predisposition to adult onset disease

Question 1

why are adults referred to genetics

Answer 1

diagnosis 
predictive testing 
carrier testing or cascade screening 
FHx incl cancer
foetal loss or recurrent miscarriages

Question 2

mechanisms of adult onset genetic disease

Answer 2

single gene - dominant, recessive, X linked
chromosomal - rearrangement, multiplication
mitochondrial - tend to worsen with age
multifactorial

+ environment

Question 3

contributions of genetic and environmental factors to human diseases

Answer 3

wide spectrum

some are mostly based on genetics, some are mostly environmental some are much more mixed

e.g. environment can contribute to age of onset of Huntington’s

genetic conditions: rare, simpler genetic influence, unifactorial, high recurrence rate
environmental conditions: common, genetics complex, multifactorial, low recurrence rate

Question 4

risk estimation in single gene disorders

Answer 4

single gene disorders w/ high penetrance = risk estimation easier

Question 5

risk estimation in multifactorial disorders

Answer 5

polygenic genetic component interacting w/ environmental factors

risk estimation more difficult

risk alleles being identified for common/multifactorial disease
predictive value of each is very small

Question 6

prediction and uncertainty - principles about genetic testing

Answer 6

test info must be usable for prevention or treatment

susceptibility testing requires adequate info about uncertainty

predictive testing requires proper counselling

children/adolescents should only be tested if there are potential medical benefits - intervention that benefits the child’s health

3rd parties should have no access

Question 7

what is shared genetic heritage

Answer 7

genetic disease affects families, not individuals

discovery of a genetic disorder implies a risk for relatives

Question 8

amyotrophic lateral sclerosis - MND

Answer 8

generally sporadic 1-2/100 000
mean age onset 55y/o, younger in familial forms
5-10% familial (AD + AR)

Question 9

clinical features of ALS

Answer 9

progressive muscle weakness, wasting and increased reflexes (UMN and LMN signs)

limb and bulbar muscles involved

pure motor signs (w/ fasciculations)

cognition spared

death due to resp failure

VARIABLE PROGNOSIS

Question 10

genetics of ALS

Answer 10

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, expressed highly by motor neurones

? toxic gain of function, toxic intracellular aggregates - eventually cause sufficient damage to the neurones to kill them

Question 11

superoxide dismutase

• locations
• components
• gene locations

Answer 11

3 forms present in humans:

• SOD1 - cytoplasm
• SOD2 - mitochondria
• SOD3 - extracellular

SOD1 and 3 - contain Cu and Zn
SOD2 - Mn in its reactive centre

genes located on chromosomes 21, 6 and 4

Question 12

role of SOD

Answer 12

presence protects many types of cells from free radical damage that is important in ageing and ischaemic tissue damage

also helps protect cells from DNA damage, lipid peroxidation, ionising radiation damage, protein denaturation and other forms of progressive cell degradation

Question 13

how is ALS passed on

Answer 13

incomplete penetrance

no certainty of getting ALS even if they have the family gene (even with mutation analysis)

Question 14

prognosis of ALS

Answer 14

variable but no cure and no satisfactory treatment

Question 15

what to discuss before offering genetic testing for ALS

Answer 15

inheritance and risks 
implications of +ve/-ve result 
variability of condition
insurance status 
employment status 
future children

Question 16

pattern of inheritance of X linked conditions

Answer 16

males are affected in more than one generation
no affected females
affected males are linked through unaffected females - no male to male transmission

Question 17

Huntington’s disease genetics

Answer 17

autosomal dominant (AD)
adult onset
unique mutation - CAG expansion in exon 1 of HTT gene

Question 18

HD clinical features

Answer 18

movement disorder - chorea, athetosis, myoclonus, rigidity
cognitive changes
personality change
psychiatric disease

Question 19

cognitive changes in HD

Answer 19

poor planning and memory 
subcortical dementia (executive function)
NOT classical dementia

Question 20

personality changes in HD

Answer 20

‘a different person’

irritable 
apathetic
loss of empathy 
disinhibition
self centere

Question 21

psychiatric disease in HD

Answer 21

anxiety
depression
paranoia
psychosis

Question 22

age of onset of HD
duration

prognosis

Answer 22

onset late 30s early 40s - but variable
15-20yrs duration

fully penetrant

no cure
unsatisfactory treatments

Question 23

possible advantages of predictive testing for HD

Answer 23

uncertainty of gene status removed
if -ve:
- concerns about self and offspring reduced
if +ve:
- make plans for the future
- arrange surveillance/treatment if any
- inform children, decide whether to have children

Question 24

disadvantages of predictive testing

Answer 24

if +ve:

• removes hope
• continues uncertainty (when)
• known risk to offspring
• impact on self, partner, family, friends
• potential problems with insurance, mortgage

if -ve:

• expectations of a ‘good’ result
• survivor guilt

Question 25

results of genetic testing may affect others

Answer 25

what right (if any) do insurers, employers, schools, or other institutions have to ask about genetic tests

subject’s duty to share info w/ at risk relatives?

physician/investigator’s duty to inform relatives at risk?

Question 26

prediction and uncertainty w/ genetic testing for disease

Answer 26

test info must be usable for prevention or treatment

susceptibility testing requires adequate info about uncertainty

predictive testing requires proper counselling

children/adolescents should only be tested if there are potential medical benefits

3rd parties should have no access