Spinal muscular atrophy Flashcards
Definition of SMA
A collection of inherited clinical syndromes causing degeneration of anterior horn cells in the spinal cord with associated destruction of alpha motor cells and presents clinically with characteristic proximal muscle weakness and atrophy
Cause of SMA
*Deletion in SMN1 gene on chromosome 5
*Results in degeneration of motor neurons
What does severity of SMA depend on?
Number of SMN2 backup gene copies
Types of SMA
- SMA Type I (aka Werdnig-Hoffman disease/non-sitters)
- SMA Type II (aka Dubowitz disease/sitters)
- SMA Type III (aka Kugelberg-Welander disease/walkers)
SMA Type I characteristics
*Onset: <6 months with limited head control, hypotonia and areflexia (no DTR)
*Severe wasting and weakness (floppy)
*‘Non-sitters’ with a frog-like posture when supine
*Tongue fasciculations and bulbar-nutritional failure
*Scoliosis
*Respiratory failure (sparing of diaphragm)
*Requires permanent ventilation, survival typically <2 years
SMA Type II characteristics
*Onset 6-18 months
*Can sit but with hypotonia, areflexia, a progressive proximal weakness that disproportionately affects the legs over arms
*Joint contractures
*Growth and nutritional failure
*Progressive scoliosis and intercostal muscle weakness result in restrictive lung disease
*Life expectancy: 30s-40s (respiratory failure main cause of death)
SMA Type III
*Presents after 18 months similarly to type II
*Progressive proximal weakness disproportionately affecting legs over arms
*However, patients are ambulatory but can require a wheelchair as the disease progresses (50% lose walking ability).
*Patients do not typically suffer from restrictive lung disease, and life expectancy is not affected
Evaluation of SMA
*Genetic testing: polymerase chain reaction (PCR) or multiplex ligation probe amplification (MLPA) can help to detect deletion in the SMN1 gene
Others:
*Creatinine kinase - normal (although can be very mildly elevated)
*Nerve conduction studies- sensory nerves = normal APs, motor nerves may show diminished APs
*Needle EMG: SMA type I: denervation changes without reinnervation. SMA II+III: Neurogenic patterns (APs with prolonged duration, increased amplitude, and diminished recruitment)
*Muscle biopsy: not used anymore as invasive but shows a neurogenic pattern
Pathophysiology of SMA
*SMN1 (Chromosome 5): Produces essential SMN protein for motor neuron survival.
*SMN2: A weaker backup due to a C>T mutation, leading to mostly non-functional SMNΔ7 protein, with only a small amount of functional SMN.
Impact on SMA
*SMA occurs when SMN1 is missing or defective.
*SMN2 copy number determines severity:
*Type 1 SMA: ~2 copies
*Type 2 SMA: ~3 copies
*Type 3 SMA: 3–4 copies (more copies = milder disease)
Treatment of SMA
- Nusinersen (Spinraza)
- Onasemnogene Abeparvovec (Zolgensma)
- Risdiplam
Nusinersen in SMA
*Lumbar puncture every 4 months
*Increases the amount of functional SMN protein produced
*Improvement in motor milestones
*Improves strength and function
Onasemnogene Abeparvovec (Zolgensma) in SMA
*One-time IV gene therapy (infusion) - lasts for 10 years
*For children under 2 for SMA type I
*Trans-gene (artificial construct of SMN1 gene) packed into viral vector (transporter)
*Replaces mutant gene with healthy gene.
*AAVs deliver genes without integrating them into the genome.
*Significantly prolongs survival of type I
*Significant motor improvements
Risdiplam for SMA
*Oral medicine increasing SMN2 expression.
*Acts on back-up gene to increase ability to express protein.
*Improves strength and function.
*Better ability to improve swallow function than others.
Non-medical intervention for SMA
- Airway clearance with cough assistance
- Nocturnal or continuous non-invasive ventilation
- Spinal fusion/braces for scoliosis - improved posture and breathing
