22. Motor Neuron Disease Flashcards
What is MND?
Group of diseases that affect motor neurons (upper & lower) in CNS.
(sensory nerves are spared)
Most common = amyotrophic lateral sclerosis
Progressive & fatal
Upper MN vs Lower MN
UMN: originate in brain/brainstem and do not directly stimulate muscles
LMN: directly innervate muscles
What are the symptoms of MND?
- 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
Diagnosis of MND
- No diagnostic test for MND
- Diagnosis is purely clinical and is a process of exclusion
*associated emotional distress due to diagnostic uncertainty
Prognosis of MND
- 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.
Treatments
Riluzole “Rilutek” from Sanofi-Aventis
- only approved therapy for MND
- moderate clinical efficacy
- no correlation between increasing dose & improvement in clinical outcome
Causes
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
Cu/Zn superoxide dismutase (SOD1)
- 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)
How does mutant SOD1 cause MND?
Toxic gain of function (not loss of function!) Specific cause unknown, some proposals: -aberrant pro-oxidant GoF -protein misfolding -protein aggregation -mt dysfunction
Genetics
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
Current research
- Unknown definitive cause
- Cannot accurately diagnose at an early stage
- Currently no valid therapeutic options
Why is increasing SOD1 activity not part of the therapeutic mechanism of action for MND drug?
SOD1 loss of function is not why people with familial forms of MND due to SOD1 mutations get sick.
What has current research recently disproved? (something that has been believed to be the case for 20 years)
More mutant SOD1
= more severe motor neuron pathology
= more severe phenotype
NOT TRUE