Lecture 03 - Spinal Muscular Atrophy

Question 1

What is spinal muscular atrophy

Answer 1

a progressive degeneration of lower motor neurons and the brain stem nuclei

Question 2

What are the signs/symptoms of spinal muscular atrophy

Answer 2

severe neonatal hypotonia
severe weakness
respiratory failure at birth
facial diplegia
lower than normal fetal movements
atrial septal defects
loss of motor skills

Question 3

What is Type 0 spinal muscular atrophy

Answer 3

onset during prenatal stages, predicted life span of <6 months, no motor control, sever hypotonia, respiratory failure at birth

Question 4

What is Type 1 spinal muscular atrophy

Answer 4

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

Question 5

What is Type 2 spinal muscular atrophy

Answer 5

onset at 6-18 months, 70% are still alive at 25 years, independent sitting when placed, developmental delay, muscle weakness

Question 6

What is Type 3 spinal muscular atrophy

Answer 6

onset at >18 months, normal lifespan, independent ambulation, muscle weakness, loss of motor skills

Question 7

What is Type 4 spinal muscular atrophy

Answer 7

onset in adulthood, normal lifespan, normal motor skills, muscle weakness and fatigue

Question 8

What is the pathophysiology of spinal muscular atrophy

Answer 8

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

Question 9

What is the incidence of spinal muscular atrophy

Answer 9

1/6000-1/10000 births

Question 10

How many healthy carriers are there of spinal muscular atrophy

Answer 10

1:40-80 in general population

Question 11

What is the difference between SMN2 and SMN1

Answer 11

SMN2 has a T residue in exon 7 while SMN1 has a C residue

Question 12

What does SMN1 produce

Answer 12

10 functional proteins

Question 13

What does SMN2 produce

Answer 13

1 functional protein, 9 non-functional proteins

Question 14

What is the phenotype of a normal person

Answer 14

SMN1, SMN2
SMN1, SMN2

Question 15

What is the phenotype of an SMA patient

Answer 15

SMN2
SMN2

Question 16

What is the phenotype of a carrier

Answer 16

SMN1, SMN2
SMN2

Question 17

What is the phenotype of a silent carrier

Answer 17

SMN2
SMN1, SMN1, SMN2

Question 18

How can someone without SMN1 still be relatively healthy

Answer 18

you can have multiple SMN2, people who have 5 usually can produce enough protein to be healthy

Question 19

What treatment do people with 5 SMN2 genes get

Answer 19

spinraza

Question 20

What treatment do people with <5 SMN2 genes get

Answer 20

gene therapy

Question 21

If a patient has no SMN1 but 1 SMN2 what are their chances of having each type of SMA

Answer 21

SMA I 96%
SMA II 4%
SMA III/IV 0%

Question 22

If a patient has no SMN1 but 2 SMN2 what are their chances of having each type of SMA

Answer 22

SMA I 79%
SMA II 16%
SMA III/IV 5%

Question 23

If a patient has no SMN1 but 3 SMN2 what are their chances of having each type of SMA

Answer 23

SMA I 15%
SMA II 54%
SMA III/IV 31%

Question 24

If a patient has no SMN1 but >/=4 SMN2 what are their chances of having each type of SMA

Answer 24

SMA I 1%
SMA II 11%
SMA III/IV 88%

Question 25

How is spinal muscular atrophy identified

Answer 25

Taqman assay (qPCR)

Question 26

How does the Taqman assay for SMA work

Answer 26

we detect the SMN1 gene via amplification using a florescent probe

Question 27

What are the expected Taqman results for a normal patient and an SMA carrier

Answer 27

normal: strong florescence carrier: weaker florescence

Question 28

What is used as an endogenous control for the Taqman assay

Answer 28

Rnase P

Question 29

When do most babies show signs of SMA

Answer 29

3 months

Question 30

If untreated by 6 months how many neurons have been lost in type 1

Answer 30

90%

Question 31

How does newborn screening help SMA

Answer 31

it detects the disorder before symptoms occur so that baby can start treatment faster

Question 32

What is spinraza

Answer 32

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

Question 33

How does Spinraza work

Answer 33

its an SMN2 splicing modifier, it promotes SMN2 to produce more functional proteins by preventing the splicing of exon 7

Question 34

What is Risdiplam

Answer 34

a treatment for SMA that was approved in alberta in 2022, it is taken orally daily

Question 35

How does Risdiplam work

Answer 35

its an SMN2 splicing modifier, it promotes SMN2 to produce more functional proteins

Question 36

What is zolgensma

Answer 36

a treatment for SMA that was approved in alberta in 2021, it is a one time intravenous injection

Question 37

How does zolgensma work

Answer 37

it is a gene replacement therapy with a viral delivery of SMN1

Question 38

What are the mechanics of Spinraza

Answer 38

it binds to the intronic splicing silencers in intron 7, this promotes the inclusion of exon 7 in mRNA which forms more functional proteins

Question 39

What did the SMA NBS pilot study find

Answer 39

47005 newborns screened 6 positive screens 5 confirmed positive (1 false positive)

Question 40

What determines a negative SMA screen

Answer 40

if the SMN1 gene is detected at all

Question 41

How is a positive SMA screen confirmed

Answer 41

a second PCR test, then diagnostic testing in calgary to confirm that there is no SMN1 and determine SMN2 copy numbers

Question 42

What are the limitations of the SMA screen

Answer 42

screen is not diagnostic, we do not report carriers, we do not determine SMN2 copy numbers, we miss 2-5% of SMA cases

Question 43

How many SMA cases are missed in alberta

Answer 43

1 case every 2.5-6 years