Motor Neuron Disease

Question 1

What is Motor Neuron Disease (MND)?

Answer 1

= also known as ALS = amyotrophic lateral sclerosis / Lou Gehrig’s Disease

= damage to upper and lower motor neurons

= progressive, fatal disease that attacks nerve cells controlling voluntary muscles

= difficult in speaking, swallowing + eventually breathing
(death due to respiratory failure)

= cognitive function normally spared
(BUT around 10% of cases develop type of dementia)

Amyotrophic
= muscle atrophy, weakness + muscle twitch
(disease of lower motor neurons)

Lateral Sceloris
= glial scar in lateral columns of the spinal cord

Question 2

What is the incidence, prevalence and survival of MND?

Answer 2

Gender
= Male / Female = 1.6 : 1

Age
= late middle age, peak 60-70 years

Incidence
= 1.5-2 / 100,000 per year

Mean duration of surviva;
= 3-5 years
(BUT not always , e.g. Stephen Hawking)

Question 3

What is familial MND / ALS?

Answer 3

Minority of MND cases due to genetic mutations

= 20% of these due to (mostly dominant) mutations in SOD1 (Cu/Zn superoxide dismutase)

= different mutations can affect clinical presentation, survival, age of onset

= mutations also identified in DNA/RNA- binding protein
(TDP-43 = TAR DNA binding protein)
(FUS = Fused in sarcoma)

= 2011, expanded hexanucleotide repeat (GGGGCC) found in C9orf72
= normally <23 repeats
= mutant protein had >30 , sometimes >100 repeats

Question 4

What are some other risk factors for MND?

Answer 4

Environmental
= β-methylaminoalanine (BMAA)
= metals
= pesticides
= viruses

Occupational
= profesional athletes
= military
= farmers

Lifestyle
= head trauma
= smoking
= diet / obesity

Elevated levels of glutamate in CSF and serum may be involved

Failure of ubiquitin-proteasome system, mitochondrial dysfunction, oxidative damage

Question 5

What is the pathology of MND?

Answer 5

= degeneration and loss of motor neurons with astrocyte gliosis

Intraneuronal inclusions
= TDP-43 (main component)

= Ubiquitin
= Bunina bodies
= SOD1 or FUS aggregates
= poly-Glu-Ala, poly-Gly,Pro, polu-Gly-Arg dipeptide repeat proteins in C9orf72

Question 6

What is the treatment for MND?

Answer 6

Only approved treatments
= Riluzole
(glutamate antagonist = delays death or time to tracheostomy)
= Edarvone
(antioxidant and free-radical scavenger = delays motor deterioration)

Treatment pipeline
= oxidative stress + mitochondrial dysfunction
= excitotoxicity
= neuroinflammation
= apoptosis + stem cell therapies
= nucleocytoplasmic transport
= DNA damage + RNA splicing / metabolism

EXTRA READING
= Antisense oligonucleotide therapy (target SOD1 gene)
= gene therapy (replace mutated or non-functional gene)
= stem cell therapy (replace damaged or lost neurons)
= neuroprotective agents (protect neurons from damage and death)
= immune system modulation (e.g. sodium chloride and rituximab)