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NEUR0010 > Spinal Muscular Atrophy > Flashcards

Spinal Muscular Atrophy Flashcards

1
Q

What are the overall symptoms of SMA?

A

Symmetrical muscle weakness and atrophy

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2
Q

Which cells are affected by SMA and how?

A

Degeneration of MNs in anterior horn of spinal cord

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3
Q

What is the inheritance pattern of SMA?

A

Autosomal recessive

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4
Q

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

A

SMN1

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5
Q

Name the 3 types of SMA

A

I
II
III

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6
Q

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

A

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

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7
Q

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

A

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

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8
Q

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

A

> 18 months onset
Stand
Die as adult

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9
Q

What are the symptoms of SMA-I?

A

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

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10
Q

What are the symptoms of SMA-II?

A

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

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11
Q

Is cognitive development affected by SMA?

A

No

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12
Q

What are the symptoms of SMA-III?

A

Falling
Unsteady gait
Limb weakness
Muscle fasciculations

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13
Q

What is the product of SMN1?

A

Full-length functional protein

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14
Q

What is the product of SMN2?

A

90% - unstable truncated protein - less efficient

10% - full-length functional protein

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15
Q

Why does SMN2 make unstable truncated protein?

A

Transcription machinery skips exon 7

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16
Q

How does the number of SMN2 copies affect disease severity?

A

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

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17
Q

In which cell types is SMN found?

A

All (ubiquitous)

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18
Q

What is the role of SMN in the nucleus?

A

Forms aggregates - gems

Involved in RNA regulation

19
Q

What is the role of SMN in the cytoplasm?

A

Associated with cytoskeleton - in dendrites and axons

20
Q

What are the roles of SMN in RNA regulation?

A

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

21
Q

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

A

Stasimon

22
Q

What are the effects of decreased SMN in mice?

A

Decreased mRNA in distal axons of MNs

Decreased axonal growth

23
Q

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

A

Early development - before NMJ maturation

SMN required at MN terminals for correct NMJ maturation

24
Q

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

A

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

25
Q

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

A

Increases Kv2.1 expression on MNs

26
Q

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

A

Alternate splicing
Decreases p53 suppression
Increases p53

27
Q

What is the effect of an SMN KO?

A

Embryonic lethality

28
Q

Which MNs are most vulnerable to death?

A

Medial motor column - for axial muscles

29
Q

How are peripheral tissues affected in SMA mice?

A

Protective hormones from liver not made

Vascular problems

30
Q

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

A

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

31
Q

How might peripheral tissue dysfunction contribute to SMA pathology?

A

May increase vulnerability of already-vulnerable MNs

32
Q

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

A

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

33
Q

Why is intrathecal administration of ASOs required?

A

ASOs do not cross BBB

34
Q

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

A

Nusinersen

35
Q

Who did the ENDEAR study test and when?

A

SMA-I infants

After symptom onset

36
Q

What did the ENDEAR study find?

A

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

37
Q

Who did the NURTURE study test and when?

A

SMA-I infants

Before symptom onset

38
Q

What did the NURTURE study find?

A

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

39
Q

How might small molecules be used to treat SMA?

A

Sit in splicing complex for SMN2 exon 7

Modify SMN2 splicing

40
Q

What is the advantage of small molecules over ASOs?

A

Orally bioavailable drug

41
Q

What is the effect of small molecules on SMA mice?

A

Increased motor function

Increased survival time

42
Q

How might gene therapy be used to treat SMA?

A

SMN2 in viral vector - target MNs

Causes 2 copies of SMN2

43
Q

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

A

Increased functional ability

Increased survival

44
Q

Do any current SMA treatments recover lost MNs?

A

No

NEUR0010 (9 decks)

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