Spinal muscular atrophy (SMA) refers to a diverse group of genetic disorders characterized by degeneration of anterior horn cells of the spinal cord and brainstem motor nuclei with resultant muscle atrophy and progressive weakness1.
SMA is categorized by its mode of inheritance and the pattern of weakness that phenotypically manifests (i.e. proximal vs. distal weakness). The most common type of SMA is autosomal recessive proximal SMA, often referred to simply as proximal SMA which accounts for 95% of cases. This form results from a homozygous deletion or mutation of the survival motor neuron 1 gene (SMN1) on chromosome 5q-132. It represents the most common genetic cause of death in infants3.
Epidemiology including risk factors and primary prevention
Spinal muscular atrophy disorders affects 1/6000 to 1/10,000 infants, with a carrier frequency in the general population of 1/405-7. SMA type 1 (SMA-1) is the most common type (60%-70% of all patients with SMA), followed by SMA-2 (20%-30%) and SMA-3 (10%-20%)8.
Humans have 2 forms of the SMN gene, SMN1 and SMN2. SMN1 produces primarily full length SMN protein but the SMN2 form is able to encode a small amount of normal SMN protein (10%-15%)4. All patients with SMA lack a working SMN1 gene, and the amount of full length protein produced by SMN2 is insufficient for normal motor neuron function. SMN2 copy number varies in the population, and the variability of SMA disease severity is primarily related a patient’s SMN2 copy number. However, other factors besides SMN2 copy number affect the phenotype such that prognosis cannot be fully predicted by the SMN2 copy number.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Various classification schemes exist for SMA. The International SMA Consortium scale published in 1991 is still commonly used and includes types 1, 2 and 3, based on age of onset and highest level of motor function achieved9. Subsequent modifications have separated type 3 SMA into two subtypes based on age of onset and added groups 0 and 4.
Table 1. Characteristics of SMA by Disease Type
Age of Onset
|SMA-0||Prenatal||Respiratory failure at birth, severe hypotonia, never sit||Death within weeks|
(~45% of cases)
|0-6 months||Never sit, weak suck, poor feeding, weak cry, progressive severe hypotonia and weakness affecting limbs and respiratory muscles||< 2 years without ventilator support|
(~20% of cases)
|6-18 months||Can sit unassisted, but unable to stand|
Initial progressive symptoms, then relative stabilization of weakness with slow progression over years
(~30% of cases)
|> 18 months||Ambulatory for some period of time, with proximal > distal weakness affecting legs > arms|
Relatively stable with slow progression over years
(< 5% of cases)
|> 30 years||Ambulatory with mild weakness developing in adulthood||Adult|
Specific secondary or associated conditions and complications
Secondary conditions related to SMA include:
- Restrictive lung disease (RLD) is most severe in SMA 0 resulting in death shortly after birth, followed by SMA 1, resulting in death within 2 years without ventilator support. In SMA 2 restrictive lung disease may be mild, but sleep-disordered breathing conditions can result in increased pulmonary infections with increased morbidity. RLD is less problematic in individuals with SMA types 3 and 4.
- Scoliosis occurs almost universally in SMA 2, but is rare in SMA 1.
- Contractures may be congenital (clubfeet) or may occur over time in association with progressive weakness.
- Constipation is common in SMA and may be due to poor abdominal muscle tone and immobility from weakness.
- Dysphagia is most common in SMA 1 and is due to bulbar weakness.
2. ESSENTIALS OF ASSESSMENT
- In SMA-1 the history reveals concern for hypotonia, progressive proximal > distal weakness with legs more affected than arms, dysphagia and respiratory distress.
- In SMA-2 progressive weakness begins occurring after 6 months; the child fails to achieve milestones of standing and has weakness in proximal > distal muscles, with legs more affected than arms.
- In SMA-3 there is often gait difficulty and proximal weakness.
- In SMA-4 there is mild weakness occurring in adulthood.
- A complete family history should be obtained as well.
