4. AR disorders - i.e. SMA

Question 1

How is SMA characterised at the cellular level?

Answer 1

Degeneration/loss of motor neurons in the anterior horn of the spinal cord

Question 2

How is SMA characterised clinically?

Answer 2

Progressive, symmetrical muscle weakness and atrophy

Forms continuum based on age of onset & severity

Question 3

What gene is involved in SMA and what is its role?

Answer 3

SMN1

Maintenance of motor neurons

Question 4

How do SMN1 and SMN2 differ?

Answer 4

99.9% homologous

Single base change in exon 7 causes functional difference

Disrupts exonic splicing enhancer –> alternative splicing in SMN2 so 90% of transcripts lack ex7

Absence of ex7 means SMN rapidly degraded

Question 5

How do mutations in SMN1 cause SMA?

Answer 5

96% of patients have hom deletion or deletion + gene conversion of SMN1 to SMN2

4% have del/gene oversion + SNV

Question 6

What genotype-phenotype correlation is observed in SMA and why?

Answer 6

Variant type has no impact

More copies of SMN2 = less severe phenotype

10% production of SMA from SMN2 so more copies = more SMN protein

Question 7

How is SMA treated?

Answer 7

Nusinersen - antisense oligonucleotide that promotes inclusion of ex7 in SMN2 transcripts

Zolgensma - gene therapy, functional copy of SMN1 introduced to motor neurons

Question 8

If a patient is shown to have 2 copies of SMN1 on MLPA, why might they still be a carrier of SMA?

Answer 8

1. 4% of people have 2 copies of SMN1 on the same chromosome - can’t differentiate between 1,1 and 2,0
2. 2% of mutations are SNVs, not detectable by MLPA

Question 9

Why might one parent of a patient with a hom SMN1 deletion have 2 copies of SMN1?

Answer 9

1. 4% of people have 2 copies of SMN1 on the same chromosome - use linkage to resolve
2. 2% of deletions are de novo