SMA Flashcards
when was SMA first described?
1891 by Werdnig and Hoffmann separately
onset of SMA and death
onset before 6 months and death by 2 years
what is SMA?
degeneration of lower, alpha motor neurones in ventral horn
progressive denervation and atrophy of skeletal muscle and paralysis
what muscles are particularly affected in SMA?
proximal
inheritance of SMA
autosomal recessive
what do 98% of patients have?
homozygous disruption of telomeric SMN1 gene
SMN1
survival motor neuron 1
what is SMN for?
essential for cell survival
what is SMN2?
centromeric SMN2 is identical but for a single nucleotide point mutation in exon 7 - truncated, unstable protein
incidence
1 in 6-10 000
what % of west are carriers?
2-3
type 1
severe, before 6 months, unable to sit, die by 2
type 2
7-18 months, never walk
type 3
after 18 months, live to adult
type 4
second or third decade, walk, die as adult
chromosome
5 (5 q 13)
more copies of SMN2=
milder disease
for mouse models, SMN protein needs to be knocked down to what level?
20% normal
mice SMA model
don’t have SMN2 - human SMN gene added
incidental problem in rat studies
fail to gain weight - not fully explained as means bones not growing normally either
SMN role in RNA processing
SMN associates with gemins of coiled bodies in assembly of SnRNPs - splicosome
splicing in SMA
problems in splicing only appear at late stages of disease
What is SMA otherwise known as
floppy baby syndrome
do not reach milestones
histological staining findings in SMA
lose alot of synapses with every motor neuron
alot of denervated muscle - some hypertrophied muscles that remain
Lower alpha motor neurons in SMA
fewer, not none
Stain for SMN protein in SMA
low
1st sign of SMA
lose nerve terminal at skeletal muscle
more copies of SMN2 =
less severe disease
SMN in axons
specifically regulated b-actin trafficking to nerve terminals
b-actin KO mice show no developmental or regenerative phenotype
is motor system normal at birth?
appears to be - can’t differentiate control vs SMA mouse
formed all synapses normally then goes wrong
what % motor neurones lost?
about 25-30% neurons lost
why motor neurons?
largest neurons in the body
hyperexcitable
longest axons
inefficient splicing of SMN2
Why are some motor neurons not affected?
not sure, some populations in same part of body survive and some don’t?
Some examples of non-neuromuscular pathology
cardiac arrhytmias
peripheral necrosis
bone, pancreas, liver
clots - platelets high SMN
hypoxia
exacerbates SMN deletion
4 types of treatments and example
Gene therapy - zolgensma
HDAC inhibitors - risdiplam
Antisense oligonucleotide - spinraza
Gene therapy
self complimentary AAV
normal copy SMN1
increase life span, not body weight
expensive - only need 1 as genetic
HDAC inhibitors
regulators of transcription
increase SMN2 promoter activity
increase lifespan
non-targeted effect
How do ASOs work?
bind to intronic splice silencers to promote inclusion of exon 7 in SMN2
increased length of protein
spinraza FDA approval
types 1,2,3
intrathecally
target of spinraza
ISS-N1
zolgensma
FDA approved April 2019
Non-SMN pathways in SMA
ubiquitin dependent pathways regulate NMJ pathologies in SMA
UBA1 and b-catenin
therapy with quercetin ameliorate neuromuscular symptoms
do not live longer
Future of SMA
track those on spinraza
screening - therapies pre symptomatically
multiple therapies
