SMA

Question 1

What is the mode of inheritance for SMA?

Answer 1

Autosomal recessive

Question 2

What is the classification of different types of SMA based upon?

Answer 2

Age of onset and motor development milestones.

Question 3

Which form of SMA is the most severe?

Answer 3

Type 1, onset is typically within 6 months of age.

Question 4

Age of onset: 6 months of age. Patient is unable to sit up and has severe respiratory dysfunction.

Answer 4

Type 1

Question 5

Which type of SMA is considered ‘intermediate’ with a variable clinical course?

Answer 5

Type 2

Question 6

Age of onset: <2 years of age. Patient is able to sit up but unable to walk.

Answer 6

Type 2

Question 7

Age of onset >2 years. Patient is able to stand and walk unaided at least in infancy

Answer 7

Type 3

Question 8

Which is the mildest form of SMA which is also adult on-set?

Answer 8

Type 4

Question 9

Describe the 4 types of SMA.

Answer 9

Acute, Intermediate, Mild and Adult.

Question 10

The complexity and instability of which chromosomal region accounts for 98% of SMA cases?

Answer 10

5q13

Question 11

Why is the SMA critical region considered to be unstable?

Answer 11

Highly repetitive

Question 12

In proximal SMA, which muscles are earliest and most severely affected?

Answer 12

Extremities closest to trunk

Question 13

What is the estimated carrier frequency for SMAs?

Answer 13

1/40 - 1/60.

Question 14

What is the estimated incidence of SMAs?

Answer 14

1/ 10,000

Question 15

What complex structure is present at the 5q13 SMA region?

Answer 15

500kb duplication ad inversion.

Question 16

SMN1 is the telomeric homolog of which highly similar gene?

Answer 16

SMN2

Question 17

Of the two SMN genes, which is considered to be the pseudogene?

Answer 17

SMN2

Question 18

Is SMN2 telomeric or centromeric?

Answer 18

Centromeric

Question 19

SMN1 and SMN2 are known to be homologues. They differ by how many base-pairs?

Answer 19

5

Question 20

In which exons do SMN1 and SMN2 differ?

Answer 20

Exon 7 and exon 8

Question 21

Name the mutational mechanisms which account for 95% of SMA cases.

Answer 21

1. Homozygous Deletion

2. Sequence-converted SMN1

Question 22

Most cases of SMA type 1 arise from…

Answer 22

Homozygous SMN 1 deletion

Question 23

Milder cases (type 2 and 3) are more likely to be caused by…

Answer 23

Sequence-conversion from SMN1 to SMN2.

Question 24

Are patients suffering from milder forms of SMA expected to have more or less copies of SMN2?

Answer 24

More

Question 25

Why would patients with milder forms of SMA have more copies of SMN2?

Answer 25

Patients with milder forms are more likely to have arisen from SMN1 to SMN2 sequence conversion, which results in more copies of SMN2.

Question 26

Which cells does SMA affect?

Answer 26

Anterior horn cells (lower motor neurons)

Question 27

Is brain function normal in patients with SMA?

Answer 27

Yes

Question 28

Is sensation affected in patients with SMA?

Answer 28

No

Question 29

Which muscles are affected in patients with SMA?

Answer 29

Extremities (usually those closest to the trunk) and Respiratory muscles.

Question 30

What is bulbar dysfunction?

Answer 30

Poor suck ability, reduced swallowing and respiratory failure.

Question 31

Are facial muscles usually affected in type 1?

Answer 31

No

Question 32

Is cognitive ability impaired?

Answer 32

No

Question 33

What prenatal observation is present in ~30% of cases?

Answer 33

Reduced fetal movement

Question 34

When would prenatal testing for SMA be appropriate?

Answer 34

Previously affected child, parent known to be a carrier

Question 35

Name 2 mechanisms which cause deletions of SMN1

Answer 35

1. Homozygous deletion of SMN 1

2. Gene conversion of SMN1 into SMN2

Question 36

What is the clinical significance of a homozygous deletion of both SMN1 and SMN2?

Answer 36

Lethal

Question 37

In general, what type of SMA results from homozygous gene deletion events?

Answer 37

Type 1

Question 38

In general, what type of SMA results from a gene conversion event and a deletion in the other allele?

Answer 38

Type 2

Question 39

In general, what type of SMA result from a gene conversion in both alleles?

Answer 39

Type 3/ type 4.

Question 40

Name 2 potential sources of false negative carrier test results

Answer 40

1. 2/0 carriers

2. Point mutations not currently detectable via dosage analysis.

Question 41

Can increased SMN2 copy number compensate for SMN1 deletion?

Answer 41

No, although some protein is still produced not as much, hence milder forms of SMA are associated with SMN2 copy number increase.

Question 42

Why does the SMN2 gene produce a less adequate protein than SMN1?

Answer 42

Exon skipping via alternative splicing (80% skips exon 7 and terminates at exon 8) = unstable protein.