22. Motor Neuron Disease Flashcards

1
Q

What is MND?

A

Group of diseases that affect motor neurons (upper & lower) in CNS.
(sensory nerves are spared)

Most common = amyotrophic lateral sclerosis

Progressive & fatal

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2
Q

Upper MN vs Lower MN

A

UMN: originate in brain/brainstem and do not directly stimulate muscles

LMN: directly innervate muscles

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3
Q

What are the symptoms of MND?

A
  • Muscle twitching
  • muscle weakness
  • difficulty speaking
  • difficulty swallowing
  • tripping, stumbling, dropping things
  • progressive paralysis
  • decreased respiratory function
  • peak age of onset 45-60 yo.
  • muscle atrophy
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4
Q

Diagnosis of MND

A
  • No diagnostic test for MND
  • Diagnosis is purely clinical and is a process of exclusion

*associated emotional distress due to diagnostic uncertainty

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5
Q

Prognosis of MND

A
  • Timeframe for symptom progression is variable
  • Confined to wheelchair within 1-2 yrs
  • Death w/in 3-5 years.
  • Death usually due to respiratory failure.
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6
Q

Treatments

A

Riluzole “Rilutek” from Sanofi-Aventis

  • only approved therapy for MND
  • moderate clinical efficacy
  • no correlation between increasing dose & improvement in clinical outcome
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7
Q

Causes

A

Fundamental causes unknown
>90% cases are sporadic (no familial history)

GENETIC FACTORS

  • Cu/Zn superoxide dismutase
  • TDP43
  • Optineurin
  • Angiogenin
  • C9 or F72

ENVIRONMENTAL

  • head trauma
  • military service
  • chemical toxins
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8
Q

Cu/Zn superoxide dismutase (SOD1)

A
  • expressed in every cell in body
  • major antioxidant enzyme
  • detoxifies toxic superoxide radicals
  • approx 150 amino acids
  • binds 1 Cu ion and 1 Zn ion
  • substitution mutations in SOD1 caused MND
  • mutations assoc. w familial amyotrophic lateral sclerosis

Oxygen radical –> H2O2 (which is further detox’d into H2O)

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9
Q

How does mutant SOD1 cause MND?

A
Toxic gain of function (not loss of function!)
Specific cause unknown, some proposals:
-aberrant pro-oxidant GoF
-protein misfolding
-protein aggregation
-mt dysfunction
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10
Q

Genetics

A

Approx. 90% cases are sporadic w no family history and no identified cause

Approx. 10% are familial

  • family history
  • molecular basis increasingly known:
  • SOD1
  • C9 or F72
  • TDP-43
  • Optineurin
  • most are autosomal dominant
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11
Q

Current research

A
  • Unknown definitive cause
  • Cannot accurately diagnose at an early stage
  • Currently no valid therapeutic options
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12
Q

Why is increasing SOD1 activity not part of the therapeutic mechanism of action for MND drug?

A

SOD1 loss of function is not why people with familial forms of MND due to SOD1 mutations get sick.

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13
Q

What has current research recently disproved? (something that has been believed to be the case for 20 years)

A

More mutant SOD1
= more severe motor neuron pathology
= more severe phenotype

NOT TRUE

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