Screening and Diagnosis of SMA
In 2018, SMA genetic screening was added to the Recommended Uniform Screening Panel for newborns in the United States.5,6 In addition, more states are adding SMA to their newborn screening panel. A positive newborn screening result allows for immediate confirmatory genetic testing and treatment to prevent SMA disease symptoms from starting or progressing.
For all patients, genetic testing for both the SMN1 and SMN2 genes is recommended to confirm the diagnosis.1,2,7 This testing should be offered to patients presenting with SMA symptoms to allow for early intervention with newly developed pharmacotherapeutics that can slow or stop disease progression.7 Previously, electromyography and muscle biopsy were required to diagnose SMA but genetic testing now is considered the gold standard for diagnosis.2 Additional laboratory tests, including creatinine kinase levels, often are within normal range.1
For adult-onset SMA (type 4), history is key to the diagnosis and may include muscle fatigue not previously experienced, difficulty with long flights of stairs, and changes in walking/running stride and coordination. Patient history should be thorough to uncover any alterations in activity due to occupational changes or new hobbies/exercise habits. Patients should be queried about changes in functional abilities with each encounter. Functional assessment instruments help standardize evaluations between examiners. Examples of motor function assessment screening tools are the Timed Up and Go Test and the Assessment of Motor Function.8,9
Physical examination findings in older children and adults may include bilateral diminished deep tendon reflexes in the lower extremities. Reflexes should be quantified on a 0 to 4+ scale with each patient encounter. Strength testing of the extremities should be quantified on a 0 to 5+ scale and monitored in serial assessments.9 This ongoing clinical assessment helps evaluate peak muscle function, which is a predictor of disease severity and life expectancy.
Management of SMA requires a multidisciplinary approach led by a pediatric neurologist (Figure).1 Given the various types of SMA and multiple clinical manifestations, treatment is individualized based on each patient’s functioning.10
Pharmacologic management of SMA became a reality in December 2016 with the approval of the first SMN-enhancing therapy, nusinersen, for all SMA types in patients of all ages.11 Since then, 2 other SMN-enhancing therapies have been approved: onasemnogene abeparvovec-xioi for patients up to 2 years of age and risdiplam for patients 2 months and older.12,13
Nusinersen binds with SMN2 genes to increase SMN protein production.11 The drug is administered intrathecally in 4 loading doses, delivered every 2 weeks for 3 doses and then after 30 days for the fourth dose. Maintenance treatment should be given every 4 months for life.11 Nusinersen is associated with an increase in the achievement of motor milestones and motor function for patients with SMA type 1. In patients with SMA types 2 and 3, this treatment has been associated with improvements in or maintenance of motor function.11
Gene therapy with onasemnogene abeparvovec-xioi is approved for the treatment of SMA in infants and children younger than 2 years.12 The treatment replaces the defective or missing SMN1 gene with a working copy and is given as a single intravenous infusion.12 Gene therapy works best when given early in the disease course, can be administered before symptom onset, and increases survival rates without permanent ventilation and the ability to sit unsupported in clinical trials.12
The newest agent, risdiplam, is approved for patients 2 months and older.13 This SMN2 pre‐mRNA splicing modifier increases SMN production and distribution in the CNS and peripheral tissues.13 Risdiplam is administered orally once daily.13 In clinical trials, risdiplam was linked to an increased rate of survival without permanent ventilation and ability to sit unsupported in infants and improved motor function in adults.