Table 2. Physical Exam
Physical Exam findings
|Type||Mobility||Self-Care||Cognition, Behavior, Affective State|
|SMA-1||Non-ambulatory, never sit independently, dependent for mobility||Dependent||Difficult to assess due to short lifespan|
|SMA-2||Non-ambulatory, needs power wheelchair for mobility||Typically can self-feed when young, but loses this skill over time. Dressing requires maximal to full assistance. Toileting is dependent due to transfers.||Normal|
|SMA-3||Achieves ambulation for some period of time, but as they age, they will have more difficulty and likely require a wheelchair before adulthood||Independent with activities of daily living with compensatory mechanisms and adaptive equipment||Normal|
|SMA-4||Typically remain ambulatory for decades||Independent but may require adaptive equipment||Normal|
In the past electromyography/nerve conduction studies (EMG/NCS) and muscle biopsy were used to identify features of denervation and were the mainstay of diagnostic workup. However molecular genetic testing has now become the standard tool for diagnosis of SMA10. It should be considered early in any infant with weakness or hypotonia or patients with symptoms of proximal predominant weakness, reduced or absent reflexes, tongue fasciculations and/or limb tremor (polyminimyoclonus).
- Genetic testing specifically for homozygous deletion will confirm the disease in 95% of patients.
- If negative, genetic testing for the other SMN related SMA (compound heterozygotes) should be undertaken starting with genetic testing for a heterozygous deletion followed by possible heterozygous mutations (e.g. frameshift, nonsense or missense mutation).
- If testing is still negative, one can consider electrodiagnostic testing, creatine kinase and imaging to assist with diagnosis.
The homozygous deletion of SMN1 is essentially 100% specific for the diagnosis of SMA. Prenatal screening by chorionic villus sampling or amniocentesis is available and can potentially be used to catch the diagnosis early in a hypotonic infant in-vitro.
Imaging studies are not helpful in the diagnosis of SMA disorders, but may be ordered as part of a workup for a hypotonic infant to exclude a central disorder.
Supplemental assessment tools
Electrodiagnostic (EDX) Testing
- Previously used when molecular testing was not widely available.
- Should be reserved only for evaluation of atypical patients and negative molecular work up (negative SMN1 deletion and SMN1mutation testing). EDX remains important for diagnostic workup in atypical cases and non-5q-related SMA to demonstrate the neurogenic etiology of the illness.
- EDX studies show variable features of motor neuron and axonal loss consistent with loss of motor neuron function with active denervation with chronic compensatory changes of re-innervation and motor unit action potential enlargement.
- On Electromyography (EMG), abnormal spontaneous activity (i.e. fibrillation potentials and positive sharp waves) is typically present. Delayed recruitment patterns with large motor unit action potentials (MUAPs) can be evident as well. In end stage individuals, MUAPs may lack clear neurogenic features of long duration and large amplitude and instead have reduced amplitude and durations.
- Nerve Conduction Studies (NCS) show chronic motor axonal loss with perseveration of sensory nerve action potentials (SNAPs).
- Conduction velocities tend to be preserved with possible slight decrease due to axonal loss.
Early predictions of outcomes
- Outcome depends on what type of SMA the patient has; that is on severity of weakness, age at onset and on the highest functional level achieved.
- Disease severity amongst groups of patients correlates by SMN2 copy number, however due to idiosyncratic factors of each individual it cannot predict an individual’s potential severity and prognosis11-13.
- Compound muscle action potential (CMAP) amplitude on NCS correlates with clinical severity, age and function and has potential to be used for prognostication14-16.
- Individuals with SMA-1 or SMA-2 will require an environment that is wheelchair accessible.
- It is recommended that individuals with SMA-1 and SMA-2 have a back-up electricgenerator in the event of a power outage, to allow functioning of respiratory support equipment.
Social role and social support system
- In a child with a diagnosis of SMA, it is important to provide anticipatory guidance to the patient’s family concerningthe child’songoing medical and care needs.
- Counseling aboutthe expectations of functional needs, and about the disease process itself, isessential to the family’s decision-makingregarding care options and management of respiratory complications of SMA.
Controversiesin the management of a child with type 1 SMA exist, and relate primarily to the decision to provide invasive ventilatory support for a condition that is progressive and non-treatable.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
The clinical management of SMA depends upon the severity of weakness and the degree of respiratory involvement. In the last few years due to advancement in the understanding of SMA genetics and molecular mechanisms, genetic therapies are becoming a reality and will change the therapeutic landscape. However, supportive care will continue to be a mainstream mode of management for SMA10.
- Restrictive lung disease is the most common cause of mortality for children with SMA. All children with SMA 1 and about 1/3rd of those with SMA-2 will develop respiratory insufficiency or failure during childhood. Therefore establishment with a pulmonary specialist is important early on during the time of initial diagnosis. Management options include noninvasive ventilatory support as well as invasive support with tracheostomy and a ventilator.
