ALS Flashcards
incidence
most common cause of neuro death in canada/worldwide.
prognosis
progressive w no cure. 100% fatal.
inheritance
less than 10% cases
how does it arise
loss of neurons... corticospinal tract = upper motor neuron lesion. motor unit (anterior horn cell) = lower motor neuron lesion.
amyotrophic lateral sclerosis
absence of muscle nourishment… lateral corticospinal tract scarring
UMN signs (wshb)
little wasting, incr tone(spasticity), hyperreflexia, babinski sign (primitive reflexs)
LMN signs (afhf)
wasting/atrophy, low/normal tone(flaccid), hyporeflexia or none, fasciculations (low threshold for MN irritation)
segments
bulbar, cervical, thoracic, lumbar, sacral
el escorial criteria
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
about el escorial criteria
specificity 99%, sensitivity 57%
10% cases undiagnosed
other criteria…
most are trials?
clin features: bulbar
poor palate elevation, weak tongue & cough, pathological cry/laugh (pseudobulbar), trouble speak/swallow, hoarse voice, clearing secretions
clin features: limbs
trouble walk, feed, dress, transfer, move. flail limb (LMN) - weakness, atrophy. spastic limb (UMN) - weakness, loss dexterity, cramps.
axial muscles
UMN - spasms, stiffness. LMN - weak neck extensors (head drop), trunk extension, hard to breathe deeply, decr lung vol, hard to walk/sit upright
resp muscles
tachypnea, soft quiet speech(hypophonic), short sentences w freq pauses, short breath (esp when flat), weak cough, sleep disordered breathing
patterns of disease (progressive, neurodegen)
UMN > PLS primary
UMN+LMN > ALS
LMN > PMA progressive muscular atrophy
primary lateral sclerosis
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
progressive muscular atrophy
pure LMN syndrome, 10% ALS cases, diffuse weakness, wasting (often paraspinals), nocturnal cramps, fasciculations, mortality 68%, slightly more M than F
clin summary
ALS affects corticospinal tract (UMN) & motor unit (LMN) … damage results in weakness (ambulation, swallow/speak, breathe)
fasciculations do NOT mean ALS
ALS - wide distrib, abundant freq, weakness atrophy UMN signs, abnormal EMG. benign - restricted, infreq, no other signs, normal EMG
histology
neurons, gliosis, inclusions - skein like, ubiquinated, bunina bodies
SOD1 superoxide dismutase
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)
cognitive changes (part of FTD frontotemporal dementia spectrum)
…estimates vary. huge implics in morbidity, decision making, caregiver stress, mortality
dementia variant: frontal (lobes)
impair exec fxn, disinhib, compulsive, self-neglect
cortical involvement
neuropath: inclusions in cortex. connection: brain inclusions in ALS, SC inclusions in dementia
TDP43 tar dna binding protein 43
for rna processing. mostly in nucleus.
TDP43 +ve inclusions also in
neurons w sporadic disease
TDP43-opathies
ALS, FTD, PLS, PMA
other genes
ATXN2 OPTN NEKI TBKI KIF5A CHCHD10
FUS (fused in sarcoma) involves
xsome 16, assoc w fALS. & dna/rna binding protein (rna processing, dna repair, transcrip regulation)
C9orf72
in families w ALS & FTD linked to xsome 9. most familial FTD-ALS, less sporadic FTD-ALS or ALS. gene fxn unknown!
C9orf72 mutation
hexanucleotide repeat GGGGCC in noncoding region (normal <23 repeats)
many neurodegen diseases due to
proteinopathy (accum proteins)
ALS = fatal disease leading to
corticospinal tract & anterior horn cell damage. weakness, death
patients have proteinacious inclusions in areas OUTSIDE
ALS - outside corticospinal tract. FTD - outside cortex
protein characterization suggests
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
dementia variant: non fluent aphasia (left frontoparietal region)
lose expressive lang, working memory, social withdrawal, depression
dementia variant: semantic dementia (left temporal)
decr lang understanding, emotional withdrawal, depression
C9orf72 mutation mech 1
haploinsufficiency of gene (downreg interfer w transcrip)
C9orf72 mutation mech 2
repeat rna med toxicity (sequester rna binding proteins, defects in splicing)
C9orf72 mutation mech 3
dipeptide repeat protein toxicity (accum sense/antisense rna repeats - unusual substrates for translation)
what does FUS do
continuously shuttle bw nucleus/cytoplasm (pathogenic mutations probably interfere w FUS transpo to nucleus)
basis for FTD ALS continuum
ALS have UB’d inclusions in motor/brain neurons. isolated cytosolic TDP43 from these inclusions. TDP43 also in inclusions in FTD brains & SCs
