Clinical scenario: SMA type 1| deletion of SMN 1 gene| Gene replacement therapy
A 2-month-old infant is referred after newborn screening detected Spinal Muscular Atrophy (SMA). Genetic testing confirms homozygous deletion of the SMN1 gene with two copies of the SMN2 gene. The infant is asymptomatic, with normal feeding and no respiratory compromise.
The parents ask about the treatment that offers the greatest potential to preserve motor neurons by replacing the defective gene before irreversible neuronal loss occurs.
Which of the following is the most appropriate treatment?
A. Nusinersen
B. Onasemnogene abeparvovec
C. Prednisolone
D. Pyridostigmine
E. Risdiplam
Correct answer & Explanation:
orrect Answer: B. Onasemnogene abeparvovec
Explanation:
Onasemnogene abeparvovec is a one-time intravenous gene replacement therapy that uses an adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the SMN1 gene to motor neurons.
The greatest benefit is achieved when treatment is given before symptom onset, as motor neuron loss in SMA is irreversible. Early treatment through newborn screening has dramatically improved survival and motor outcomes.
Why the other options are incorrect
- A. Nusinersen: An intrathecal antisense oligonucleotide that modifies SMN2 pre-mRNA splicing to increase SMN protein production. It is disease-modifying but does not replace the SMN1 gene.
- B. Onasemnogene abeparvovec: Correct. It is the only approved therapy that replaces the defective SMN1 gene through a single intravenous infusion.
- C. Prednisolone: No established role in the treatment of SMA.
- D. Pyridostigmine: Used for myasthenia gravis, not SMA.
- E. Risdiplam: An oral SMN2 splicing modifier that increases SMN protein production but does not replace the SMN1 gene.
Learning Point
Disease-modifying therapies for SMA include:
| Therapy | Mechanism | Route |
|---|---|---|
| Onasemnogene abeparvovec | SMN1 gene replacement | Single IV infusion |
| Nusinersen | SMN2 splicing modifier (antisense oligonucleotide) | Intrathecal |
| Risdiplam | SMN2 splicing modifier | Oral |
The best outcomes are achieved when treatment is initiated presymptomatically through newborn screening, before irreversible loss of anterior horn cells
