spinal muscular atrophy (SMA) Flashcards
what is SMA
- genetic disease affecting the nerves in the spinal cord
- does not affect cognition
SMA cause
- autosomal recessive
- genetic mutation of SMN1 (survival motor nueron 1)
SMN1 purpose
makes SMN proteins
SMA impacts ?
physical functions (walking, breathing, swallowing)
SMN2 purpose
- back-up SMN1
- makes SMN proteins on a smaller scale
- more SMN2 copies = less severe
how many SMN2 copies do we have usually
- 0-3 copies
- indicates severity and type of SMA
SMA steps
- genetic mutation of SMN1 –> fewer SMN proteins
- fewer SMN proteins –> motor neuron death
- no signals sent –> muscle atrophy
types of SMA
- type 1
- type 2
- type 3
- type 4
what differentiates SMA types
- age of onset
- highest milestone reached
- number of SMN2 gene copies
type 1 SMA (age of onset, copies, milestones)
“non-sitters
- 0-6 months
- 2 copies
- cannot sit independently
type 2 SMA (age of onset, copies, milestones)
“sitters”
- 6 mo. to 2 years
- 3 copies
- unable to walk
- respiration difficulties
type 3 SMA (age of onset, copies, milestones)
“walkers”
- 18 mo. to teens
- 3-4 copies
- learn to stand and walk, might lose it
type 4 SMA (age of onset, copies, milestones)
- 35+ years
- 3-4 copies
- rare and slow progression
- affects walking
typical infant postures in SMA
- “rag doll posture” (floppy, slips in vertical and ventral suspension)
- “frog legged posture” (on back, knees splay outward)
? deletion of SMN1 gene
homozygous deletion
why does SMN2 gene not makeup for SMN1 gene
- 10% of SMN proteins are functional
- 90% is defunct and can’t be used
why SMA types will develop scoliosis
- type 1: 100% (if they live long enough)
- type 2: majority
SMA treatment goal
alter natural history of SMA
SMA treatments
- nusinersen (spinraza)
- AVXS-101
nusinersen (what is it, outcomes, how often is the medication needed)
- SMA treatment
- antisense oligonucleotide
- given intrathecally into CSF via LP
- increase SMN2 gene production for more protein
- achieve motor milestones more appropriately
- maintain and hold suck/swallow abilities
- repeated treatment in LP 3x per year for life
antisense oligonucleotide purpose
- short oligonucleotides
- targeted bind to RNA
- modify protein expressions
what is the only comercially available gene therapy treatment in ireladn
nusinersen
how to get the best treatment outcomes
administer pre-symptomatic
AVXS-101
- SMA treatment, unavailable
- being trialled in Europe
- treatment delivered through the AAV9 virus (genetically modified to package the SMN1 gene)
- 1 time treatment, sustained effect in treatment
- 60 minute infusion, virus deseminates systemically
nusinersen vs. AVXS-101
- nusinersen to SMN2 gene needed 3x per year for life
- AVXS-101 packages SMB1 gene, 1 60 minute infusion