- Immunization against influenza, pneumococcus and respiratory syncytial virus is recommended as a preventative strategy.
- Parents should be educated about various care options and the role of invasive ventilation as well as related complications. They should also be educated about use of cough-assist devices, oral secretion management, chest physiotherapy and postural drainage.
Gastro-intestinal (GI) & Nutrition Management
- Dysphagia due to bulbar dysfunction can occur. Possible options for management include modification of diet consistencies to compensate for poor swallowing and protect against aspiration.
- For malnutrition due to poor oral intake, potential use of a gastrostomy tube can be considered.
- Constipation is a common complication due to immobility and can be managed by placement on a bowel program and encouraging mobility.
- In non-ambulatory patients, contracture prevention and management is important. This can be treated with regular stretching, bracing, serial casting, physical and occupational therapy. Adaptive equipment for mobility and ADL needs may include medical strollers, manual or power wheelchairs and any other related home medical equipment.
- Non-ambulatory patients will benefit from referral to a physical and occupational therapist for evaluation of adaptive equipment for mobility and ADLs, which may include an adaptive stroller, manual wheelchair or bath equipment. Some young children may use a supine standing frame if they have adequate trunk control, although tolerating this frame is difficult for older children who have developed lower extremity contractures.
- Physical exercise and therapy can optimize both endurance and strength. Patients should be encouraged to continue being as physically active as possible and encouraged to be involved in aqua-therapy and adaptive sports.
- Scoliosis, a likely complication in non-ambulatory patients, should be monitored regularly and treated as indicated with bracing for early stages or spinal fusion surgery for more severe cases. Spinal fusion surgery is the most effective and definitive treatment option.
Communities and home set-ups that are wheelchair accessible are important for individuals with SMA 1 and SMA 2. Additionally, it is recommended that individuals with SMA 1 and SMA 2 have a back-up electric generator in the event of a power outage to allow functioning of respiratory support equipment.
Coordination of care
Multidisciplinary care is recommended. It is typically performed in a clinic setting with a neurologist, physiatrist, pulmonologist and orthopedist available. Patients benefit from early referral to physical and occupational therapists.
Patient & family education
Patient/family education and anticipatory guidance is critical due to the serious implications of a diagnosis of SMA. Counseling about the expected functional needs, goals and disease process itself is essential in order for the family to make decisions regarding care options.
Standard outcome measures have not yet been established. Physiologic measures such as motor unit number estimation , compound motor action potentials and MRI have been used. Non-disease specific functional outcome measures that have been used include the Alberta Infant Motor Scale, Wee Functional Independence Measure (WeeFIM), and the Hammersmith scale.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Cognition is not affected in SMA, but children with SMA may be placed in inappropriate, cognitively unchallenging class settings due to the severity of their motor impairments. It is important to advocate for testing so that they are placed in the least restrictive setting to achieve optimal academic achievement.
- The disease-modifying antisense oligonucleotide therapy (ASO), nusinersen (Spinraza®, Biogen, Cambridge, MA), was FDA approved for the treatment of all types of SMA related to loss of SMN1 This ASO increases SMN protein expression from the SMN2 gene and is now in clinical use18,19.
- Clinical trials are underway exploring the use of gene therapy to transfer a functional SMN gene using adeno-associated virus subtype 9 (ClinicalTrials.gov Identifier: NCT02122952).
- Small molecule therapies to induce full length SMN expression from the SMN2 gene have shown promising results in preclinical studies but are less developed in clinical application20-22.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
- Advances in our understanding of the genetics of SMA have led to an improved understanding of the pathophysiology of the various forms of SMA.
- An ASO therapy, nusinersen, was recently approved by FDA in December 2016.
- Other gene therapy and small molecules are being investigated to increase SMN protein expression in order to modulate disease.
- The need for pre-symptomatic genetic testing is now a pressing issue in light of the development of effective therapies that are now in clinical use.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
- The reason why low levels of SMN protein are insufficient for normal motor neuron function remains uncertain.
- Nusinersen has shown exciting results in clinical trials and was recently approved for all types of SMA. Yet, the clinical trial data was obtained in infants and children. The role for this therapy in adults with SMA remains uncertain.
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Original Version of the Topic
William Arnold, MD
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Monal Desai, MD
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