Spinal muscular atrophy Flashcards
(20 cards)
Mode of inheritance?
Autosomal recessive
Carrier frequency?
1/50 (variable- ethnicity plays a role)
Main feature of SMA?
Symmetrical proximal muscle weakness due to progressive degeneration and loss of the anterior horn cells of the spinal cord
Type 1
Severe muscle weakness with absence of movement and hypotonia in first few months; fatal respiratory failure by age 2 (onset usually before 6 months)
Type 2
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
Type 3
Less severe than 1 and 2, will initially walk independetly but will later need a wheelcheer. Usually survive into adult life
Type 4
Adult onset, occurs around age 30
What SMA caused by?
Mutations in SMN1 (survival motor neurone) gene on 5q13. Region is highly unstable and prone to frequent deletions and gene conversion events
98% of disease alleles are…?
exon 7 deletions (most patients have bi-allelic deletions)
2% of disease alleles are…
small intragenic mutations (in a small proportion of patients this is the second “hit”)
What is SMN2?
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
Molecular basis of different SMA types
:
Allele one: 1 x SMN1 and 1 x SMN2
Allele two: 1 x SMN1 and 1 x SMN2
unaffected
Molecular basis of different SMA types:
Allele one: deletion of SMN1 and 1 x SMN2
Allele two: deletion of SMN1 and 1 x SMN2
Type 1
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)
Type 2
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)
Type 3
Testing performed for SMA?
SMN1 exon 7 and 8 deletion analysis- MLPA
SMN1 sequence analysis using Sanger (although less than 1% are homozygous for a pathogenic sequence variant)
MLPA kit used for SMA?
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
Limitation of copy number testing of SMN1?
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)
de novo mutations occur in about …% of individuals and the majority of these are …. in origin
2%, paternal
What needs to be considered when doing Bayes for SMA?
Possibility of germline mosaicism
