ALS

Question 1

incidence

Answer 1

most common cause of neuro death in canada/worldwide.

Question 2

prognosis

Answer 2

progressive w no cure. 100% fatal.

Question 3

inheritance

Answer 3

less than 10% cases

Question 4

how does it arise

Answer 4

loss of neurons...
corticospinal tract = upper motor neuron lesion.
motor unit (anterior horn cell) = lower motor neuron lesion.

Question 5

amyotrophic lateral sclerosis

Answer 5

absence of muscle nourishment… lateral corticospinal tract scarring

Question 6

UMN signs (wshb)

Answer 6

little wasting, incr tone(spasticity), hyperreflexia, babinski sign (primitive reflexs)

Question 7

LMN signs (afhf)

Answer 7

wasting/atrophy, low/normal tone(flaccid), hyporeflexia or none, fasciculations (low threshold for MN irritation)

Question 8

segments

Answer 8

bulbar, cervical, thoracic, lumbar, sacral

Question 9

el escorial criteria

Answer 9

presence:
signs of LMN degen by clin, electrophgy, neuropath exam… signs of UMN degen by clin exam & progressive spreading.
absence:
electrophgy evidence of other diseases to explain degen, neuroimaging to explain clin/electrophgy signs

Question 10

about el escorial criteria

Answer 10

specificity 99%, sensitivity 57%
10% cases undiagnosed
other criteria…
most are trials?

Question 11

clin features: bulbar

Answer 11

poor palate elevation, weak tongue & cough, pathological cry/laugh (pseudobulbar), trouble speak/swallow, hoarse voice, clearing secretions

Question 12

clin features: limbs

Answer 12

trouble walk, feed, dress, transfer, move. flail limb (LMN) - weakness, atrophy. spastic limb (UMN) - weakness, loss dexterity, cramps.

Question 13

axial muscles

Answer 13

UMN - spasms, stiffness. LMN - weak neck extensors (head drop), trunk extension, hard to breathe deeply, decr lung vol, hard to walk/sit upright

Question 14

resp muscles

Answer 14

tachypnea, soft quiet speech(hypophonic), short sentences w freq pauses, short breath (esp when flat), weak cough, sleep disordered breathing

Question 15

patterns of disease (progressive, neurodegen)

Answer 15

UMN > PLS primary
UMN+LMN > ALS
LMN > PMA progressive muscular atrophy

Question 16

primary lateral sclerosis

Answer 16

pure UMN syndrome,
affect corticospinal&bulbar tracts, result in progressive spasticity, limbs & bulbar muscles, ~ legs before arms,, slow progression maybe > 30 yrs, 1-5% motor neuron disease

Question 17

progressive muscular atrophy

Answer 17

pure LMN syndrome, 10% ALS cases, diffuse weakness, wasting (often paraspinals), nocturnal cramps, fasciculations, mortality 68%, slightly more M than F

Question 18

clin summary

Answer 18

ALS affects corticospinal tract (UMN) & motor unit (LMN) … damage results in weakness (ambulation, swallow/speak, breathe)

Question 19

fasciculations do NOT mean ALS

Answer 19

ALS - wide distrib, abundant freq, weakness atrophy UMN signs, abnormal EMG. benign - restricted, infreq, no other signs, normal EMG

Question 20

histology

Answer 20

neurons, gliosis, inclusions - skein like, ubiquinated, bunina bodies

Question 21

SOD1 superoxide dismutase

Answer 21

1st gene ID’d, acc for 20% all fALS cases. genetic linkage of fALS to Cu/Zn SOD1 which catalyze conversion of superoxide (free rad) to O2. mutant protein accum in cytoplasmic inclusions (NOT seen in sporadic ALS)

Question 22

cognitive changes (part of FTD frontotemporal dementia spectrum)

Answer 22

…estimates vary. huge implics in morbidity, decision making, caregiver stress, mortality

Question 23

dementia variant: frontal (lobes)

Answer 23

impair exec fxn, disinhib, compulsive, self-neglect

Question 24

cortical involvement

Answer 24

neuropath: inclusions in cortex. connection: brain inclusions in ALS, SC inclusions in dementia

Question 25

TDP43 tar dna binding protein 43

Answer 25

for rna processing. mostly in nucleus.

Question 26

TDP43 +ve inclusions also in

Answer 26

neurons w sporadic disease

Question 27

TDP43-opathies

Answer 27

ALS, FTD, PLS, PMA

Question 28

other genes

Answer 28

ATXN2 OPTN NEKI TBKI KIF5A CHCHD10

Question 29

FUS (fused in sarcoma) involves

Answer 29

xsome 16, assoc w fALS. & dna/rna binding protein (rna processing, dna repair, transcrip regulation)

Question 30

C9orf72

Answer 30

in families w ALS & FTD linked to xsome 9. most familial FTD-ALS, less sporadic FTD-ALS or ALS. gene fxn unknown!

Question 31

C9orf72 mutation

Answer 31

hexanucleotide repeat GGGGCC in noncoding region (normal <23 repeats)

Question 32

many neurodegen diseases due to

Answer 32

proteinopathy (accum proteins)

Question 33

ALS = fatal disease leading to

Answer 33

corticospinal tract & anterior horn cell damage. weakness, death

Question 34

patients have proteinacious inclusions in areas OUTSIDE

Answer 34

ALS - outside corticospinal tract. FTD - outside cortex

Question 35

protein characterization suggests

Answer 35

ALS part of continuum of degen disease (FTD > ALS)… see inclusions in fam cases, help understand sporadic ones… new proteins (TDP43, FUS, C9orf72) - new targets for treatment

Question 36

dementia variant: non fluent aphasia (left frontoparietal region)

Answer 36

lose expressive lang, working memory, social withdrawal, depression

Question 37

dementia variant: semantic dementia (left temporal)

Answer 37

decr lang understanding, emotional withdrawal, depression

Question 38

C9orf72 mutation mech 1

Answer 38

haploinsufficiency of gene (downreg interfer w transcrip)

Question 39

C9orf72 mutation mech 2

Answer 39

repeat rna med toxicity (sequester rna binding proteins, defects in splicing)

Question 40

C9orf72 mutation mech 3

Answer 40

dipeptide repeat protein toxicity (accum sense/antisense rna repeats - unusual substrates for translation)

Question 41

what does FUS do

Answer 41

continuously shuttle bw nucleus/cytoplasm (pathogenic mutations probably interfere w FUS transpo to nucleus)

Question 42

basis for FTD ALS continuum

Answer 42

ALS have UB’d inclusions in motor/brain neurons. isolated cytosolic TDP43 from these inclusions. TDP43 also in inclusions in FTD brains & SCs