Spinal muscular atrophy (SMA) is a severe neuromuscular disease and is the leading genetic cause of infant death.^7,8 It is characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness.⁸ The most common form of SMA, 5q SMA, makes up more than 95% of all cases and is an autosomal recessive disorder caused by homozygous deletion or deletion and mutation of the alleles of the survival motor neuron 1 (SMN1) gene.^1,2 The present CADTH Common Drug Review (CDR) submission for nusinersen lists 5q SMA as the indication and 5q SMA is presently referred to as SMA. While deletion or mutation of the SMN1 gene results in SMN protein deficiency, the SMN2 gene produces a relatively small amount of functional SMN protein and SMN2 copy numbers modulate the severity of the disease.^1,7–9

SMA is a rare disease and estimates of its incidence and prevalence vary between studies. Most of these studies relied on clinical rather than genetic diagnosis and were often performed in small cohorts based in Europe.² The incidence of SMA is often cited as being approximately 10 in 100,000 live births.² One recent review found estimates ranging from 5.0 to 24 in 100,000 births.² Prevalence is estimated to be approximately 1 to 2 in 100,000 persons² and is affected by the drastically shortened life expectancy in the most common type of SMA.

The disease first manifests in various ways, depending on age of onset. Infants present with severe hypotonia and feeding difficulties while later onset in young children may appear as difficulty with stairs and frequent falls.¹⁴ Adult-onset SMA presents as mild proximal muscle weakness.⁸ Genetic testing gives a definitive diagnosis for 5q SMA and the first step is to test for SMN 1 gene deletion.⁹ If homozygous SMN1 deletion is not found, sequencing of the SMN1 coding region may identify a causative mutation.⁹

Preclinical studies have shown that SMN deficiency results in defects in multiple components of the motor system, including the motor neurons.⁸ Electrophysiological studies and clinical findings in SMA patients show that patients typically experience a sharp decline in motor function with motor unit loss soon after symptom onset, followed by a long plateau period of relative stability in motor function.^3,8 According to the clinical expert, motor function decline is irreversible aside from possible gains in strength and gross motor abilities in infants still undergoing normal muscle hypertrophy in the first two years of life. Muscle weakness tends to be symmetrical, more proximal rather than distal, and more severe in the lower limbs than in the upper limbs.⁹

SMA is divided into four clinical subtypes which vary in age of onset, highest motor milestone achieved, and prognosis. While the subtypes provide a convenient means of classifying patients, it should be noted that patients exist along a continuum of disease severity with overlap in symptoms between subtypes.

Type I: These patients show symptoms before 6 months of age, never achieve the motor milestone of sitting unsupported, and generally do not survive past two years of age due to respiratory failure.^1,7–9 SMA type I is the most common type of SMA, accounting for about 60% of SMA diagnoses.² Almost all SMA type I patients have two or three copies of SMN2, giving rise to a broad range of phenotypes.¹⁵ Additional subtypes of IA, IB, and IC have been proposed based on age of onset, with IA being the earliest and most severe subtype. SMA type 0 is sometimes included in classification systems and presents in neonates as joint contractures, severe weakness and hypotonia, respiratory insufficiency, and a life expectancy of less than six months.^1,7 Muscle weakness in SMA type I is severe to the point where patients typically cannot perform antigravity limb movements and have no head control, though facial muscles are spared.⁹ Fine motor skills are affected, with infants unable to grasp using their whole hand.¹⁹ Weakness in the intercostal muscles in combination with sparing of the diaphragm leads to paradoxical breathing and a bell-shaped chest.^1,9 Bulbar weakness results in difficulty swallowing and feeding, with risk of failure to thrive and aspiration.^1,9 Reflux and impaired cough and swallowing contribute to risk of aspiration and recurrent pulmonary infections.^1,7,9 A gastrostomy tube for feeding combined with nighttime and possibly daytime non-invasive ventilation with bi-level positive airway pressure (BiPAP) can improve quality of life^1,7 and life expectancy.⁴⁹ Aggressive intervention with a tracheostomy and permanent ventilation is also possible and can prolong life expectancy; however, this is a decision to be made by the family with the support of health care providers.^1,7

