SMA

Question 1

4 subtypes of SMA

Answer 1

TYPE I - severe; <6 mnths, never sit, death <2years
TYPE II - intermediate; 7-18 months, sit but never walk
TYPE III - mild; >18 mnths, stand and walk independently
TYPE IV - very mild; 20-30s

Question 2

Clinical features of SMA (generally)

Answer 2

• symmetrical proximal muscle weakness
• feeding difficulties
• hypotonic neonate
• developmental delay
• scoliosis

Question 3

Cause of SMA

Answer 3

SMN1 exon 7 deletion/gene conversion (98%) 
Point mutations (2%)

Question 4

Underlying pathogenesis of SMA

Answer 4

SMN protein important in survival of anterior horn motor neurons of the spinal cord, which send signals to muscles to contract. Lack of SMN causes anterior horn cells to degenerate –> fewer, weaker signals

Question 5

% identity between SMN1 and SMN2

Answer 5

99.9%, 5bp different

Question 6

Copy number of SMN1 and SMN2 in normal individuals

Answer 6

0-4 per chromosome for each SMN1 and SMN2

Question 7

Functional difference between SMN1 and SMN2

Answer 7

Synonymous C>T change in exon 7 of SMN2 (pseudogene of SMN1) > inactivates exonic splicing enhancer > leaky splicing.
90% transcripts lack exon 7; truncated and degraded. SMN2 only produces 10% of the protein SMN1 does

Question 8

How does SMN2 copy number affect phenotype

Answer 8

DOSAGE DEPENDENT DISEASE MODIFIER
Multiple copies of SMN2 can increase SMN protein levels and reduce severity of phenotype HOWEVER not reliable so not used diagnostically

Question 9

Genetics of type 1 SMA

Answer 9

Caused by homozygous deletion of at least exon 7 of SMN1.

20% of SMN protein produced

Question 10

Genetics of type 2 SMA

Answer 10

Comp het for del of at least exon 7 of SMA1 and gene conversion event.
30% of SMN protein produced

Question 11

Genetics of type 3 SMA

Answer 11

Homozygous for gene conversion event

40% SMN protein produced

Question 12

Can genotype be used to predict phenotype

Answer 12

No - as its really difficult to determine SMN1 and SMN2 copy number due to variable copy number per allele in normal individuals. PLUS there are modifier genes

Question 13

Principles of gene conversion

Answer 13

OCCURS IN CIS

1. double strand breaks
2. 5’ and 3’ ends are moved away from each other
3. broken strands align with donor sequence of high homology
4. mismatch repair occurs; broken strand is remade using donor strand as template

Question 14

Genetic testing in SMA

Answer 14

MLPA - uses probes specific to small number of differences in seq between SMN1 and SMN2

Question 15

What proportion of NORMAL people lack SMN2

Answer 15

10%

Question 16

What proportion of normal chromosomes have two copies of SMN1? and are the limitations of this?

Answer 16

4%

could mask a carrier of a deletion (2:0)

Question 17

What proportion of mutations in SMA are de novo

Answer 17

2%