Lecture 03 - Spinal Muscular Atrophy Flashcards
What is spinal muscular atrophy
a progressive degeneration of lower motor neurons and the brain stem nuclei
What are the signs/symptoms of spinal muscular atrophy
severe neonatal hypotonia
severe weakness
respiratory failure at birth
facial diplegia
lower than normal fetal movements
atrial septal defects
loss of motor skills
What is Type 0 spinal muscular atrophy
onset during prenatal stages, predicted life span of <6 months, no motor control, sever hypotonia, respiratory failure at birth
What is Type 1 spinal muscular atrophy
onset at <6 months, predicted life span of 8-10 months, some head control, sit with support only, loss of head control, variable suck and swallow difficultiese
What is Type 2 spinal muscular atrophy
onset at 6-18 months, 70% are still alive at 25 years, independent sitting when placed, developmental delay, muscle weakness
What is Type 3 spinal muscular atrophy
onset at >18 months, normal lifespan, independent ambulation, muscle weakness, loss of motor skills
What is Type 4 spinal muscular atrophy
onset in adulthood, normal lifespan, normal motor skills, muscle weakness and fatigue
What is the pathophysiology of spinal muscular atrophy
autosomal recessive inheritance
loss of SMN1 gene
- 96-98% homozygous deletion of SMN1 exon 7 or gene conversion to SMN2
- 2-5% deletion of exon 7/intergenic pathogenic variant
What is the incidence of spinal muscular atrophy
1/6000-1/10000 births
How many healthy carriers are there of spinal muscular atrophy
1:40-80 in general population
What is the difference between SMN2 and SMN1
SMN2 has a T residue in exon 7 while SMN1 has a C residue
What does SMN1 produce
10 functional proteins
What does SMN2 produce
1 functional protein, 9 non-functional proteins
What is the phenotype of a normal person
SMN1, SMN2
SMN1, SMN2
What is the phenotype of an SMA patient
SMN2
SMN2
What is the phenotype of a carrier
SMN1, SMN2
SMN2
What is the phenotype of a silent carrier
SMN2
SMN1, SMN1, SMN2
How can someone without SMN1 still be relatively healthy
you can have multiple SMN2, people who have 5 usually can produce enough protein to be healthy
What treatment do people with 5 SMN2 genes get
spinraza
What treatment do people with <5 SMN2 genes get
gene therapy
If a patient has no SMN1 but 1 SMN2 what are their chances of having each type of SMA
SMA I 96%
SMA II 4%
SMA III/IV 0%
If a patient has no SMN1 but 2 SMN2 what are their chances of having each type of SMA
SMA I 79%
SMA II 16%
SMA III/IV 5%
If a patient has no SMN1 but 3 SMN2 what are their chances of having each type of SMA
SMA I 15%
SMA II 54%
SMA III/IV 31%
If a patient has no SMN1 but >/=4 SMN2 what are their chances of having each type of SMA
SMA I 1%
SMA II 11%
SMA III/IV 88%
How is spinal muscular atrophy identified
Taqman assay (qPCR)
How does the Taqman assay for SMA work
we detect the SMN1 gene via amplification using a florescent probe
What are the expected Taqman results for a normal patient and an SMA carrier
normal: strong florescence
carrier: weaker florescence
What is used as an endogenous control for the Taqman assay
Rnase P
When do most babies show signs of SMA
3 months
If untreated by 6 months how many neurons have been lost in type 1
90%
How does newborn screening help SMA
it detects the disorder before symptoms occur so that baby can start treatment faster
What is spinraza
a treatment for SMA that was approved in alberta in 2018, it consists of loading doses every 14 days for three doses, then another loading dose 30 days after that, then maintenance doses every 4 months
How does Spinraza work
its an SMN2 splicing modifier, it promotes SMN2 to produce more functional proteins by preventing the splicing of exon 7
What is Risdiplam
a treatment for SMA that was approved in alberta in 2022, it is taken orally daily
How does Risdiplam work
its an SMN2 splicing modifier, it promotes SMN2 to produce more functional proteins
What is zolgensma
a treatment for SMA that was approved in alberta in 2021, it is a one time intravenous injection
How does zolgensma work
it is a gene replacement therapy with a viral delivery of SMN1
What are the mechanics of Spinraza
it binds to the intronic splicing silencers in intron 7, this promotes the inclusion of exon 7 in mRNA which forms more functional proteins
What did the SMA NBS pilot study find
47005 newborns screened
6 positive screens
5 confirmed positive (1 false positive)
What determines a negative SMA screen
if the SMN1 gene is detected at all
How is a positive SMA screen confirmed
a second PCR test, then diagnostic testing in calgary to confirm that there is no SMN1 and determine SMN2 copy numbers
What are the limitations of the SMA screen
screen is not diagnostic, we do not report carriers, we do not determine SMN2 copy numbers, we miss 2-5% of SMA cases
How many SMA cases are missed in alberta
1 case every 2.5-6 years