Type II: Patients with type II SMA achieve the milestone of sitting unsupported, but never walk independently. Symptoms generally appear between 6 to 18 months after birth and most patients will survive past the age of 25,^7,14 with life expectancy improved by aggressive supportive care.¹⁴ Type II patients represent about 20% to 30% of SMA cases² and most SMA type II patients have three copies of SMN2.¹⁵ In addition to the inability to walk independently, common symptoms are fine tremors of the upper extremities, tongue fasciculation, joint contractures, and scoliosis.^1,9,14 Scoliosis and weak intercostal muscles can cause restrictive lung disease.¹ There is a range in severity, with weaker patients requiring non-invasive ventilation.⁹ Difficulty swallowing is less common than in type I patients and difficulty with feeding comes from masticatory muscle weakness.⁹

Type III: Type III SMA makes up about 10% to 20% of SMA cases² and presents between 18 months of age and adulthood. These patients are able to walk independently at some point in their life and typically have a normal life expectancy.¹⁴ Most type III patients have three or four copies of SMN2.¹⁵ An age of onset prior to 3 years is associated with estimated probabilities of 73%, 44%, and 34% of walking 10, 20, and 40 years after onset.¹⁶ In those with age of onset after 3 years, the estimated probabilities are 97%, 89%, and 67% for walking 10, 20, and 40 years after onset.¹⁶ SMA type III patients have little or no respiratory weakness.¹ Ambulatory patients may exhibit abnormal gait characteristics due to proximal weakness¹⁴ while patients who lose the ability to walk often develop scoliosis.⁹

Type IV: A very small proportion of SMA cases are type IV or adult-onset SMA, the mildest form of the disease. Although muscle weakness is present, these patients retain the ability to walk, have a normal life expectancy, and do not suffer from respiratory or nutritional issues.⁹

Aside from nusinersen, there are currently no effective treatments for SMA and supportive care seeks to improve quality of life. Respiratory management is essential for all children with type I SMA and some with type II. Non-invasive ventilation with BiPAP can help with disordered breathing at nighttime and can be used during the day as needed for hypercapnia.¹ Secretion mobilization is also important in patients with weak cough and this can be achieved with postural drainage, assisted coughing, and oral suction.^7,9 When noninvasive ventilation is no longer sufficient, tracheostomy and permanent, invasive ventilation is an option. However, there is no consensus in guidelines with respect to the suitability of this intervention and its implementation remains a choice for the family.^7,14 In patients with difficulty chewing and swallowing, changing food consistency can help with feeding and reduce risk of aspiration. A gastrostomy tube can also be placed, though there is no consensus on when this should occur.¹⁴

For gross motor function, management strategies include mobility aides, bracing, and physical therapy. Patients able to bear weight may make use of a standing frame or ankle-foot orthoses (AFOs), and physical activity such as swimming can increase stamina.¹⁴ Manual and motorized wheelchairs provide mobility to those who can use them. Scoliosis is very common in non-ambulatory type II and type III patients and can be corrected with surgery.¹⁴ Bracing, seating modification, and physical therapy may slow scoliosis progression in a child until they can undergo surgery.⁷

In summary, 5q SMA is a rare and often debilitating neuromuscular disease that is the leading genetic cause of infant death. The incidence of SMA is approximately 10 in 100,000 live births.² The homozygous deletion or deletion and mutation of the SMN1 alleles leads to irreversible and progressive decline in motor function. Variation among patients in the number of copies of the less effective SMN2 gene accounts for part of the wide spectrum of disease severity. In general, an earlier disease onset is associated with more severe symptoms and lower probability of achieving motor milestones. Patients less than six months of age at disease onset will never sit independently and will likely to die of respiratory failure before two years of age. In contrast, those with adult-onset SMA may experience muscle weakness but will have a normal life expectancy and remain ambulatory. With the exception of nusinersen, there is currently no disease-modifying therapy available.