What is the treatment approach for infantile spinal muscular atrophy (SMA), also known as Minnier's disease or Werndig-Hoffmann disease, in infants?

Treatment of Spinal Muscular Atrophy (SMA) in Infants

Three disease-modifying therapies are now available for infantile spinal muscular atrophy and should be initiated as early as possible—ideally presymptomatically or within the first weeks of life—to maximize motor neuron preservation and improve survival and quality of life. 1

Available Disease-Modifying Therapies

The therapeutic landscape for SMA transformed dramatically in 2016 with three FDA-approved treatments that compensate for deficient survival motor neuron (SMN) protein 1:

• Nusinersen (Spinraza®): An antisense oligonucleotide administered intrathecally that modifies SMN2 gene splicing to increase functional SMN protein production 1, 2

• Onasemnogene abeparvovec (Zolgensma®): A one-time intravenous gene replacement therapy that delivers a functional copy of the SMN1 gene 1, 2

• Risdiplam: An oral small-molecule splicing modifier that increases SMN protein levels 1

Critical Timing of Treatment Initiation

All three therapies demonstrate significantly greater efficacy when administered before symptom onset or as early as possible after symptom development 1:

• Treatment effectiveness is time-dependent because motor neuron loss in severe infantile SMA is substantial even in the youngest cases, with remaining neurons showing abnormal chromatolytic morphology indicating irreversible cellular damage 3

• Newborn screening programs in some countries now enable diagnosis soon after birth, allowing presymptomatic treatment initiation 1

• Early subtle symptoms may be missed, and disease onset can occur in utero in severe SMA subtypes, making rapid diagnosis and treatment essential 1

• Even in preterm infants (as early as 32 weeks gestation), treatment with nusinersen and onasemnogene abeparvovec within the first 2 months of life has been reported, though clinicians should carefully weigh efficacy and safety in this population 2

Comprehensive Supportive Care

While disease-modifying therapies are the cornerstone of treatment, supportive management remains essential 4, 5:

• Respiratory management: Monitor for respiratory insufficiency, provide non-invasive ventilation support, and manage secretions to prevent aspiration and pneumonia 4

• Nutritional support: Assess swallowing function, provide gastrostomy tube feeding when oral intake is inadequate, and optimize caloric intake to prevent failure to thrive 4

• Orthopedic management: Address progressive scoliosis, contractures, and skeletal deformities through physical therapy, bracing, and surgical intervention when indicated 4

• Psychiatric/psychosocial support: Provide family counseling and support services to address the emotional burden of this life-limiting condition 4

Monitoring Treatment Response

Establish baseline assessments and serial monitoring to evaluate therapeutic benefit 1:

• Document motor function using validated outcome measures appropriate for age and disease severity
• Perform regular respiratory function testing to assess ventilatory capacity
• Monitor growth parameters and nutritional status
• Assess for treatment-related toxicity specific to each therapy
• Recognize that treatment-modified disease characteristics may differ from the natural history, requiring new approaches to long-term management 1

Important Clinical Considerations and Pitfalls

The window for maximal therapeutic benefit is narrow—motor neuron loss is already substantial at birth in severe cases 3:

• Ventral horn neuron populations show marked depletion even in the youngest infantile SMA patients, with remaining neurons displaying morphological features of cellular injury 3

• Clarke's column sensory-associated neurons also demonstrate cellular damage, indicating pathology extends beyond the ventral horn 3

• Grey and white matter structures show aberrant development affecting overall spinal cord dimensions, suggesting systemic developmental abnormalities 3

• Despite these limitations, minor enhancement of SMN protein levels can be clinically beneficial, justifying early aggressive intervention 4

• The high cost of these therapies (particularly gene replacement therapy) must be weighed against the dramatic improvements in lifespan and quality of life they provide 1

• No absolute cure exists—these therapies modify disease progression but do not reverse established motor neuron loss 4, 5