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NEUROLOGY - LIGUORI STUDY SET EXAM
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NEUROLOGY - LIGUORI STUDY SET EXAMALS (amyotrophic lateral sclerosis); What neurons are affected?
fatal degenerative disease of the motor neurons marked by muscle weakness and
atrophy
AKA Lou Gerhig disease
* Upper and lower motor neurons
ALS pathophysiology
Protein aggregation --> Neuron degenrates and dies --> Retrogade neuronal
degenration --> Gliosis
ALS subtypes
Spectrum of subtypes
PLS - UMN (w/ rare & little LMN S/S)
Other types: bulbar type (>80yo, 2-yr survival), flail arm (proximal), flail leg
(proximal), spinal onset, hemiplegic, pseudopolyneuritic)
PMA - LMN (UMN evidence seen on autopsy/brain MRI but S/S masked by severe
LMN signs like atrophy)
ALS prognosis and prognostic markers
Prognosis: 2-10 years survival (2 with bulbar type)
Prognostic markers:
Degree of denervation on EMG = greater = worse (mean survival & disability)
Evidence of genioglossus inv. on EMG → worse (→ increase FU, prepare…)
CSF NFL → more = worse
,ALS etiology
Unknown. Possible genetic predisposition.
fALS ≈ 10%
‘Becoming’ more frequent as more genes are identified
~35 genes known, in 30-40% cases gene is unknown
Europe: c9orf79 > SOD1 > TARDBP
Asia: SOD1 > FUS > c9orf79
Subtypes sometimes correlate with specific genes (e.g. flail leg - SOD1)
sALS ≈ 90%
Phenotypic pleiotrophy in ALS
mutations ass. w/ ALS are also a/w other diseases (Motor: parkinsonism, CBS,
Huntington’s Disease, olivopontocerebellar degeneration + non Motor: AD, FTD,
psychiatric disease) → always cross investigate!
S/S ALS
-Weakness in any or all muscles
-Flaccid/spastic paralysis
-Progressive muscle atrophy
-NO cognitive, sensory, or autonomic symptoms
List:
dysarthria, dysphonia, dysphagia, hypotonia or hypertonia, muscle atrophy &
weakness, gait and posture disturbances and deformities, DTR - hyperreflexia
(UMN) or hyporeflexia (LMN), paralysis, paresis, fatigue, Babinski sign (UMN)
ALS Dx
EMG (fasciculations, positive sharp waves, fibrillation potential - spontaneous
,activity)
Brain MRI (siderosis, abnormalities in corticospinal tract, cortical atrophy)
Increased creatinine kinase
*Always check: strength, trophism, tone, DTR, superficial plantar reflex (Babinski)
Tx ALS
Doesn’t really exist | pts are followed up on every 1-2 months
Riluzole → first, doubtfully effective (no survival benefit compared to placebo)
Edaravone → great improvement, but not properly randomized & unknown reason
for why some did improve and others didn’t
Antisense Oligonucleotides (ASO) = DNA-RNA hybrid targets for diff. mut. /
splice sites / translation start sites ⇒ ↓ abnormal production of proteins
Study on SOD1 patients → works well, total ALS scale improved, slower disease
progression, stronger force
Spinal Muscular Atrophy (SMA); is it LMN or UMN
A neuromuscular disease characterized by degeneration of motor neurons resulting
in progressive muscular atrophy and weakness.
Primarily LMN
Always: mainly/only LMN
Severe type 1: mainly LMN + CNS inv. + sensory sural nerve inv.
SMA S/S
Lower motor neurons signs; usually more proximal than distal.
* decreased muscle tone, Fasciculations, Decreased or absent DTRs
, SMA etiology
genetic caused by defect in chromosome 5q
5q SMA → bi-allelic mutation in SMN1 gene
a very common autosomal recessive neuromuscular disease
Mutation in SMN1 (the main gene responsible for the normal Survival Motor
Neuron Protein, because SMN2 only makes 10% stable protein, due to a mutation
(C to T) causing splicing of exon 7 in the other 90%)
Clinical severity types of SMA
Type 0 → die in weeks, contractures, cardiomyopathies
Type 1 → 1A = severe weakness and resp. problems at birth > 1B > 1C
Highest incidence
Type 2 → can sit, but no independent ambulation | type 2A > 2B | w/ new standard
of care + NIV → survival ↑↑
Type 3 → early loss of ambulation, normal life span
Highest prevalence
Type 4 → ambulant until later, normal life span
SMA prognosis
Prognostic/phenotypic markers:
SMN2 copy number (1-6) → higher = better + more chance for type 3 instead of
2/1
SMA Dx
detection of SMN1 mutations/deletions + SMN2 copy number
SMA Tx
ASOs that modulate the RNA splicing of SMN2 gene so that exon 7 is activated →
all mRNA segments are produced –> ↑ functional protein
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