Genetics - Predisposition to adult onset disease Flashcards
Why are adults referred to genetics?
- Diagnosis
- Predictive testing
- Carrier testing or cascade screening
- Family history (including cancer)
- Fetal loss or recurrent miscarriages.
What are the genetic mechanisms that may be involved in adult-onset genetic disease?
- •Single gene - x linked etc
- •Chromosomal
- •Mitochondrial
- Multifactorial
What is the relationship between genetics and environment in disease?
All disease have genetic and environmental components.
More genetic disease are:
- Rare
- Genetics are simple
- Unifactorial
- HIgh recurrence rate
- Such as MND, Huntingtons
More environmental diseases:
- Common
- Complex genetics
- Multifactorial
- Low recurrence rate
- Such as TB and DM2
DIsease are essentially on a spectrum of a relationship between genetics and environment.
With what gene disorders is it easier to estimate risk, and which are more difficult?
- Single gene disorders with high penetrance
- risk estimation easier
- Multifactorial conditions
- a polygeneic genetic component interacting with environmental factors
- risk estimation more difficult
- Risk alleles being identified for common / mutifactorial disease
- predictive value of each is very small
What are the 4 ethical prinicples of medicine?
- Respect for autonomy
- Beneficence
- Non-maleficence
- Justice
Outline the issues of uncertainty in the prediction of genetic diseases?
What other issues around genetic testing can arise?
- Test information must be usable for prevention or treatment.
- Susceptibility testing requires adequate information about uncertainty
- Predictive testing requires proper counselling - due to implications for people
- Children or adolescents should only be tested if there are potential medical benefit as children
- Third parties (employers, insurers) should have no access
What is a Shared Genetic Heritage? And the risk it outlines?
Genetic disease affects families, not individuals
Discovery of a genetic disorder implies a risk for relatives
This can come as a big shock, and with passing on diseases there may be guilt, or paranoia about familial diseases.
What is the genetic risk of MND?
Mean age of onset?
5-10% familial (AD +AR)
Sporadic - 1-2/100,000
Mean age onset 55yrs (younger in familial forms)
What are the clinical features of MND?
- Progressive muscle weakness, wasting and increased reflexes
- (ie upper and lower neurone signs)
- Limb and bulbar muscles involved
- Pure motor signs (with fasciculations)
- Cognition spared
- Death due to respiratory failure
What is the pathophysiology ALS/MND?
- Cu/Zn superoxide dismutase (SOD):
- ~20% of familial cases, 2% of all cases
- 1y function: catalyses conversion of intracellular superoxide radicals produced during normal metabolism
- Ubiquitous enzyme, motor neurones express it highly
- ?toxic gain of function ?toxic intracellular aggregates
In humans, three forms of superoxide dismutase are present
- SOD1 is located in the cytoplasm
- SOD2 in the mitochondria
- SOD3 is extracellular
- SOD1 and SOD3 contain copper and zinc,
- SOD2 has manganese in its reactive centre.
- The genes are located on chromosomes 21, 6 and 4
SLIDE 20
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What are the main issues to discuss with someone wanting a genetic test for MND?
- Incomplete penetrance…..no certainty even with mutation analysis
- No cure
- No satisfactory treatment
Outline X -lined inheritance
X linked inheritance is one of the ways in which single gene defects can be passed on.
In X linked inheritance the gene defect is found on the X chromosome, in females (who have 2 X chromosomes) they are only carriers because the other unaffected X will make up for/override the abnormality of the other.
However, X linked inheritance will affect males because they have a mixture of X and much shorter Y chromosomes, being unlike females they have no gene to take over for the defective X.
Mothers will carry - and there is a 50% chance of giving the gene to the son.
What are the inheritance/onset of Huntington’s Disease?
- Autosomoal Dominant
- Adult onset
- Unique mutation identified
What are the clinical features of Huntington’s Disease?
- Movement Disorder
- Chorea
- Athetosis
- Myoclonis
- Rigidity
- Cognitive changes
- poor planning & memory
- subcortical dementia (executive function)
- NOT classical dementia
- •Personality change
- –Irritable
- –Apathetic
- –loss of empathy - ‘A different person’
- –disinhibition
- –self centred
- Psychiatric Disease
- Depression, Paranoia, Psycosis
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- Depression, Paranoia, Psycosis
