22. Motor Neuron Disease

Question 1

What is MND?

Answer 1

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

Most common = amyotrophic lateral sclerosis

Progressive & fatal

Question 2

Upper MN vs Lower MN

Answer 2

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

LMN: directly innervate muscles

Question 3

What are the symptoms of MND?

Answer 3

• 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

Question 4

Diagnosis of MND

Answer 4

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

*associated emotional distress due to diagnostic uncertainty

Question 5

Prognosis of MND

Answer 5

• 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.

Question 6

Treatments

Answer 6

Riluzole “Rilutek” from Sanofi-Aventis

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

Question 7

Causes

Answer 7

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

Question 8

Cu/Zn superoxide dismutase (SOD1)

Answer 8

• 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)

Question 9

How does mutant SOD1 cause MND?

Answer 9

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

Question 10

Genetics

Answer 10

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

Question 11

Current research

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

Answer 13

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

NOT TRUE