What are the treatment options for Spinal Muscular Atrophy (SMA)?

Treatment of Spinal Muscular Atrophy (SMA)

For pediatric patients less than 2 years of age with SMA and bi-allelic SMN1 mutations, onasemnogene abeparvovec (gene therapy) is FDA-approved and should be strongly considered, as it delivers a functional SMN gene copy via a single intravenous infusion, with demonstrated improvements in motor function and survival. 1

Disease-Modifying Therapies

Gene Therapy: Onasemnogene Abeparvovec (Zolgensma)

Onasemnogene abeparvovec is the only FDA-approved gene therapy for SMA, indicated for pediatric patients less than 2 years of age with bi-allelic SMN1 mutations. 1

Dosing and Administration

• The recommended dose is 1.1 × 10^14 vector genomes per kilogram (vg/kg) of body weight, administered as a single intravenous infusion over 60 minutes 1
• Begin systemic corticosteroids (equivalent to oral prednisolone 1 mg/kg/day) one day prior to infusion and continue for 30 days, then taper gradually over 28 days if liver function is normal 1
• Postpone infusion in patients with active infections until resolved and patient is clinically stable 1

Critical Pre-Infusion Requirements

• Assess liver function by clinical examination and laboratory testing (patients with preexisting liver impairment are at higher risk for acute liver failure) 1
• Obtain baseline creatinine, complete blood count including hemoglobin and platelet count 1
• Test for anti-AAV9 antibodies 1
• Ensure patient is clinically stable (adequate hydration, nutritional status, absence of infection) 1

Post-Infusion Monitoring

• Monitor liver function weekly for the first month, then every other week for months 2-3, and at other times as clinically indicated 1
• Monitor platelet counts at least weekly for the first month, then every other week for months 2-3 until platelet counts return to baseline 1
• Consider cardiac evaluation after infusion due to potential troponin I elevation 1
• If liver function abnormalities persist ≥2× upper limit of normal after 30 days of corticosteroids, promptly consult a pediatric gastroenterologist or hepatologist 1

Limitations

• Safety and effectiveness of repeat administration have not been evaluated 1
• Not evaluated in patients with advanced SMA (complete paralysis of limbs, permanent ventilator-dependence) 1

Alternative Disease-Modifying Therapy: Nusinersen

• Nusinersen is an antisense oligonucleotide therapy that modifies SMN2 splicing to increase functional SMN protein production 2
• Patients exclusively on nusinersen showed a 10.2-point increase on the CHOP-INTEND scale over 18 months 3
• Patients transitioning from nusinersen to onasemnogene abeparvovec showed a 33-point increase on the CHOP-INTEND scale, likely related to earlier treatment initiation 3

Clinical Outcomes with Disease-Modifying Therapies

• 70% of treated SMA type 1 patients reached motor milestones, 90% experienced no respiratory decline, and 30% maintained oral feeding 3
• Earlier treatment initiation correlates with better motor, respiratory, and bulbar function outcomes 3
• No serious adverse effects or deaths were recorded in recent cohort studies of disease-modifying therapies 3

Multidisciplinary Supportive Care

All SMA patients require management at specialized reference centers with multidisciplinary teams including pediatric neurologists, pulmonologists, physical medicine and rehabilitation specialists, orthopedic surgeons, psychologists, and physiotherapists. 4, 5, 6

Orthopedic Management

Scoliosis

• Scoliosis surgery is almost systematic in SMA type 2 due to trunk muscular deficiency and intercostal muscle insufficiency 4
• Surgical techniques have evolved to be less invasive and more growth-friendly to follow child development 4
• The goal is 3-dimensional deformity correction with spino-pelvic realignment to allow comfortable seated position and better ventilation 4

Other Orthopedic Considerations

• Address muscular contractures, hip joint disorders, and fractures with established orthopedic procedures 7
• Provide appropriate technical devices and assistive equipment 7
• Balance conservative versus surgical treatment based on disease severity and functional goals 7

Respiratory Management

• Monitor respiratory function regularly, as respiratory involvement is a major complication 7
• Provide ventilatory support as needed based on disease progression 3
• Coordinate perioperative respiratory care for surgical procedures 7

Nutritional Support

• Assess swallowing function and signs of dysphagia regularly 3
• Provide nutritional support and modify food consistency as needed 3
• Monitor nutritional status as part of overall clinical stability assessment 7

Rehabilitation and Functional Assessment

• Use validated scales such as the CHOP-INTEND to monitor motor function 3
• Assess developmental milestones regularly 3
• Implement daily activity monitoring to characterize activity type, duration, intensity, and frequency 4
• Focus on comfort of installation and prevention of neuro-orthopedic degradation 4

Psychosocial Management

• Address psychosocial challenges of patients with prolonged survival and novel therapies 6
• Provide psychological support through dedicated team members 5, 6
• Plan for transitions to adulthood in long-term survivors 6

Emergency Management

• Establish clear emergency protocols within the multidisciplinary team 6
• Ensure coordination across all care providers for acute complications 6

Critical Pitfalls to Avoid

• Do not delay disease-modifying therapy—earlier treatment initiation is associated with significantly better outcomes 3
• Do not administer onasemnogene abeparvovec to patients with active infections; postpone until infection resolves 1
• Do not stop systemic corticosteroids abruptly after onasemnogene abeparvovec infusion 1
• Do not overlook liver function monitoring, as acute liver failure with fatal outcomes has been reported 1
• Do not manage SMA patients outside of specialized reference centers with multidisciplinary expertise 4, 5, 6