SMA

Question 1

Mechanism of SMA?

Answer 1

o Autosomal Recessive Disorder
o Neuromuscular disorder
*Caused by homozygous loss of SMN1 (exon 7)
*Either hom. deletion or compound het with point mutation

*Causes:
o Degeneration of anterior horn cells of spinal chord
o Leads to atrophy and paralysis of voluntary muscles

Question 2

Why is it important to consider SMN2?

Answer 2

• SMN2 is centromeric homolog to SMN1
• Identical to SMN1, but has a C>T difference with alters splicing
• SMN2 produces about 10% functional protein
• Thought that higher copy number SMN2 can compensate for loss of SMN1

Question 3

Treatment for SMA?

Answer 3

antisense oligonucleotide therapy which targets SMN2 before exon 7, and increases efficiency of splicing to include exon 7, resulting in transcription of full length surviro motor neuron protein (artificially imitating more copies of SMN2 gene). This same method of treatment is being trialled in HD (must be administered through lumbar puncture directly into spinal fluid as drug cannot cross blood-brain barrier.