replication of the germinal line
an elevated number of repeats affects what two aspects of the disease profile
more repeats = earlier onset and higher severity
when does HD have 100% penetrance?
If individuals have more than 40 repeats
when do symptoms of HD start?
Symptoms start between the ages of 30-50 years (40+ CAG), although late onset (36-39 CAG) and juvenile manifestation (60+ CAG) also occur.
there is a strong inverse relationship between the age of onset and …
the number of CAG repeats
how long is the prognosis from the onset of symptoms?
(usually)
15-20 years
what are the two levels of CAG repeats in unaffected individals?
Normal: 26 or less, no disease
Intermediate: 27-35, do not develop symptoms but their children are at a risk for developing huntingtons
there are case reports of those in the intermediate range developing mild symptoms of HD
what are the levels of CAG repeats in affected individuals?
reduced penetrance: 36-39, may or may not develop symptoms at any age or may develop symtoms in old age
full penetrance: 40 or more, have disease
what are the three stages of disease progression in HD?
Presymptomatic
Prodromal - some symptoms manifested, may or may nnot be picked up by a clinician
Manifest - motor and cognitive impairment increase as well as chorea
what are the two phases of huntingtons disease?
Two phases,
Early: subtle psychomotor dysfunction - signal and connectivity affected (neuronal dysfunction)
Late: manifest progressive disease as neurons begin to die, motor impairment, chorea, and decrease in functional status
symptomatic changes in HD affect what three main areas
- Movement: Involuntary & Voluntary
- Behaviour: Changes in behaviour and personality
- Cognitive: Difficulties with planning and thinking
- The movement disorder is usually the most obvious first symptom.
- The behavioural disorder is usually the one that gives patients & carers the most concern.
- The cognitive disorder is usually the symptom people find affects them most in daily life.
why can symptoms be present a long time before diagnosis of HD?
Professionals and families can mistake HD for a different illness such as PD (parkinsons) or AD (alzheimers)
what are the different presentations of physical symptoms of HD
- The symptoms of HD are like having ALS, PD & AD simultaneously.
- Motor deficits (jerky/fidgety motor).
- May seem clumsy or stumble more than usual.
- Voluntary movement are affected.
- Abnormal eye movement.
- Speech becomes slurred.
- As disease progresses, swallowing problems become common.
- Weight loss (excessive movements and malnutrition through dysphagia) and central effects on appetite.
- Incontinence.
- Involuntary movements cannot be consciously suppressed and stop only with sleep.
what are the different presentations of the cognitive symptoms of HD?
- Memory and concentration problems
- Hard to plan and think ahead, difficult to switch between tasks.
- Lack of motivation – appear lazy.
- Reduced ability to read facial expression.
- Emotional changes –subtle changes to mood/behaviour.
- Aggressive, demanding, stubborn and self-centred.
- Impulsive or irrational, behaving in a disinhibited way or obsessive with things. depression, anxiety and anger.
- Relationships at high risk.
- May lead to social isolation.
what are the different presentations of the cognitive symptoms of HD?
- Memory and concentration problems
- Hard to plan and think ahead, difficult to switch between tasks.
- Lack of motivation – appear lazy.
- Reduced ability to read facial expression.
- Emotional changes –subtle changes to mood/behaviour.
- Aggressive, demanding, stubborn and self-centred.
- Impulsive or irrational, behaving in a disinhibited way or obsessive with things. depression, anxiety and anger.
- Relationships at high risk.
- May lead to social isolation.
what are the major reasons of mortality in those with HD
injuries
heart disease
suicide
respiratory/ heart problems
Respiratory/cardiac/suicide (major reasons for mortality – 3-13%).
what structures make up the basal ganglia?
Striatum: caudate nucleus & putamen
Globus pallidus