SMA

Question 1

when was SMA first described?

Answer 1

1891 by Werdnig and Hoffmann separately

Question 2

onset of SMA and death

Answer 2

onset before 6 months and death by 2 years

Question 3

what is SMA?

Answer 3

degeneration of lower, alpha motor neurones in ventral horn

progressive denervation and atrophy of skeletal muscle and paralysis

Question 4

what muscles are particularly affected in SMA?

Answer 4

proximal

Question 5

inheritance of SMA

Answer 5

autosomal recessive

Question 6

what do 98% of patients have?

Answer 6

homozygous disruption of telomeric SMN1 gene

Question 7

SMN1

Answer 7

survival motor neuron 1

Question 8

what is SMN for?

Answer 8

essential for cell survival

Question 9

what is SMN2?

Answer 9

centromeric SMN2 is identical but for a single nucleotide point mutation in exon 7 - truncated, unstable protein

Question 10

incidence

Answer 10

1 in 6-10 000

Question 11

what % of west are carriers?

Answer 11

2-3

Question 12

type 1

Answer 12

severe, before 6 months, unable to sit, die by 2

Question 13

type 2

Answer 13

7-18 months, never walk

Question 14

type 3

Answer 14

after 18 months, live to adult

Question 15

type 4

Answer 15

second or third decade, walk, die as adult

Question 16

chromosome

Answer 16

5 (5 q 13)

Question 17

more copies of SMN2=

Answer 17

milder disease

Question 18

for mouse models, SMN protein needs to be knocked down to what level?

Answer 18

20% normal

Question 19

mice SMA model

Answer 19

don’t have SMN2 - human SMN gene added

Question 20

incidental problem in rat studies

Answer 20

fail to gain weight - not fully explained as means bones not growing normally either

Question 21

SMN role in RNA processing

Answer 21

SMN associates with gemins of coiled bodies in assembly of SnRNPs - splicosome

Question 22

splicing in SMA

Answer 22

problems in splicing only appear at late stages of disease

Question 23

What is SMA otherwise known as

Answer 23

floppy baby syndrome

do not reach milestones

Question 24

histological staining findings in SMA

Answer 24

lose alot of synapses with every motor neuron

alot of denervated muscle - some hypertrophied muscles that remain

Question 25

Lower alpha motor neurons in SMA

Answer 25

fewer, not none

Question 26

Stain for SMN protein in SMA

Answer 26

low

Question 27

1st sign of SMA

Answer 27

lose nerve terminal at skeletal muscle

Question 28

more copies of SMN2 =

Answer 28

less severe disease

Question 29

SMN in axons

Answer 29

specifically regulated b-actin trafficking to nerve terminals b-actin KO mice show no developmental or regenerative phenotype

Question 30

is motor system normal at birth?

Answer 30

appears to be - can't differentiate control vs SMA mouse | formed all synapses normally then goes wrong

Question 31

what % motor neurones lost?

Answer 31

about 25-30% neurons lost

Question 32

why motor neurons?

Answer 32

largest neurons in the body hyperexcitable longest axons inefficient splicing of SMN2

Question 33

Why are some motor neurons not affected?

Answer 33

not sure, some populations in same part of body survive and some don't?

Question 34

Some examples of non-neuromuscular pathology

Answer 34

cardiac arrhytmias peripheral necrosis bone, pancreas, liver clots - platelets high SMN

Question 35

hypoxia

Answer 35

exacerbates SMN deletion

Question 36

4 types of treatments and example

Answer 36

Gene therapy - zolgensma HDAC inhibitors - risdiplam Antisense oligonucleotide - spinraza

Question 37

Gene therapy

Answer 37

self complimentary AAV normal copy SMN1 increase life span, not body weight expensive - only need 1 as genetic

Question 38

HDAC inhibitors

Answer 38

regulators of transcription increase SMN2 promoter activity increase lifespan non-targeted effect

Question 39

How do ASOs work?

Answer 39

bind to intronic splice silencers to promote inclusion of exon 7 in SMN2 increased length of protein

Question 40

spinraza FDA approval

Answer 40

types 1,2,3 | intrathecally

Question 41

target of spinraza

Answer 41

ISS-N1

Question 42

zolgensma

Answer 42

FDA approved April 2019

Question 43

Non-SMN pathways in SMA

Answer 43

ubiquitin dependent pathways regulate NMJ pathologies in SMA UBA1 and b-catenin therapy with quercetin ameliorate neuromuscular symptoms do not live longer

Question 44

Future of SMA

Answer 44

track those on spinraza screening - therapies pre symptomatically multiple therapies