Last updated 2mo ago
A 3-month-old infant presents with severe hypotonia, weakness, and tongue fasciculations. She has a frog-leg posture and paradoxical breathing. She never achieved head control.
AR; SMN1 deletions/variants (95% homozygous deletion)
Understanding SMN1 vs SMN2:
SMN1 and SMN2 are nearly identical genes on chromosome 5q13, but differ by a single C→T nucleotide change in exon 7 of SMN2. This small difference has major consequences:
- SMN1 produces full-length functional SMN protein from all transcripts
- SMN2 skips exon 7 in ~90% of transcripts → produces truncated, unstable, non-functional protein
- However, ~10% of SMN2 transcripts still include exon 7 → produce functional SMN protein
Why SMN2 copy number matters:
- More SMN2 copies = more functional SMN protein produced (even though each copy is inefficient)
- Type 1 (severe): typically 1-2 SMN2 copies
- Type 2 (intermediate): typically 3 SMN2 copies
- Type 3 (mild): typically 3-4 SMN2 copies
- Type 4 (adult): typically ≥4 SMN2 copies
This relationship explains why all SMA treatments target SMN2 to increase exon 7 inclusion.
Types:
- Type 0: Prenatal onset, most severe
- Type 1 (Werdnig-Hoffmann): Onset <6 months, never sit, death <2 years without treatment
- Type 2: Onset 6-18 months, sit but never walk
- Type 3: Onset >18 months, walk, milder
- Type 4: Adult onset
- Lower motor neuron: hypotonia, weakness, areflexia, fasciculations
- Tongue fasciculations characteristic
- Intellect preserved
- First-line test is targeted analysis for homozygous deletion of SMN1 exon 7 (positive in ~95%)
- If only one SMN1 copy is deleted, sequence the remaining allele for an intragenic variant (compound heterozygote)
- Quantify SMN2 copy number, which predicts severity and guides treatment decisions
- Increasingly identified presymptomatically via newborn screening (on RUSP); carrier screening detects the common deletion, but counsel on residual risk from silent two-copies-in-cis carriers
- AR inheritance: 25% recurrence risk; offer carrier and prenatal/preimplantation testing
- Nusinersen (antisense oligonucleotide) binds to SMN2 pre-mRNA and promotes exon 7 inclusion (prevents it from being skipped). This results in more full-length, functional SMN protein
- Onasemnogene abeparvovec (gene replacement therapy)
- Risdiplam (oral drug that also promotes inclusion of SMN2 in exon 7, causing more functional protein to be produced)
- On RUSP (newborn screening)
"SMN in SMA": SMN (Survival of Motor Neurons) is the causative gene in SMA.
"te1omeric" and "centwomeric": SMN1 is telomeric ("te1omeric"), SMN2 is centromeric ("centwomeric"). This helps remember which gene is which.
SMN2 copy number: 2 copies = SMA1 (sit with support only), 3 copies = SMA2 (independent sitting), 4+ copies = SMA3/4 (walks/normal milestones).
"Zo1-gen-SMA": Zolgensma is a 1-time gene therapy for SMA (for children <2 years old).