Neurogenetics

Question 1

what type of inheritance is duchenne MD

Answer 1

x linked recessive

Question 2

what is the onset and progression of duchennes

Answer 2

delay in motor development
onset of weakness 3-4 years (pelvic and shoulder girdle)
wheelchair bound by 10-12 years
death from involvement of respiratory and cardiac muscles

Question 3

what is the characteristic posture of duchennes

Answer 3

accentuated lumbar lordosis

Question 4

what hypertrophies in duchennes

Answer 4

calf muscles

Question 5

what causes duchenes

Answer 5

mutation in dystrophin gene in X chromosome that causes a dystrophin deficiency (dystrophin connects the contractile elements of the cell- muscle cells unable to renew and so degenerate with age)

Question 6

what are the majority of mutations in duchennes

Answer 6

large scale mutations (70%)

Question 7

how is duchennes diagnosed

Answer 7

gowers sign, toe walking 
raised serum CK 
electromyography (EMG)
muscle biopsy (not done as painful)
molecular genetic testing

Question 8

what is autosomal recessive limb girdle muscular dystrophies

Answer 8

dystrophy similar to duchennes

mutation not in X chromosome so affects boys and girls equally in a recessive pattern

Question 9

why are females protected from x linked conditions

Answer 9

as have other working x chromosome

Question 10

if a mother is carrier of duchennes what is the chance of a son getting it

Answer 10

1 in 2

Question 11

how many cases of duchennes are not inherited but caused by a new mutation

Answer 11

1/3rd

Question 12

how prevelant is duchennes

Answer 12

1 in 3000

Question 13

what mutation testing can be done in duchennes

Answer 13

can identify in affects or in female carriers

pre natal testing in female carriers

Question 14

what is the screening test for duchennes

Answer 14

serum CPK

Question 15

how prevelant is huntingtons disease

Answer 15

1 in 20,000

Question 16

what is huntingtons disese and its symptoms

Answer 16

progressive neurodegenerative disorder

• onset between 30-50
• involuntary movements
• dementia
• progresses to severe dependency and death

Question 17

what is the inheritance of huntingtons

Answer 17

autosomal dominant

age dependant penetrance

Question 18

what are the early clinical signs of huntingtons

Answer 18

clumsiness
agitation 
irritability 
apathy 
anxiety 
disinhibition 
delusions, hallucinations 
abnormal eye movements 
depression

Question 19

what are the intermediate clinical signs of huntingtons

Answer 19

dystonia 
involuntary movements 
balance and gait problems 
reduced manual dexterity 
slow voluntary movements 
difficulty initiating movements 
inability to control speed and force of movement 
weight loss (swallowing difficulties)
speech difficulties (dysarthric speech)
stubborness

Question 20

what is dystonia

Answer 20

sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures

Question 21

what are the late clinical signs of huntingtons

Answer 21

rigidity 
bradykinesia (difficulty initiating and continuing movements)
severe chorea 
serious weight loss
inability to walk 
inability to speak 
swallowing problems, danger of choking 
dependence

Question 22

what is caudate atrophy

Answer 22

loss of cortical tissue (caudate nuclei- usually project into the lateral ventricles)
get it in huntingtons

Question 23

what causes huntingtons

Answer 23

mutations in the huntingtons gene
CAG (Codes for glutamine- in huntingtons this gene is expanded causing an accumulation of glutamine which has a neurotoxic effect)

Question 24

why does huntingtons have earlier onset in each generation

Answer 24

as more repeats of the CAG gene get added each generation- neurogenerative condition

Question 25

what does age dependent penetrance in huntingtons mean

Answer 25

the older you get the lower your risk of getting the condition

Question 26

what genetic testing is done for huntingtons

Answer 26

pre natal and pre gestational | no known treatment to stop progession so essential to have informed consent

Question 27

what is spinal muscular atrophy

Answer 27

a neurodegenerative disorder that causes progressive loss of anterior horn cells in spinal cord and brain stem nuclei

Question 28

what is the inheritance of spinal muscular atrophy

Answer 28

autosomal recessive | variable age of onset and rate of progression (types 0-4 depending on age of onset)

Question 29

what are the features of spinal muscular atrophy

Answer 29

proximal muscles weakness | tongue fasciculation

Question 30

what causes spinal muscular atrophy

Answer 30

SMN1 deficiency (essential for survival of LMNs) due to mutation making gene unable to make mRNA

Question 31

if both parents are carriers for spinal muscular atrophy what is the chance of the child being affected

Answer 31

1 in 4

Question 32

how do drugs work against spinal muscular atrophy

Answer 32

mRNA which alters the pattern of slicing and allows it to retain the exon (exon 7) that would be missing in the disease- retains the proteins that would be deficient Drug needs to be intra-thecal injected = lumbar puncture

Question 33

what condition does alzheimer disease cause

Answer 33

dementia

Question 34

who gets alzheimers

Answer 34

usually occurs in old age can cause pre senile dementia some clustering in families

Question 35

what causes alzheimers

Answer 35

``` loss of cortical neurones neurofibrillary tangles (intracellular proteins) senile plaques (extracellular protein deposits) ```

Question 36

what are senile plaques

Answer 36

extracellular protein deposits containing amyloid beta protein

Question 37

what is the inheritance of alzheimers

Answer 37

autosomal dominant in 5-10% of cases (usually early onset) common multifactoral forms get it in down syndrome (onset in 3rd or 4th decade) is genetically heterogenious (same phenotype produced)

Question 38

what mutations cause autosomal dominant alzheimers

Answer 38

APP (amyloid precursor gene- senile plaques) presenilin 1 and 2 (more common than APP) ApoE (associated with familial clusters) (APP gene involves in splicing secretase)

Question 39

what are the types of ApoE genotypes associated with in alzheimers

Answer 39

E4 prediposes to the disease with clustering in families | E2 associated with longevity and old age without the disease

Question 40

what is the inheritance of multiple sclerosis

Answer 40

multifactoral - polygenic | some clustering in families