What are the symptoms of Spinal Muscular Atrophy (SMA) and how are they managed?

From the Guidelines

Symptom management for Spinal Muscular Atrophy (SMA) should prioritize a multidisciplinary approach focusing on respiratory, nutritional, and musculoskeletal support to improve quality of life and prevent complications. When considering the management of SMA symptoms, it's crucial to address the multifaceted nature of the disease, which affects various bodily systems.

• Respiratory support is vital and may include airway clearance techniques, non-invasive ventilation, and the use of devices like cough assist machines to manage secretions effectively.
• Nutritional support is also critical, potentially requiring gastrostomy tube placement for patients with significant swallowing difficulties, ensuring adequate nutrition to support overall health and muscle function.
• Musculoskeletal management involves physical and occupational therapy to maintain function and prevent contractures, alongside the use of orthotic devices for proper positioning and support.
• Pharmacological interventions, such as those discussed in the context of Duchenne Muscular Dystrophy 1, highlight the potential for treatments like glucocorticoids to optimize muscle strength and function, although their application in SMA would need careful consideration based on the most recent and relevant evidence.
• Pain management is an essential component, often involving NSAIDs for pain relief and gabapentin for neuropathic pain, with a focus on proper positioning to minimize discomfort.
• Regular monitoring of respiratory function, nutritional status, and musculoskeletal complications is fundamental to adjusting the management plan as needed and preventing potential complications. Given the complexity of SMA, a comprehensive and tailored approach is necessary, incorporating disease-modifying treatments where appropriate, such as nusinersen, onasemnogene abeparvovec, and risdiplam, alongside meticulous symptom management to enhance the patient's quality of life and outcomes.

From the FDA Drug Label

The efficacy of EVRYSDI for the treatment of patients with infantile-onset, later-onset, and pre-symptomatic SMA was evaluated in three clinical studies, Study 1 (NCT02913482) and Study 2 (NCT02908685), and Study 3 (NCT03779334), respectively The overall findings of these studies support the effectiveness of EVRYSDI in SMA pediatric and adult patients and appear to support the early initiation of treatment with EVRYSDI. Effectiveness was established based on the ability to sit without support for at least 5 seconds (as measured by Item 22 of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) gross motor scale) and on the basis of survival without permanent ventilation The primary endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) after 12 months of treatment in Part 2; 29% of patients (n = 12/41) achieved this milestone.

The management of SMA symptoms with risdiplam (EVRYSDI) includes:

• Improving the ability to sit without support for at least 5 seconds
• Increasing survival without permanent ventilation
• Other efficacy endpoints as shown in Table 3, such as the proportion of patients able to achieve certain motor milestones 2 Key points:
• The efficacy of EVRYSDI was evaluated in three clinical studies
• The overall findings support the effectiveness of EVRYSDI in SMA patients
• Early initiation of treatment with EVRYSDI appears to be supported by the studies 2

From the Research

SMA Symptom Management

• SMA is an autosomal recessive motor neuron disease characterized by progressive weakness and atrophy of skeletal muscles 3
• Current disease modifying therapies, including nusinersen, onasemnogene abeparvovec, and risdiplam, have demonstrated impressive effectiveness in SMA treatment 3
• These therapies target the SMN2 gene to enhance SMN expression and can stabilize disease progression and potentially obtain neurological improvement 3, 4

Disease Modifying Therapies

• Nusinersen is an antisense oligonucleotide that modifies alternative splicing of SMN2 pre-mRNA and is effective in SMA children and adults 3
• Onasemnogene abeparvovec is an adeno-associated viral vector that carries the human SMN1 gene and is administered intravenously once in a lifetime for SMA patients less than 2 years of age 3, 4
• Risdiplam is a small molecule that targets SMN2 pre-mRNA and is effective in SMA children and adults with administration via oral intake once per day 3

Combination Therapy

• Combination therapy with nusinersen and onasemnogene abeparvovec-xioi may not be more effective than a single intervention alone, and early treatment is more important than combined therapy 5
• Patients who received both therapies had the same motor function trajectory as those who received monotherapy, and the evolution of motor function was better in the 6 months following the first therapy than in the first 6 months after adding the second treatment 5

Lung Function and Respiratory Muscle Strength

• Disease-modifying therapies have improved survival, motor function, and functional muscle strength in patients with SMA, but their effects on lung function and respiratory muscle strength need further clarification 6
• A systematic review and meta-analysis found that nusinersen does not improve FVC, FEV1, peak expiratory flow, or maximum inspiratory pressure in subjects with SMA types I, II, III, or IV, but may have stabilized lung function and respiratory muscle strength 6

Real-World Treatment Strategies

• There is limited information on real-world treatment strategies for SMA, and more research is needed to determine the best approaches for patients with SMA 7
• A case study of an infant with SMA type 1 who underwent onasemnogene abeparvovec treatment after nusinersen treatment found that the patient's motor function improved, and the patient was able to sit without support and was weaned from non-invasive positive pressure ventilation 7