amyotrophic lateral sclerosis (ALS)

Question 1

diseases directly affecting cell bodies of LMN

Answer 1

• poliomyelitis (acute viral infection causing degeneration of motoneurons and muscles
• syringomyelia (large cysts affecting SC and pathways)
• amyotrophic lateral sclerosis

Question 2

amyotrophic lateral sclerosis

Answer 2

• affects motoneurons themselves (as well as UMN in the cerebral cortex)
• causes severe weakness of various groups of muscles

Question 3

incidence of ALS

Answer 3

• 200 NZers affects
• 90% have no family history = sporadic
• 10% familial
• death within 2-5yrs usually

Question 4

symptoms of ALS

Answer 4

• progressive wasting, weakness, and atrophy leading to paralysis
• wasting and weakness of legs, arms and hands
• dysphagia & dysarthria (speech)
• impairment of respiration
• muscle stretch reflexes exaggerated and muscle tone increased
• muscle denervation (e.g. fibrillations and fasciculations)
• no involvement of sphincters or extraocular muscles
• no sensory or intellectual deficits

Question 5

causes of ALS

Answer 5

progressive degeneration of:

• motoneurons (alpha & gamma) in the SC
• motoneurons in the brainstem
• UMN –> spasticity

Question 6

oxidative stress hypothesis

Answer 6

Damage of neurons due to free radicals (reactive O2 & N)

When production of radicals exceed the detoxification capacity of specific enzymes e.g. superoxide dismutase (mutation in familial ALS)

Question 7

excitotoxic hypothesis

Answer 7

Excessive activation of AMPA and/or NMDA receptors by glutamate

A) a decreased activity of astrocytic glutamate transporter GLT1 causes increased extracellular glutamate

B) decreased GluR2 subunit expression (subunit of AMPA receptor)
-Motoneurons affected in ALS have a lower abundance of GLuR2 subunits in their AMPA receptors. This predisposes motoneurons to higher Ca2+ influx.

Question 8

TDP-43 / FUS mutation hypothesis

Answer 8

TDP-43 / FUS proteins are involved in RNA processing, normally found in the nucleus

The genes coding for these proteins mutate in some forms of familial ALS and the 2 proteins are shifted to the cytoplasm where they form insoluble aggregates affecting neuronal function

Proteolytic stress

Question 9

treatment for ALS

Answer 9

no effective Tx against course of disease

• riluzole = blocks glutamate release
  slows disease process for a few months
• baclophen = agonist of GABA-B receptor
  reduces spasticity
• other symptomatic Tx