8: Motoneuron Disorder

Question 1

Motoneuron Disorders

Answer 1

Disorder of 1st motoneuron
• spasticity
• Hyperreflexia
• Positive pyramidal tract signs
-> primary lateral sclerosis (PLS)

Disorder of 2nd motoneuron
• palsy (lähmung)
• Atrophy (muskeldegeneration)
• Fasciculation
-> spinal muscular atrophy (SMA)

Combined motoneuron disorder (1st and 2nd affected): Amyotrophic lateral sclerosis (ALS)

Question 2

ALS; Prevalence

Answer 2

• Prevalence: 100-200 / 1 million
• m:f=1.25:1
• Mean onset ~60 years
• Mean disease duration 3-4 years -> rapidly progressive
• But: 10% of patients survive > 10 years

Question 3

ALS phenotypes

Answer 3

• Spinal (motoneurons of hands/arms affected)
• Bulbar (speaking, swallowing affected)
• Flail arm/leg (cannot lift arms)
• Respiratory
• Asymmetric
• LMN dominant
• UMN dominant

Question 4

Misleading signs and symptoms

Answer 4

• Pain, cramps -> rheumatological/orthopedic problem
• weakness -> psychogenic
• dysphagia -> age related
• Dysarthria -> stroke
• Bulbar affect (problems in controlling emotions)-> depression in elderly
• -> leads to delayed suspicion of ALS -> diagnostic journey often very long

Question 5

Gold Coast Criteria; ALS

Answer 5

• Progressive motor impairment
• preceded by normal motor function
• Presence of upper&lower motor neuron dysfunction in at least one region,
• or lower motor neuron dysfunction in at least 2 body regions
• Investigations excluding other disease processes

Question 6

Differential Diagnosis; ALS

Answer 6

• Cervical myelopathy (compression of spinal cord)
• Multifocal motor neuropathy (MMN)
• Inflammatory neuropathy (HIV-ALS like disorder, borreliosis)
• Paraneoplastic MND
• Actinic MND
• Parathyreoid dysfunction

Question 7

Examination; ALS

Answer 7

• ENMG (electroneuromyogram)
• Laboratory work-up
• CSF examination
• Cerebral/cervical MRI
• Molecular genetic examinations: SOD1, FUS, …
• We need: good biomarker

Question 8

ALS & FTD

Answer 8

• most ALS patients have slight cognitive deficits: EF, behav. abnormalities
• ~5% with overt fronto-temporal dementia (FTD)

• Superoxide dismutase 1 (SOD1) -associated ALS
• Sporadic ALS and FTD and the role of RNA-binding proteins
• Hexanucleotide repeat (C9ORF72) -associated ALS and FTD (most common)

ALS:
• 90% sporadic / 10% familial
FTD:
• 70% sporadic / 30% familial
-> Genetic overlap: Many genes that cause ALS also cause FTD

Question 9

Therapy

Answer 9

• no cure yet
-> Symptomatic therapies:
• Riluzole: delays progression (1994)
• Edavarone (no proven effect on survival, high costs)

Palliative Care in Neurology
• not shortening of life expectancy or end of life care
• Aim: best possible quality of life for the patient and his caregivers
Palliative therapies:
• pain, cramps, spasticity
• Bulbar dysfunction: dysarthria, pseudobulbar affectice disturbances
• Respiratoy dysfunction -> too much CO2 in blood -> fatigue -> CO2 intoxication
• Physio, Ergo, Logopedic therapy
• Walking aids
• End of life therapy
-> BiPAP therapy -> increases quality of life and survival

Genetic therapy:
• Vector gene replacement
• Gene silencing

Question 10

PLS

Answer 10

• onset: 50
• No genetic basis
• Slowly progressive spasticity
• 40% lower motoneuron signs after 3-10 years -> ALS
• MRI: Focal atrophy of precentral gyrus

Question 11

SMA

Answer 11

• Deletions of SMN1/SMN2 genes
• Distal SMA and hereditary motor neuropathies
• Rare, many different phenotypes and genes
• Nusinersen
• Treatment with antisense oligonucleotides (ASO) or RNA
• High costs
• Gene therapy

Question 12

Kennedy disease

Answer 12

• x-linked: mutations in androgen receptor gene
• Hand tremor /cramps

Question 13

Hirayama disease

Answer 13

• monomelic amyotrophy
• Male 10x more
• Progression over several months to 4 (8-10) years, then plateau
• Often physical exercise before onset
• Flexion myelopathy

Question 14

Benign Fasciculations

Answer 14

• Affect same muscle site repetitively
• Normal strength and no atrophy in fasciculating muscles
• Exacerbated by exercise, hyperventilation & tension
• May be associated with tendency to cramps and myalgias

Question 15

SOD1

Answer 15

• SOD1-mediated ALS: only small fraction of patients
• is not associated with FTD
• Mutations in SOD1 cause 20% of familial ALS

• ALS-linked mutations disrupt the stable dimeric form of wild-type SOD1
• Knockout SOD1 -> no ALS
• Transgenic mice overexpressing mutant SOD1 faithfully recapitulate human disease
• Neighbouring cells to motoneuron like microglia/astrocytes are also affected

-> Therapies: get rid of mutant SOD1, but also targets healthy SOD, not a problem
-> Tofersen (targets SOD1)

Question 16

TDP-43

Answer 16

• RNA-binding protein
• Sporadic ALS and FTD
• Mutations in TDP-43 cause ~5% of familial ALS
• Autosomal dominant, >35 mutations known to cause ALS, Cluster in the glycine-rich region
• TDP localized around nucleus and not in nucleus like normal
• multifunctional RNA-binding protein misregulated in ALS and FTD

Question 17

Ataxin 2

Answer 17

Inhibition of ataxin-2 synthesis as a therapeutic strategy for ALS
• Loss of the stress granule component ataxin-2 rescues TDP-43 toxicity in yeast
• Ataxin-2 knockout or reduction of ataxin-2 improves survival of TDP-43 overexpression mice
• Potential for ataxin-2 ASO-mediated therapy
• Long poly-Q expansions in ataxin-2 cause spinocerebellar ataxia type 2
• Intermediate poly-Q expansions in ataxin-2 are a risk factor of ALS
-> take away ataxin-2 bc you cant take away TDP
-> ION541 silences ataxin2

Question 18

FUS

Answer 18

• Fused in sarcoma or TLS: Translocated in liposarcoma
• Rare but very aggressive
• Mutations disrupt the Nuclear Localization Signal (NLS)
• Juvenile onset ALS associated with FUS mutations
-> ION363 targets FUS

Question 19

C9ORF72

Answer 19

Hexanucleotide repeat-associated ALS and FTD
• ~40% of fALS, ~29% of FTLD and >90% of FTLD-ALS families have C9ORF72 expansions
• Reduced levels of C9ORF72 transcripts in patients with repeat expansions
• Probably does not trigger disease – C9ORF72 KO mice do not get ALS/FTD
• BUT loss of C9ORF72 function causes inflammation that may contribute to neurodegeneration

-> cerebellum is unaffected in ALS