L54 - Molecular basis of neurodegenerative disease - ALS

Question 1

Prevalence, age of onset of ALS?

Answer 1

Prevalence: 4/100,000

• The average age of ALS onset is 55 (12 –98)
• 80% of ALS cases begin between the ages of 40 to 70

Question 2

Etiology of ALS?

Answer 2

• Sporadic ALS: 90% of ALS cases

* Familial ALS: 10% of ALS cases

Question 3

Which CNS region is affected by ALS?

Answer 3

both upper and lower motor neuron damage

Question 4

List symptoms of ALS due to upper motor neuron damage?

Answer 4

Upper motor neuron damage (corticospinal tract):
 Stiffness (spasticity)
 Muscle twitching (fasciculations)
 Muscle shaking (clonus)

> > Chronic fatigue and/or cramping

Question 5

List symptoms of ALS due to lower motor neuron damage?

Answer 5

Lower motor neuron damage (control limb muscles, breathing muscles):
 Muscle weakness
 Muscle shrinking (atrophy)

> > Tripping, stumbling, falling
Loss of muscle control and strength in hands and arms
Difficulty breathing

Question 6

List symptoms of ALS due to brainstem motor neuron damage?

Answer 6

difficulty speaking, swallowing

Question 7

2 subtypes of ALS?

Answer 7

1. Spinal onset = 75%

2. Bulbar onset = 25%

Question 8

Describe the progression of spinal onset ALS?

Answer 8

• 6 months of progressive weakness of hand grip
• Fasciculations of muscle in affected limb
• Cramps and spasms**
• Progressive Weight loss

Question 9

Describe the progression of bulbar onset ALS?

Answer 9

• 9 months of progressive difficulty in Speaking and swallowing
• Severe, rapid Weight loss ***
• Inappropriate laughing and crying ***
• Breathless when lying flat

Question 10

How to Dx ALS?

Answer 10

No Dx test (progressive pure motor syndrome not confined to single site)

Inappropriate laughing, crying

EMG = supportive paraclinical test

Question 11

Prognosis of ALS?

Answer 11

50% patients died after three years

Question 12

Cytopathological changes to motor neurons and spinal cord in ALS?

Answer 12

Motor neurons:
- BUNINA bodies

In Anterior horns:

• HYALINE bodies
• ‘SKEINS’ and rare glial inclusions
• Dystrophic neurites

Question 13

List 2 mutant genes that cause ALS and inheritance pattern?

Answer 13

SOD1&raquo_space; Typical ALS, Familial ALS
Dynactin&raquo_space; Adult onset, slow progressive ALS

Both Autosomal dominant

Question 14

Pathogenesis of SOD1 mutation causing ALS? (normal and abnormal function)

Answer 14

Regulate SOD1 = dimutase&raquo_space; Reduce Cu2+ to turn superoxide ion (O2-). into hydrogen peroxide (H2O2)

Pathogenic:

a) Loss of function mutation = accumulation of superoxide ion
b) Gain of function:
- Accept larger molecules than superoxide&raquo_space; aberrant redox rxns ***
- Failure of degradation = accumulate SOD1 aggregates **

Question 15

Describe the normal anterograde and retrograde transport in neurons?

Answer 15

polarized cells: positive / negative poles provide driving force to regulate axonal transport

1. Anterograde transport (positive pole) = along microtubules away from cell body to neuronal end by KINESIN
2. Retrograde transport (negative pole) = from neuronal end back to cell body by DYNEIN + DYNACTIN complex

Question 16

Pathogenesis of dynactin mutation in ALS?

Answer 16

Axonal transport defects:

1. Dynactin mutation = decrease retrograde transport **
2. Damage to mitochondria, less ATP, worsen defective axonal transport

Question 17

Summarize the pathological damage done to motor neurons in ALS?

Answer 17

• Increase oxidative stress (loss of function SOD1)
• Increase SOD1 aggregration
• Mitochondria dysfunction
• Disruption of axonal transport (Dynactin)
• Glutamate excitotoxicity

> > Trauma and apoptosis of motor neurons