NeuroGenetics

Question 1

What inheritance pattern does Duchenne Muscular Dystrophy (DMD) follow?

Answer 1

X-linked recessive

=> females can be carriers, males will always be affected if they have the gene

Question 2

What symptoms are usually present at onset of DMD, and at what age does this usually occur?

Answer 2

Delayed motor development
Weakness of pelvic and shoulder girdle muscles

Onset at age 3-4 years

Question 3

Children with DMD usually take longer to learn to walk. TRUE/FALSE?

Answer 3

TRUE

Question 4

If a child isn’t walking by 18 months, what serum marker should be checked to possibly diagnose DMD?

Answer 4

Creatinine kinase

this leaks out of damaged muscle

Question 5

WHy does death occur so young in DMD?

Answer 5

Respiratory and cardiac muscles also develop weakness

=> incompatible with life

Question 6

Describe the typical posture of a child with DMD?

Answer 6

Accentuated lumbar lordosis

- compensating for weak pelvic girdle

Question 7

What muscle may actually show hypertrophy in DMD, rather than atrophy?

Answer 7

Calf muscles

Question 8

The mutation in DMD codes for which protein?

Answer 8

Dystrophin

Question 9

What does the dystrophin protein do?

Answer 9

Connects contractile filaments to the cell membrane

=> muscle cells fail to renew themselves properly without dystrophin

Question 10

What findings would lead to a diagnosis of DMD?

Answer 10

• Developmental delay
• Positive Gower’s sign
• increased serum CK
• positive muscle biopsy

Question 11

Describe Gower’s sign

Answer 11

If asked to jump up from a lying/sitting position

children with DMD will walk their hands up their legs in order to stand up

Question 12

What other muscular dystrophies present similarly to DMD and how are they inherited?

Answer 12

Sarcoglycan and dystroglycan muscular dystrophies

These are autosomal recessive as these proteins are not found within the X chromosome

Question 13

At what age to DMD patients usually end up wheelchair bound?

Answer 13

roughly by 10-12 years

Question 14

What is Huntington’s and when does it usually present?

Answer 14

Progressive neurodegenerative disorder

• Onset usually between 30 and 50 years (this is variable e.g. from teens -> 70s)

Question 15

What symptoms are usually present in Huntington’s?

Answer 15

• involuntary movements (chorea)

- dementia

Question 16

How long does it take for Huntington’s patients to become severely dependent?

Answer 16

15-20 years

Question 17

How is Huntington’s inherited?

Answer 17

Autosomal dominant

Question 18

What is meant by age dependent penetrance?

Answer 18

As a patient gets to 50, their likelihood of developing the disease decreases.
This continues as they age, therefore when they are 70 they have an even smaller chance of having inherited the disease.

Question 19

What early symptoms are often present in Huntington’s disease?

Answer 19

• Clumsiness
• Agitation
• Anxiety
• Disinhibited
• Delusions/Hallucinations
• Abnormal eye movements
• Depression

=> very NON-SPECIFIC

Question 20

What later symptoms can be seen in Huntington’s?

Answer 20

• Involuntary movement
• Trouble with balance, walking, coordination of movement
• Weight loss
• Speech difficulties
• Swallowing problems

Question 21

Give some examples of subtle chorea (involuntary) movements.

Answer 21

Raising eyebrows uncontrollably

Tilting head back

Question 22

What evidence of Huntington’s can be seen in the brain?

Answer 22

Caudate atrophy around the lateral ventricles

Question 23

What can strokes in the area of the caudate nucleus cause?

Answer 23

chorea-like symptoms

Question 24

Describe the genetic component of huntingtons disease?

Answer 24

Mutation in the Huntington’s gene
CAG repeat expansion
36 repeats (Or more) rather than normal 20

Question 25

What does the CAG repeat in Huntington’s cause pathophysiologically?

Answer 25

Excess glutamine production

- this is neurotoxic

Question 26

What is predictive genetic testing?

Answer 26

Adults can be tested for their likelihood of the disease, before deciding to have children.

Question 27

Huntington’s passed on to the next generation will have an earlier onset than that of the last generation. TRUE/FALSE?

Answer 27

TRUE

Question 28

Having more repeats in the CAG sequence attributes to an earlier onset of Huntington’s. TRUE/FALSE?

Answer 28

TRUE

Question 29

What genetic testing method is used for Huntington’s?

Answer 29

PCR

primers are directed at CAG sequence to determine how many repeats are present

Question 30

What spinal muscular atrophy?

Answer 30

progressive loss of anterior horn cells

- Both in spinal cord and brain stem nuclei

Question 31

How do patients usually present with spinal muscular atrophy and who usually is affected?

Answer 31

Infants normally affected
Present with:
– hypotonia
– proximal muscle weakness
– tongue fasiculation (rippling movement)

Question 32

How is spinal muscular atrophy acquired?

Answer 32

Autosomal Recessive (=> affects males and females equally)

Question 33

Deficiency of what gene is responsible for Spinal Muscular Atrophy?

Answer 33

SMN1 (on chromosome 5)

SMN1 protein produced by this gene betters survival of the lower motor neurones

Question 34

Describe how a new drug has been produced in order to lessen the deificiency of SMN1?

Answer 34

SMN2 makes similar mRNA to SMN1 (excpt one exon is missing)

A drug has been made which alters the splicing of the SMN2 mRNA to keep this exon in
=> it functions more similarly to SMN1

Question 35

How is the new drug for Spinal muscular atrophy delivered?

Answer 35

injected via lumbar puncture into the CSF

Question 36

What does alzheimers disease cause and who does it usually affect?

Answer 36

Common cause of dementia (50-70% of cases)

Usually occurs in old age

Question 37

Alzheimer’s disease tends to cluster in families. TRUE/FALSE?

Answer 37

TRUE

Question 38

What pathological signs are indicative of Alzheimer’s disease?

Answer 38

• Loss of cortical neurones
• Neurofibrillary tangles (intracellular protein)
• Senile plaques (extracellular)

Question 39

What protein do senile plaques deposit and why is this relevant to Alzheimer’s disease?

Answer 39

amyloid β protein

this is a product of the APP (amyloid precursor protein) gene on Chromosome 21, which is often mutated in Alzheimers

Question 40

A small percentage of Alzheimer’s disease is inherited autosomal dominantly. TRUE/FALSE?

Answer 40

TRUE

around 5-10%

Question 41

What particular group are more at risk of Alzheimer’s disease due to over-representation of chromosome 21?

Answer 41

Down Syndrome - Trisomy 21
=> more APP genes to create more amyloid β protein deposits
=> onset is EARLIER (3rd/4th decade)

Question 42

Other than APP mutations, what genetic mutations can contribute to Alzheimer’s disease?

Answer 42

• Presenilin 1 (chromosome 14)

* Presenilin 2 (chromosome 1)

Question 43

Old age Alzheimer disease cluster in families usually have what genetic component?

Answer 43

ApoE gene involvement

- if they have e4 variant then the predisposition to alzheimers is higher

Question 44

First degree relatives of patients with Multiple Sclerosis (MS) are at high risk of developing the condition. TRUE/FALSE?

Answer 44

FALSE - multifactorial disease

Some families do have clusters but relative risk for 1st and 2nd degree relatives is LOW