Spinal Muscular Atrophy

Question 1

What are the overall symptoms of SMA?

Answer 1

Symmetrical muscle weakness and atrophy

Question 2

Which cells are affected by SMA and how?

Answer 2

Degeneration of MNs in anterior horn of spinal cord

Question 3

What is the inheritance pattern of SMA?

Answer 3

Autosomal recessive

Question 4

The deletion of both alleles of which gene is the most common cause of SMA?

Answer 4

SMN1

Question 5

Name the 3 types of SMA

Answer 5

I
II
III

Question 6

When is the onset of SMA-I, how does it affect sitting/standing, and when do sufferers die?

Answer 6

<6 months old onset
Never sit
<2 yrs old die

Question 7

When is the onset of SMA-II, how does it affect sitting/standing, and when do sufferers die?

Answer 7

<18 months old onset
Sit but never stand
>2 yrs old die

Question 8

When is the onset of SMA-III, how does it affect sitting/standing, and when do sufferers die?

Answer 8

> 18 months onset
Stand
Die as adult

Question 9

What are the symptoms of SMA-I?

Answer 9

Severe and rapid progression
Hypotonia - mainly affects limbs
Areflexia
Respiratory muscle weakness - bell-shaped chest
Bulbar denervation - tongue fasciculations, dysphagia

Question 10

What are the symptoms of SMA-II?

Answer 10

Slow progression
Hypotonia - mainly affects limbs
Areflexia
Respiratory muscle weakness - bell-shaped chest
Bulbar denervation - tongue fasciculations, dysphagia

Question 11

Is cognitive development affected by SMA?

Answer 11

No

Question 12

What are the symptoms of SMA-III?

Answer 12

Falling
Unsteady gait
Limb weakness
Muscle fasciculations

Question 13

What is the product of SMN1?

Answer 13

Full-length functional protein

Question 14

What is the product of SMN2?

Answer 14

90% - unstable truncated protein - less efficient

10% - full-length functional protein

Question 15

Why does SMN2 make unstable truncated protein?

Answer 15

Transcription machinery skips exon 7

Question 16

How does the number of SMN2 copies affect disease severity?

Answer 16

More copies increases amount of full-length protein made by total SMN2
Decreases SMA-I chance - decreases severity

Question 17

In which cell types is SMN found?

Answer 17

All (ubiquitous)

Question 18

What is the role of SMN in the nucleus?

Answer 18

Forms aggregates - gems

Involved in RNA regulation

Question 19

What is the role of SMN in the cytoplasm?

Answer 19

Associated with cytoskeleton - in dendrites and axons

Question 20

What are the roles of SMN in RNA regulation?

Answer 20

In multiple spliceosomal complexes - essential for splicing introns with U12 and U7 signals
3’ end processing of histone mRNA
Axonal transport of mRNA to distal end of developing neurons - most important role

Question 21

Which U12 intron-containing SMN target is needed for motor circuit function in Drosophila?

Answer 21

Stasimon

Question 22

What are the effects of decreased SMN in mice?

Answer 22

Decreased mRNA in distal axons of MNs

Decreased axonal growth

Question 23

When in development does an SMN decrease have the most detrimental effect on the NMJ and what does this suggest?

Answer 23

Early development - before NMJ maturation

SMN required at MN terminals for correct NMJ maturation

Question 24

How is early sensory-motor connectivity altered in SMA model mice and what does this suggest?

Answer 24

Fewer proprioceptive afferent synapses onto MNs - before loss of MNs
DRG afferents maintain MNs

Question 25

How does excitatory afferent drive increase MN firing and enable proper motor functioning in mice?

Answer 25

Increases Kv2.1 expression on MNs

Question 26

How does the absence of SMN affect the splicing of certain p53 suppressors?

Answer 26

Alternate splicing Decreases p53 suppression Increases p53

Question 27

What is the effect of an SMN KO?

Answer 27

Embryonic lethality

Question 28

Which MNs are most vulnerable to death?

Answer 28

Medial motor column - for axial muscles

Question 29

How are peripheral tissues affected in SMA mice?

Answer 29

Protective hormones from liver not made | Vascular problems

Question 30

What are the vascular defects seen in SMA mice and SMA-I patients?

Answer 30

Decreased capillary density in skeletal muscle Decreased capillary density in ventral spinal cord Increased hypoxic cells in ventral horn

Question 31

How might peripheral tissue dysfunction contribute to SMA pathology?

Answer 31

May increase vulnerability of already-vulnerable MNs

Question 32

What is the aim of ASOs as a treatment for SMA?

Answer 32

Target splice site at end of SMN2 intron 6 Cause inclusion of exon 7 in SMN2 mRNA Increase SMN protein levels

Question 33

Why is intrathecal administration of ASOs required?

Answer 33

ASOs do not cross BBB

Question 34

What is the name of the ASO approved to treat SMA?

Answer 34

Nusinersen

Question 35

Who did the ENDEAR study test and when?

Answer 35

SMA-I infants | After symptom onset

Question 36

What did the ENDEAR study find?

Answer 36

Improved motor ability Improved respiratory outcome Improved speech Decreased risk of death

Question 37

Who did the NURTURE study test and when?

Answer 37

SMA-I infants | Before symptom onset

Question 38

What did the NURTURE study find?

Answer 38

Greatly improved motor ability - more than in ENDEAR No deaths No permanent ventilation Nusinersen well-tolerated

Question 39

How might small molecules be used to treat SMA?

Answer 39

Sit in splicing complex for SMN2 exon 7 | Modify SMN2 splicing

Question 40

What is the advantage of small molecules over ASOs?

Answer 40

Orally bioavailable drug

Question 41

What is the effect of small molecules on SMA mice?

Answer 41

Increased motor function | Increased survival time

Question 42

How might gene therapy be used to treat SMA?

Answer 42

SMN2 in viral vector - target MNs | Causes 2 copies of SMN2

Question 43

What is the effect of gene therapy in SMA-I infants?

Answer 43

Increased functional ability | Increased survival

Question 44

Do any current SMA treatments recover lost MNs?

Answer 44

No