What is the mode of inheritance of huntingtons disease ?
Autosomal dominant
When does symptoms of huntingtons usually arise ?
between 30-50
If a patient has an autosomal dominant condition what are the chances that their child will inherit the condition ?
50%
Define each of the following terms in genetic speak:
- Penetrance
- Anticipation
- Heritability
- Transformation
- Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait
- In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted.
- Contribution of a genetic component to a certain character (disease), compared to that of the environment
- transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s).
What are the early symptoms of huntingtons disease?
- Mood swings - irritability or aggressive behaviour
- depression e.g. low mood, lack of interest in things, feeling of hopelessness
- Choreiform movements - repetitive and rapid, jerky, involuntary movement that appears to be well-coordinated
- poor coordination - e.g. stumbling and clumsiness
- Memory lapses - e.g. trouble learning new information or making decisions.
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What are the later symptoms of huntingtons disease which may develop?
- Choreiform movements become more pronounced
- Difficulty speaking clearly – eventually they may find all communication very difficult
- Swallowing problems – can predispose to pneumonia or chocking
- Increasingly slow or rigid movements
- Personality changes – sometimes they may change so they don’t seem like their former self at all e.g.
- Decline in thinking (short and long term memory deficits) and reasoning abilities, may have dementia (progressive global cognitive decline)
- Breathing problems
- Difficulty moving around – they may eventually lose the ability to walk or sit up by themselves
Mutations in what gene cause huntingtons disease and what abnormality does the gene mutation cause (talking about problems with DNA)?
Due to a defect in HTT gene on chromsome 4 - resulting in trinucleotide repeat disorder: repeat expansion of CAG:
- Normally, the CAG segment is repeated 10 to 35 times within the gene.
- In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times.
- People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder.
How long do patients with huntingtons disease survive usually after onset of symptoms ?
15-20years - so die young usually
What 3 main features is seen in the classic appearance of someones brain with alzhimers disease ?
- shrinkage of cerebral cortex
- Shrinkage of hippocampus
- Enlargement of ventricles
Widening of sulci and narrowing of gyri - due to shrinkage of cerebral cortex
What is the life-expectancy of someone following alzhimers disease?
7yrs
Describe the neuropathological process for the development of alzhimers ?
- Alzheimers involves the formation of extracellular beta amyloid plaques, which cause inflammation (neuronal damage) and neurofibrillary tangles.
- Inside the cells- tau protein involved in the microtubules (important for structure of neuron and intracellular transport) is hyperphosphorylated and causes the tangles
- ACh neurotransmitter is also lost through neuron degeneration
What are the general risk factors for alzhimers disease and for alzhimers (not talking about early onset) what do studies suggest are the 2 main factors which play a role in its development ?
Multifactorial - environmental and genetic
Eg. Smoking, ApoE4, 1st degree relative affected, depression, loneliness
What mutations cause early-onset alzhimers disease and what is the mode of inheritance of these mutations?
- Occurs between 30s to mid 60s (for exam purpose it will probably be someone like 30sih or low 40s)
- Tend to have 3 affected individuals in family
- Amyloid protein precursor (APP) mutations, presenilin-1 (PSEN1) mutations, and presenilin-2 (PSEN2 )mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). These mutation may be present
What condition is strongly associated with alzhimers disease ?
Downs syndrome
What area of the brain is the first to be affected in alzhimers disease ?
Nucleus basalis of meynert (this is the main source of cholingeric projections i.e. related to ACh)
What is the lifetime risk of alzhimers disease and what is the risk if a 1st degree relative is affected by it
- Standard is 10%
- If 1st degree relative affected then roughly 25%
What mode of scanning when used in conjunction with clinical history and other diagnostic tests, is helpful when evaluating patients who are experiencing cognitive decline and should be used to help differentiate between the main forms of dementia - Alzhimers, vascular dementia, Lewy body dementia and fronto-temopral dementia ?
SPECT - allows doctors to see how blood flows to tissues and organs
Match the SPECT scan appearance to the type of dementia:
- Decreased uptake in the posterior cingulate gyrus, parietal and medial temporal lobes
- Decreased uptake in frontal and temporal lobes
- a vascular pattern of decreased uptake in multiple areas (patchy attenuation throughout the brain)
- decreased occipital lobe uptake
- Decreased uptake in the posterior cingulate gyrus, parietal and medial temporal lobes - Alzhimers
- Decreased uptake in frontal and temporal lobes - Fronto-temporal lobe dementia
- a vascular pattern of decreased uptake in multiple areas (patchy attenuation throughout the brain) - Vascular dementia
- decreased occipital lobe uptake - Lewy body dementia
What percentage of the UK pop have Bipolar I and what % have bipolar II?
Bipolar I - 1%
Bipolar II - 2%
What is the mode of inheritance of bipolar disorder ?
Multifactorial (==> there is an element of genetic inheritance but also environmental)
How strong is the genetic link for inheritance of bipolar disorder ?
Very
- Recurrence in dizygotic twins: 14%
- Recurrence in monozygotic twins: 57%
Is genetic testing useful in bipolar disorder, explain reasoning
No - as we don’t know the genetic mutations which cause bipolar disorder
What is the pathological hallmark of huntingtons disease ?
The pathological hallmark of HD is the degeneration and atrophy of the striatum (esp the caudate nucleus), but as the disease progresses there is also involvement of the cerebral cortex and other subcortical structures
What is the pathological macroscopic appearance of huntingtons disease?
- There is atrophy of basal ganglia, particularly of the caudate nucleus, and to a lesser extent the putamen
- Compensatory expansion of lateral and 3rd ventricles
- Cortical atrophy occurs later
