Spinal Muscular Atrophy Flashcards
What are the overall symptoms of SMA?
Symmetrical muscle weakness and atrophy
Which cells are affected by SMA and how?
Degeneration of MNs in anterior horn of spinal cord
What is the inheritance pattern of SMA?
Autosomal recessive
The deletion of both alleles of which gene is the most common cause of SMA?
SMN1
Name the 3 types of SMA
I
II
III
When is the onset of SMA-I, how does it affect sitting/standing, and when do sufferers die?
<6 months old onset
Never sit
<2 yrs old die
When is the onset of SMA-II, how does it affect sitting/standing, and when do sufferers die?
<18 months old onset
Sit but never stand
>2 yrs old die
When is the onset of SMA-III, how does it affect sitting/standing, and when do sufferers die?
> 18 months onset
Stand
Die as adult
What are the symptoms of SMA-I?
Severe and rapid progression
Hypotonia - mainly affects limbs
Areflexia
Respiratory muscle weakness - bell-shaped chest
Bulbar denervation - tongue fasciculations, dysphagia
What are the symptoms of SMA-II?
Slow progression
Hypotonia - mainly affects limbs
Areflexia
Respiratory muscle weakness - bell-shaped chest
Bulbar denervation - tongue fasciculations, dysphagia
Is cognitive development affected by SMA?
No
What are the symptoms of SMA-III?
Falling
Unsteady gait
Limb weakness
Muscle fasciculations
What is the product of SMN1?
Full-length functional protein
What is the product of SMN2?
90% - unstable truncated protein - less efficient
10% - full-length functional protein
Why does SMN2 make unstable truncated protein?
Transcription machinery skips exon 7
How does the number of SMN2 copies affect disease severity?
More copies increases amount of full-length protein made by total SMN2
Decreases SMA-I chance - decreases severity
In which cell types is SMN found?
All (ubiquitous)
What is the role of SMN in the nucleus?
Forms aggregates - gems
Involved in RNA regulation
What is the role of SMN in the cytoplasm?
Associated with cytoskeleton - in dendrites and axons
What are the roles of SMN in RNA regulation?
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
Which U12 intron-containing SMN target is needed for motor circuit function in Drosophila?
Stasimon
What are the effects of decreased SMN in mice?
Decreased mRNA in distal axons of MNs
Decreased axonal growth
When in development does an SMN decrease have the most detrimental effect on the NMJ and what does this suggest?
Early development - before NMJ maturation
SMN required at MN terminals for correct NMJ maturation
How is early sensory-motor connectivity altered in SMA model mice and what does this suggest?
Fewer proprioceptive afferent synapses onto MNs - before loss of MNs
DRG afferents maintain MNs
How does excitatory afferent drive increase MN firing and enable proper motor functioning in mice?
Increases Kv2.1 expression on MNs
How does the absence of SMN affect the splicing of certain p53 suppressors?
Alternate splicing
Decreases p53 suppression
Increases p53
What is the effect of an SMN KO?
Embryonic lethality
Which MNs are most vulnerable to death?
Medial motor column - for axial muscles
How are peripheral tissues affected in SMA mice?
Protective hormones from liver not made
Vascular problems
What are the vascular defects seen in SMA mice and SMA-I patients?
Decreased capillary density in skeletal muscle
Decreased capillary density in ventral spinal cord
Increased hypoxic cells in ventral horn
How might peripheral tissue dysfunction contribute to SMA pathology?
May increase vulnerability of already-vulnerable MNs
What is the aim of ASOs as a treatment for SMA?
Target splice site at end of SMN2 intron 6
Cause inclusion of exon 7 in SMN2 mRNA
Increase SMN protein levels
Why is intrathecal administration of ASOs required?
ASOs do not cross BBB
What is the name of the ASO approved to treat SMA?
Nusinersen
Who did the ENDEAR study test and when?
SMA-I infants
After symptom onset
What did the ENDEAR study find?
Improved motor ability
Improved respiratory outcome
Improved speech
Decreased risk of death
Who did the NURTURE study test and when?
SMA-I infants
Before symptom onset
What did the NURTURE study find?
Greatly improved motor ability - more than in ENDEAR
No deaths
No permanent ventilation
Nusinersen well-tolerated
How might small molecules be used to treat SMA?
Sit in splicing complex for SMN2 exon 7
Modify SMN2 splicing
What is the advantage of small molecules over ASOs?
Orally bioavailable drug
What is the effect of small molecules on SMA mice?
Increased motor function
Increased survival time
How might gene therapy be used to treat SMA?
SMN2 in viral vector - target MNs
Causes 2 copies of SMN2
What is the effect of gene therapy in SMA-I infants?
Increased functional ability
Increased survival
Do any current SMA treatments recover lost MNs?
No