Motor Neurone Disease

Question 1

What is MND?

Answer 1

Progressive degeneration of motor neurons in the brain and spinal cord innervating skeletal muscle.
Causes muscle contraction weakness, loss of muscle mass and inability to control movement.
The age of onset is typically between 40 and 60.
Median survival is 4 years, but can be up to 20.
Affects your ability to walk, talk, eat, drink and breathe.
Causes of death include respiratory weakness and pneumonia.
Some patients experience additional cognitive and behavioural symptoms - 35% experience a mild cognitive change affecting executive functions and a further 5-10% show signs of frontotemporal dementia.

Question 2

Types of MND

Answer 2

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, is the most common type. Median onset of 60 years old, median survival of 2-5 years. ALS develops due to degeneration of all motor neurones, both upper and lower. There is a loss of ACh tone at the NMJ, resulting in a loss of muscle tone. Symptoms include weakness and wasting in limbs, muscle stiffness and cramps. It affects tongue, hand, and leg muscles first. Eye movements spared.
Progressive bulbar palsy (PBP) affects UMNs.
Progressive muscular atrophy (PMA) affects LMNs. There are flail arm/leg variants.
Primary lateral sclerosis (PLS) affects UMNs and is progressive but non-fatal.

Question 3

Diagnosis

Answer 3

Physical examination to identify symptoms.
Blood tests show increased creatine kinase due to muscle breakdown - also seen in heart attack, muscle injury, liver disease, etc.
Electromyography (EMG) to record nerve impulses.
Nerve conduction tests.
Transcranial Magnetic Stimulation (TMS) stimulates and measures the threshold and response of upper motor neurons.
MRI used to rule out other possible explanations, e.g. stroke, AD, PD, MS, tumours, trapped nerves, spinal injury

Question 4

Ghost cells

Answer 4

Ghost cells develop in the ventral horn as this area shrinks. These have spheroids of misfolded proteins → cause decreased ACh, decreased motorneuron terminal sprouting and increased glutamate levels.

Question 5

What proportion of cases are genetic?

Answer 5

5-10% of ALS cases are genetic.
These can be due to autosomal dominant or recessive mutations.
Twin studies suggest 60% heritability.

Question 6

Genetics

Answer 6

• C9orf72 influences mRNA production. Mutations that increase the GGGGCC hexanucleotide repeat (>30) expansions result in ALS. It is unclear how the C9orf72 protein is affected by the expansions. Autosomal dominant mutations found in 25-40% of familial and 7% of sporadic cases of ALS, and also in 25% of FTD cases.
• SOD1 (superoxide dismutase) is an antioxidant protein, converting superoxide to hydrogen peroxide and oxygen. Mutants form aggregates. Autosomal dominant mutations associated with 10-15% of familial and 1-2% of sporadic cases.
• ALS2 encodes ALSIN, a guanine exchange factor involved in G-protein recycling. It is involved in the development of axons and dendrites and essential for the transmission of nerve impulses. The long form is neuroprotective but the short form results in ALS. Affected by autosomal recessive mutations
• Vesicle-associated membrane protein B mutations are associated with atypical late-onset forms of ALS. They cause dysfunction of membrane trafficking.
• Sentaxin mutations are associated with rare, autosomal dominant juvenile ALS. This affects DNA/RNA helicase controlling RNA processing.
• TAR DNA binding protein (TARDBP) is one of the most commonly mutated genes. It’s involved in transcription and forms aggregates in ALS.
• Fused in sarcoma (FUS) is another commonly mutated gene. It is an RNA binding protein, involved in transcription, DNA repair, RNA splicing. Aggregates are found in sporadic ALS.

Question 7

Ubiquilin 2

Answer 7

Non-familial cases may be caused by protein mishandling.
Ubiquilin 2 is unable to remove damaged proteins due to a disorganised immune response → more likely to affect the longer LMNs.
The immune system may begin to attack and kill healthy cells.

Question 8

Mechanisms of motor neuron degeneration

Answer 8

3 suggested mechanisms for MN death.
1. Glutamate-mediated excitotoxicity.
2. Superoxide dismutase 1 (SOD1) mutations causing the protein to aggregate, decreasing zinc binding and disturbing the structure of intermediate filaments.
3. Mutation of neurofilament genes, leading to disorganised neurofilaments and so blocked axonal transport.

Question 9

Symptomatic treatment

Answer 9

Respiratory support - airway clearance, ventilation, respiratory strength training
Pain - analgesics, particularly opiates - respiratory depression is an issue
Spasticity - GABA-B agonist Beclofen

Question 10

Treatments

Answer 10

Riluzole decreases glutamate release and excitotoxicity.
Edaravone scavenges free radicals, which may slow disease progression.
Sodium Phenylbutyrate and Taurursodiol slow the progression of MND by reducing ER stress and mitochondrial dysfunction.
Tofersen antisense oligonucleotide (ASO) downregulation of SOD1 is a disease-modifying approach - works in the 2% of MND cases associated with mutations in this gene.
Stem cells - cannot replace motor neurons as these are too long, but could differentiate into astrocytes and microglia and perform neurotrophic functions.