Disease Prevalence and Incidence

Spinal muscular atrophy (SMA) is a severe neuromuscular disease and is the leading genetic cause of infant death.^1,2 It is characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness.¹ 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.^3,4 While deletion or mutation of the SMN1 gene results in SMN protein deficiency, a second nearby gene, the SMN2 gene, produces a relatively small amount of functional SMN protein and SMN2 copy number modulates the severity of the disease.^1–3,16

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.⁴ The incidence of SMA is often cited as being approximately 10 in 100,000 live births.⁴ One recent review found estimates ranging from 5.0 to 24 in 100,000 births.⁴ Prevalence is estimated to be approximately one to two in 100,000 persons⁴ and is affected by the drastically shortened life expectancy in the most common type of SMA. However, one study that examined the Cure SMA database (a voluntary registry that is one of the largest patient-reported repositories in the world) reported the birth prevalence in the US at about 1 in 20,000 live births.⁵

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.¹⁷ Adult onset SMA presents as mild proximal muscle weakness.² Genetic testing gives a definitive diagnosis for 5q SMA and the first step is to test for SMN1 gene deletion.¹ If homozygous SMN1 deletion is not found, sequencing of the SMN1 coding region may identify a causative mutation.¹ The patients input received echoes these findings, where it describes SMA affecting patients with widely ranging degrees of severity depending on age of onset. SMA type I presents by the age of six months and is the most common genetic cause of infant mortality. In SMA type II, age of onset is six to 18 months and patients have delayed motor milestones, respiratory issues, and the possibly of a shortened life expectancy. Patients with SMA type III are those with onset from 18 months to 18 years of age; they experience muscle weakness. SMA type IV is adult onset with varying degrees of muscle weakness. Common to all types of SMA is a progressive decline in muscle function.

SMN deficiency results in defects in multiple components of the motor system, including the motor neurons.² Electrophysiological studies and clinical findings in patients with SMA 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.^2,18 Clinical expert input to CADTH indicated that 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.¹

SMA is divided into four clinical subtypes that 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. This spectrum is represented in Figure 1, as published in Talbot 2017.¹⁹

Figure 1

Continuous Spectrum of Spinal Muscular Atrophy Phenotype. MM = minimal manifestations; SMA = spinal muscular atrophy; SMN = survival motor neuron. Source: Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017; (more...)

Type I: These patients show symptoms before six 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.^1–3,5,16 SMA type I is the most common type of SMA, accounting for about 60% of SMA diagnoses.⁴ Almost all patients with SMA type I have two or three copies of SMN2, giving rise to a broad range of phenotypes.⁶ 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.^3,16 Muscle weakness in patients with 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.¹ Fine motor skills are affected, with infants unable to grasp using their whole hand.²⁰ Weakness in the intercostal muscles in combination with sparing of the diaphragm leads to paradoxical breathing and a bell-shaped chest.^1,3 Bulbar weakness results in difficulty swallowing and feeding, with risk of failure to thrive and aspiration.^1,3 Reflux and impaired cough and swallowing contribute to risk of aspiration and recurrent pulmonary infections.^1–3,16 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 (QoL)^3,16 and life expectancy.²¹ 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.^3,16 In one study that examined 1,966 patients in the Cure SMA database (with data available between 2010 and 2016), the median survival for those with type I SMA was 13.6 months.⁵

Type II: Patients with type II SMA achieve the milestone of sitting unsupported, but never walk independently. Symptoms generally appear between six and 18 months after birth and most patients will survive past the age of 25,^16,17 with life expectancy improved by aggressive supportive care.¹⁷ Patients with type II SMA represent about 20% to 30% of SMA cases² and most patients with SMA type II have three copies of SMN2.⁶ In addition to the inability to walk independently, common symptoms are fine tremors of the upper extremities, tongue fasciculation, joint contractures, and scoliosis.^1,3,17 Scoliosis and weak intercostal muscles can cause restrictive lung disease.³ There is a range in severity, with weaker patients requiring non-invasive ventilation.¹ Difficulty swallowing is less common than in patients with type I and difficulty with feeding comes from masticatory muscle weakness.¹ In one study that examined 1,966 patients in the Cure SMA database (with data available between 2010 and 2016), the median survival for those with type II SMA was 59.9 years.⁵

