Spinal muscular atrophy

Question 1

Mode of inheritance?

Answer 1

Autosomal recessive

Question 2

Carrier frequency?

Answer 2

1/50 (variable- ethnicity plays a role)

Question 3

Main feature of SMA?

Answer 3

Symmetrical proximal muscle weakness due to progressive degeneration and loss of the anterior horn cells of the spinal cord

Question 4

Type 1

Answer 4

Severe muscle weakness with absence of movement and hypotonia in first few months; fatal respiratory failure by age 2 (onset usually before 6 months)

Question 5

Type 2

Answer 5

Intermediate, onset slightly later. May be able to sit up but can’t walk unaided; may survive into adult life but die young. Often have feeding diffiultties and may have scoliosis

Question 6

Type 3

Answer 6

Less severe than 1 and 2, will initially walk independetly but will later need a wheelcheer. Usually survive into adult life

Question 7

Type 4

Answer 7

Adult onset, occurs around age 30

Question 8

What SMA caused by?

Answer 8

Mutations in SMN1 (survival motor neurone) gene on 5q13. Region is highly unstable and prone to frequent deletions and gene conversion events

Question 9

98% of disease alleles are…?

Answer 9

exon 7 deletions (most patients have bi-allelic deletions)

Question 10

2% of disease alleles are…

Answer 10

small intragenic mutations (in a small proportion of patients this is the second “hit”)

Question 11

What is SMN2?

Answer 11

Homologous near-copy of SMN1; not a full transcript but does provide some of the protein, therefore acts to modify the effects of SMN1 mutation

Question 12

Molecular basis of different SMA types
:
Allele one: 1 x SMN1 and 1 x SMN2

Allele two: 1 x SMN1 and 1 x SMN2

Answer 12

unaffected

Question 13

Molecular basis of different SMA types:

Allele one: deletion of SMN1 and 1 x SMN2

Allele two: deletion of SMN1 and 1 x SMN2

Answer 13

Type 1

Question 14

Molecular basis of different SMA types:

Allele one: deletion of SMN1 and 1 x SMN2

Allele two: 2 x SMN2 (a gene conversion from SMN1 to SMN2 has taken place)

Answer 14

Type 2

Question 15

Molecular basis of different SMA types:

Allele one: 2 x SMN2 (a gene conversion from SMN1 to SMN2 has taken place)

Allele 2: 2 x SMN2 (a gene conversion from SMN1 to SMN2 has taken place)

Answer 15

Type 3

Question 16

Testing performed for SMA?

Answer 16

SMN1 exon 7 and 8 deletion analysis- MLPA

SMN1 sequence analysis using Sanger (although less than 1% are homozygous for a pathogenic sequence variant)

Question 17

MLPA kit used for SMA?

Answer 17

P060-B2. Kit also detects copy number of SMN1 and SMN2 but SMN2 levels are difficult to interpret in relation to how disease will progress

Question 18

Limitation of copy number testing of SMN1?

Answer 18

Where a parent has 2 copies of SMN1, kit cannot distinguish between

a) 1x SMN1 on allele a, 1x SMN1 on allele b (NORMAL)

or b) 2x SMN1 on allele a, 0x SMN1 on allele b (CARRIER)

Question 19

de novo mutations occur in about …% of individuals and the majority of these are …. in origin

Answer 19

2%, paternal

Question 20

What needs to be considered when doing Bayes for SMA?

Answer 20

Possibility of germline mosaicism