Motor Neuron Disease/Amyotrophic Lateral Sclerosis (ALS) PART I Flashcards Preview

NMH: Module 2 > Motor Neuron Disease/Amyotrophic Lateral Sclerosis (ALS) PART I > Flashcards

Flashcards in Motor Neuron Disease/Amyotrophic Lateral Sclerosis (ALS) PART I Deck (47)
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1

Define Motor Neuron Disease/ Amyotrophic Lateral Sclerosis (ALS)

Chronic neurodegenerative condition causing
muscle wasting, paralysis and death usually
within 3-5 years due to respiratory failure

2

Neuropathological features of ALS?

- Amyotrophy
- scarring of the corticospinal tracts

3

Compare ALS risk in men vs women

Greater in men

4

Specific targets of ALS?

Upper motor neurons and Lower motor neurons

5

What makes UMN and LMN vulnerable to ALS severe symptoms?

- Both have long axons
(length / cell diameter
~10,000)
- Very active
- High energy demands

6

Briefly describe the outcomes of UMN and LMN pathology in ALS

UMN -> spasticity
LMN -> atrophy

7

Describe the features of ALS symptoms

- progressive denervation + secondary muscle weakness of limbs, trunk, tongue, resp (intercostal) muscles
- Impaired speech & swallowing (bulbar signs)
- Spastic weakness + paralysis in almost all skeletal muscle
- NO impairment of bladder/bowel/sexual function
- SPARED occulomotor/sensory/autonomic function

{NB: cognitive function affected in a minority of cases]

8

Describe the onset and progression of ALS

Starts focally and spreads

Usually starts in distal muscles of limb/bulbar and then spreads

9

Specific examples of early ALS symptoms

- Wasting of thenar eminenence

- Wasting of the tongue (bulbar)

10

Early diagnostic tests for ALS (and positive results)?

- Muscle biopsy -(stain for ATPase)-> atrophic fibres
- Electromyogram (nerve conduction test) -> impaired conduction (and compensatory mechanism)

11

How do motor units compensate for the effects of ALS

Sprouting of neighbouring axons from neighbouring motor units (collateral branches)

12

How to distinguish ALS from other motor neurone diseases?

Presence of both upper and lower motor neurone signs

13

Examples of LMN signs?

Muscle weakness, wasting, fasciculations, cramps

14

Examples of UMN signs?

Stiffness, slowness of movement, slow and clumsy speech, Babinski

15

What could bulbar symptoms indicate in the context of ALS?

(i.e. UMN and LMN)

Progressive bulbar palsy

16

Describe Primary Lateral Sclerosis (PLS)

Effects on UMNs predominate:
- spasticity
- hyperreflexia

{20 yr survival)

17

Features of an MRI of pt with ALS (PLS)

- Wide precentral sulcus
- Atrophy of adjacent gyri

18

Give an overview of the treatment of ALS

speech & swallowing- speech therapist

mobility around home- occupational therapist

swallowing & feeding- NG tube or PEG

breathing- oxygen, assisted ventilation

slowing disease progression- Riluzole (extends survival ~3 months_

19

Sites targeted in ALS?

- motor cortex (UMN)
- brainstem (LMN)
- spinal cord (LMN)

20

Histological features of ALS?

Ubiquinated inclusion in neuronal cell bodies and proximal axons

21

What is an ubiquitinated protein?

Post-translational modification by a small 76 amino acid regulatory protein, ubiquitin

Substrate designated for degradation is tagged w/ ubiquitin. This is recognised by proteosome, which carries out this process.

22

Ubiquitinated proteins are characteristic of what conditions?

ALS (sporadic & familial) and a subset of fronto-temporal dementia

23

Two forms of ubiquitinated inclusions?

- filamentous
- compact

24

What protein is a major component of ubiquitinated inclusions (in SALS/FALS/FTLD)?

TDP-43

25

What proportion of ALS cases are familial?

10%

26

What is the molecular mechanisms that have been identified in ALS?

Abnormalities in:
- RNA binding proteins
- proteostasis

(- cytoskeletal proteins)

27

Gene pathways involved in FALS?

- RNA processing]- (TDP-43, FUS)
- protein quality control ("waste disposal")]- (VAPB, P4HB, SOD1, VCP, ubiquitin2, P62, OPTN
- excitotoxicity]- DAO

28

What gene encodes for TDP-43?

TARDBP (TAR DNA binding protein)

NB: TAR = Trans activating response

29

Describe the actions of TARDBP

TARDBP encodes TDP-43

Binds TAR DNA sequences in DNA/RNA, acting as a transcriptional repressor

i.e. inhibits splicing and regulates mRNA transport/local translation

30

Sites possibly responsible for TDP-43 and FUS mislocalisation?

- Nuclear localisation signal (enable protein to be taken into nucleus)]- FUS

- Nuclear export signal (enable protein to leave nucleus -> cytoplasm)]- (Importin is the nuclear transport protein)