SMA Flashcards
What is the mode of inheritance for SMA?
Autosomal recessive
What is the classification of different types of SMA based upon?
Age of onset and motor development milestones.
Which form of SMA is the most severe?
Type 1, onset is typically within 6 months of age.
Age of onset: 6 months of age. Patient is unable to sit up and has severe respiratory dysfunction.
Type 1
Which type of SMA is considered ‘intermediate’ with a variable clinical course?
Type 2
Age of onset: <2 years of age. Patient is able to sit up but unable to walk.
Type 2
Age of onset >2 years. Patient is able to stand and walk unaided at least in infancy
Type 3
Which is the mildest form of SMA which is also adult on-set?
Type 4
Describe the 4 types of SMA.
Acute, Intermediate, Mild and Adult.
The complexity and instability of which chromosomal region accounts for 98% of SMA cases?
5q13
Why is the SMA critical region considered to be unstable?
Highly repetitive
In proximal SMA, which muscles are earliest and most severely affected?
Extremities closest to trunk
What is the estimated carrier frequency for SMAs?
1/40 - 1/60.
What is the estimated incidence of SMAs?
1/ 10,000
What complex structure is present at the 5q13 SMA region?
500kb duplication ad inversion.
SMN1 is the telomeric homolog of which highly similar gene?
SMN2
Of the two SMN genes, which is considered to be the pseudogene?
SMN2
Is SMN2 telomeric or centromeric?
Centromeric
SMN1 and SMN2 are known to be homologues. They differ by how many base-pairs?
5
In which exons do SMN1 and SMN2 differ?
Exon 7 and exon 8
Name the mutational mechanisms which account for 95% of SMA cases.
- Homozygous Deletion
2. Sequence-converted SMN1
Most cases of SMA type 1 arise from…
Homozygous SMN 1 deletion
Milder cases (type 2 and 3) are more likely to be caused by…
Sequence-conversion from SMN1 to SMN2.
Are patients suffering from milder forms of SMA expected to have more or less copies of SMN2?
More
Why would patients with milder forms of SMA have more copies of SMN2?
Patients with milder forms are more likely to have arisen from SMN1 to SMN2 sequence conversion, which results in more copies of SMN2.
Which cells does SMA affect?
Anterior horn cells (lower motor neurons)
Is brain function normal in patients with SMA?
Yes
Is sensation affected in patients with SMA?
No
Which muscles are affected in patients with SMA?
Extremities (usually those closest to the trunk) and Respiratory muscles.
What is bulbar dysfunction?
Poor suck ability, reduced swallowing and respiratory failure.
Are facial muscles usually affected in type 1?
No
Is cognitive ability impaired?
No
What prenatal observation is present in ~30% of cases?
Reduced fetal movement
When would prenatal testing for SMA be appropriate?
Previously affected child, parent known to be a carrier
Name 2 mechanisms which cause deletions of SMN1
- Homozygous deletion of SMN 1
2. Gene conversion of SMN1 into SMN2
What is the clinical significance of a homozygous deletion of both SMN1 and SMN2?
Lethal
In general, what type of SMA results from homozygous gene deletion events?
Type 1
In general, what type of SMA results from a gene conversion event and a deletion in the other allele?
Type 2
In general, what type of SMA result from a gene conversion in both alleles?
Type 3/ type 4.
Name 2 potential sources of false negative carrier test results
- 2/0 carriers
2. Point mutations not currently detectable via dosage analysis.
Can increased SMN2 copy number compensate for SMN1 deletion?
No, although some protein is still produced not as much, hence milder forms of SMA are associated with SMN2 copy number increase.
Why does the SMN2 gene produce a less adequate protein than SMN1?
Exon skipping via alternative splicing (80% skips exon 7 and terminates at exon 8) = unstable protein.