Type III: Type III SMA makes up about 10% to 20% of SMA cases⁴ and presents between 18 months of age and adulthood. These patients are able to walk independently at some point in their lives and typically have a normal life expectancy.¹⁷ Most patients with type III SMA have three or four copies of SMN2.⁶ An age of onset prior to three years is associated with estimated probabilities of 73%, 44%, and 34% of walking 10, 20, and 40 years after onset.²² In those with age of onset after three years, the estimated probabilities are 97%, 89%, and 67% for walking 10, 20, and 40 years after onset.²² Patients with SMA type III have little or no respiratory weakness.³ Ambulatory patients may exhibit abnormal gait characteristics due to proximal weakness,¹⁷ while patients who lose the ability to walk often develop scoliosis.¹

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.¹

The correlation between the genotype, specifically the number of SMN2 genes, and the clinical phenotype (SMA types) is probabilistic in nature. In one natural history study, of 39 patients diagnosed as SMA types 1b or 1c, 16 patients (41%) had two copies of the SMN 2 gene, 21 patients (54%) had three copies of the SMN2 gene, and one patient (3%) had four copies of the SMN2 gene.⁶ The same study showed that out of 87 patients diagnosed as SMA types 2a or 2b, two patients (2%) had two copies, 75 patients (86%) had three copies, and seven patients (8%) had four copies of the SMN2 gene.⁶ Of 66 patients that were diagnosed as SMA types 3a or 3b assessed in the same study, one patient (2%) had two copies, 19 patients (29%) had three copies, 40 patients (61%) had four copies, and two patients (3%) had five copies of the SMN2 gene.⁶ The study also assessed five patients diagnosed as SMA type IV; of these patients, four (80%) had four copies of the SMN2 gene, and one patient was not reported.⁶ A summary of these subtypes is presented in Table 2, as published in Talbot 2017.¹⁹

Table 2

Spinal Muscular Atrophy Clinical Classification.

Standards of Therapy

Aside from nusinersen, there are currently no approved treatments for SMA and supportive care seeks to improve QoL. 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.³ Secretion mobilization is also important in patients with weak cough and this can be achieved with postural drainage, assisted coughing, and oral suction.^1,16 When non-invasive ventilation is no longer sufficient, tracheostomy and permanent, invasive ventilation is an option. However, there is no consensus in guidelines over the suitability of this invention and its implementation remains a choice for the family.^16,17 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.¹⁷

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 and physical activity such as swimming can increase stamina.¹⁷ Manual and motorized wheelchairs provide mobility to those who can use them. Scoliosis is very common in patients with non-ambulatory types II and III SMA and can be corrected with surgery.¹⁷ Bracing, seating modification, and physical therapy may slow scoliosis progression in a child until they can undergo surgery.¹⁶ Recommendations for the diagnosis and management of patients with SMA were published earlier in 2018. The recommendations added emphasis on a proactive approach in respiratory management, whereby clinicians are encouraged to use non-invasive ventilation before any respiratory symptoms manifest.^23,24

Drug

Nusinersen (Spinraza) is indicated for the treatment of 5q SMA. It is an antisense oligonucleotide that increases the proportion of exon 7 inclusion in SMN2 messenger ribonucleic acid transcripts made, through binding to a specific site in the SMN2 pre-messenger ribonucleic acid. This leads to the translation of the messenger ribonucleic acid into functional full-length SMN protein. Nusinersen is administered via intrathecal injection by lumbar puncture in a 5 mL solution containing 12 mg of nusinersen. It is given in a regimen of four loading doses at day 0, day 14, day 28, and day 63, with subsequent maintenance doses at a four-month frequency.²⁵ The manufacturer has requested nusinersen be reimbursed for the treatment of 5q SMA across all types, including pre-symptomatic patients, and all ages.