Neurogenetics

Question 1

Duchenne inheritance

Answer 1

X-linked recessive

Question 2

What age does onset of weakness occur in duchenne’s?

Answer 2

3-4 years

• pelvic and shoulder girdles
• wheelchair bound by 10-12 years

Question 3

Why do people with duchenne’s die?

Answer 3

Involvement of cardiac and respiratory muscles (weakness etc)

-usually die in their 20’s

Question 4

Which conditions might you see calf hypertrophy in?

Answer 4

DMD and Becker’s

Question 5

What modification of the dystrophin gene leads to duchenne’s?

Answer 5

• Large scale deletions of dystrophin gene in 70% of DMD boys
• Point mutations, small insertions and deletion in remaining 30%

Question 6

What else might cause a muscular dystrophy?

Answer 6

Sarcoglycan deficiencies

Question 7

Huntington inheritance

Answer 7

Autosomal dominant

Question 8

Features of Huntington’s disease

Answer 8

• Involuntary movements
• Depression
• Progression to severe dependency and death over 15-20 years

Question 9

Early clinical signs of huntington’s

Answer 9

Clumsiness
Irritability 
Agitation
Apathy 
Anxiety 
Abnormal eye movements
Disinhibition 
Delusions Hallucinations  
Depression

Question 10

Gowers sign

Answer 10

DMD

Question 11

Toe-walking

Answer 11

DMD

Question 12

How would you diagnose DMD?

Answer 12

• raised serum CK
• EMG
• muscle biopsy
• molecular genetic testing (screen for deletions)

Question 13

DDX for DMD?

Answer 13

Autosomal recessive limb girdle muscular dystrophies - caused by sarcoglycan deficiencies

Question 14

Onset of Huntington’s

Answer 14

Onset between ages 30 and 50

age dependent penetrance - variable

Question 15

Caudate atrophy in which disease?

Answer 15

Huntington’s

Question 16

CAG repeats and Huntington’s

Answer 16

Disease becomes penetrant when you get 40+ CAG repeats

Question 17

Age dependent penetrance and Huntington’s

Answer 17

age 20: 1 in 2
age 50: 1 in 3
age 70: 1 in 11

(i.e. if no symptoms the older you get, the less likely you are to develop HD)

Question 18

Predictive testing available for HD

Answer 18

• pre-natal testing

- pre-gestational testing

Question 19

Loss of cortical neurones
Neurofibrillary tangles
Senile plaques

Answer 19

Alzheimer’s disease

Question 20

The name given to extra-cellular protein deposits containing amyloid beta protein?

Answer 20

Senile plaques

Question 21

Inheritance of hereditary dementia? (early onset)

Answer 21

Autosomal dominant

Question 22

When might people with Down syndrome develop dementia?

Answer 22

3rd or 4th decade

Question 23

What does e4 allele predispose? (this allele is on the ApoE gene)

Answer 23

e4 predisposes to Alzheimer disease

-e2 is associated with longetivity

Question 24

MS risk for 1st degree relatives

Answer 24

3%

Question 25

MS risk for 2nd degree relatives

Answer 25

1%

Question 26

Population risk of MS

Answer 26

0.2%

Question 27

Twin studies in MS

Answer 27

Monozygotic twins - 25% | Dizygotic twins - 3%

Question 28

DMD incidence

Answer 28

1/3000

Question 29

DMD signs of muscle weakness

Answer 29

Gower's sign | Toe walking

Question 30

What carrier testing can you offer in DMD?

Answer 30

- you can identify the mutation in boys - using this, you can then ask the females in the family if they want to find out whether they are carriers or not - female carriers can then be offered pre-natal testing

Question 31

Huntington disease incidence

Answer 31

1/20 000

Question 32

Early clinical signs

Answer 32

``` Clumsiness Agitation Irritability Apathy Anxiety Disinhibition Delusions Hallucinations Abnormal eye movements Depression ```

Question 33

Later clinical signs

Answer 33

``` Dystonia Involuntary movements Trouble with balance and walking Trouble with activities that require manual dexterity Slow voluntary movements Difficulty initiating movement Inability to control speed and force of movement Weight loss Speech difficulties Stubbornness ```

Question 34

Very late clinical signs

Answer 34

``` Rigidity Bradykinesia (difficulty initiating and continuing movements) Severe chorea (less common) Serious weight loss Inability to walk Inability to speak Swallowing problems, danger of choking Inability to care for oneself ```

Question 35

What does CAG code for?

Answer 35

Glutamine

Question 36

Atrophy in which part of the brain especially, in HD?

Answer 36

Caudate nucleus

Question 37

What testing can you give for huntington's disease?

Answer 37

Predictive testing: prenatal and pre-gestational

Question 38

Amyloid beta protein is a fragment of what?

Answer 38

Fragment of the product of the APP gene 21 | APP --> amyloid precursor protein

Question 39

Chromosome mutations associated with AD alzheimer's disease?

Answer 39

``` APP mutations (chromo 21) Presenilin 1 (chromo 14) Presenilin 2 (chromo 1) ```

Question 40

e3

Answer 40

Most common

Question 41

e2

Answer 41

Associated with longetivity

Question 42

e4

Answer 42

Associated with AD alzheimers

Question 43

Difference between e3/e4 and e4/e4

Answer 43

e3/e4 --> 27% affected by 80 years | e4/e4 --> 55% afected by 85 years