Spinal Muscular Atrophy (SMA)

Question 1

Discuss treatment options

Question 2

What is Spinal Muscular Atrophy ?

Answer 2

• progressive degeneration of lower motor neurons and the brain stem nuclei
• deletion in exon 7 of SMN1 gene = loss of motor skills

Question 3

Which type of SMA I is the most severe ? most mild ?

Answer 3

• Type 0 is the most severe
• Type 4 is the most mild

NOTE: Type 0 to 4

Question 4

inheritance pattern of SMA

Answer 4

autosomal recessive
- deletion in exon 7 of SMN1 in both parents

Question 5

Difference between SMN1 and SMN2

Answer 5

exon 7 is deleted in SMN2 proteins because of a
C to T change

Question 6

If SMN1 and SMN2 have >99.9% genetic similarity, why can’t
SMN2 proteins compensate for defective SMN1 proteins in SMA patients ?

Answer 6

• most SMN2 genes have a C to T change in exon 7 = deletion of exon 7
• 90% of SMN2 proteins are non-functional
• 10% functional SMN proteins is not enough to compensate

Question 7

T or F: SMA individuals with multiple copies of SMN2 will have milder symptoms

Answer 7

TRUE; SMA individuals with multiple copies of SMN2 will have milder symptoms
- can have 8 copies max.

Question 8

Method used to diagnose SMA

Answer 8

Taqman qPCR

Question 9

Describe how SMA is detected using Taqman qPCR

Answer 9

Target: (C) nucleotide

Fluorescent-quencher probe: complementary sequence (G)
- binds to exon 7
- PCR dissociates quencher = fluorescent signal is detected = normal OR carrier

• no fluorescence = no exon 7 for probe to bind = deleted exon 7 in SMN1 = affected SMA

Question 10

How is non-specific SMN2 amplification avoided in SMA detection ?

Answer 10

• Blocker (A) that is complementary to SMN2 (T) will preferably bind
• Fluorescent-quencher probe (G) cannot bind and remains intact

Question 11

T or F: heterozygotes for SMN1 are differentiated in taqman qPCR results

Answer 11

FALSE; fluorescence in qPCR = negative regardless of lower intensity (heterozygotes)
- do not report carriers

Question 12

What is the endogenous control used in taqman qPCR for SMA ?

Answer 12

RNAse P amplification
- will have a representative curve

Question 13

Treatment for SMA

Answer 13

• ## newborn screening before symptoms

Question 14

Describe treatment type: nusinersen/ “spinraza”

Answer 14

• for mild SMA
• treatment plan + maintenance doses
• SMN2 splicing modifier = inactivates intronic splicing silencer = produces MORE SMN2 for compensation

Question 15

Describe Treatment type: Zolgensma

Answer 15

• one-time intravenous injection for severe SMA
• gene replacement therapy = viral vector delivers healthy SMN1 gene