Lecture 22 - Motor Neurone Disease Flashcards
Give a brief description of MND
A group of diseases
• The most common of which is Amyotrophic lateral scerlosis
• Affects motor neurons
- Progressive
- Fatal
What are the symptoms of MND?
1. Loss of muscle function: • Muscle twitching • Muscle weakness • Difficulty speaking • Difficulty swallowing • Tripping, stumbling, dropping things • Progressive paralysis • Decreased respiratory function
- Loss of muscle mass
• Muscle atrophy
What are the two forms of motor neurons?
Which are affected in MND?
Upper motor neurons
• Originate in brain / brain stem
• Do not directly innervate muscle
Lower motor neurons
• Directly innervate muscle
• Originate in the spinal cord
Both are affected in MND
What is the average age of onset of MND?
45-60 years
Mid-late adulthood, after reproduction
What happens to sensory neurons in MND?
Usually spared
What happens to cognitive ability in MND?
Generally thought to be spared
May be some degeneration (?)
How is MND diagnosed?
Why is this so?
Diagnosis is purely clinical (no test)
• Process of exclusion
• Not easy to diagnose
• Much uncertainty about diagnosis
Hard to diagnose because the underlying causes are not known
What is the prognosis of MND?
- Progressive: continues getting worse
- Timeframe for symptom progression is variable
Generally:
• Confined to wheelchair within 1-2 years
• Death within 3-5 years
What normally causes death in MND?
Respiratory failure
What treatments are there at the moment for MND?
Riluzole
• Only drug on the market
• Moderate, controversial clinical efficacy
• Works by enhancing glutamate uptake from the synapse
What was seen in the RCT of Riluzole?
Not much of a correlate between dose and effect of drug.
With increasing dose, there was not an increased life expectancy
Only a small increase in life expectancy between drug and placebo
Why is there no good drug for MND?
The fundamental causes of the diseases are not known
What are the causes of MND?
90% of cases are sporadic
The 10% that aren't: 1. Genetic factors: Mutations in various genes: • SOD1 • TDP43 • Angiogenin • Optineurin etc. It is unclear whether the mutations are loss or gain of function
- Environmental factors:
• Head trauma
• Military service (Gulf war)
• Chemical toxins
What are some biochemical observations in MND?
NB not just motor neurons, but astrocytes & microglia as well
Astrocytes:
• Impaired glutamate uptake from synapse
Discuss in general mutations in Cu/Zn superoxide dismutase
Gene known to be commonly mutated in MND
Still not known how this affects pathogenesis
What is Cu/Zn superoxide dismutase (SOD)?
Antioxidant:
(detoxifies reactive oxygen species in cells)
Found in every cell in the body
Superoxide → Hydrogen peroxide → water
What is the structure of SOD?
150 aa long
Binds one Cu and one Zn atom
What sort of mutations in SOD1 cause MND?
Substitution → toxic gain of function
What are the proposed toxic gain of function mechanisms of SOD?
Toxic gain of function mutation that we still don't know about: ?? • Aberrant pro-oxidant GoF • Protein mis-folding • Protein aggregation • Mitochondrial dysfunction
Describe the genetic component of MND
90% are sporadic → not familial
10% familial • Family history present • Specific genes: - SOD1 - Optineurin etc.
Curious research questions ?
- The genes identified as mutated in MND are all very different, but they cause the same disease
- The mutations are in genes whose products are important around the body, but they only seem to affect motor neurons
What is the inheritance of the mutations in MND?
Most are autosomal dominant
What are some models being used to research MND?
- Tissue biopsies from people who have died from MND
• Difficult to come by - Mouse models
• Allows create a genetic model of the disease
• Can induce mice to get MND through specific mutations
What is seen with more and more mutant SOD1 in mice models?
More severe motor neurone pathology → more severe phenotype
However, this has recently been disproved in studies in mice
The drug used in mice with SOD1 mutation increased the levels of mutant SOD
