NORD gratefully acknowledges Etienne Leveille, MD, Yale School of Medicine, and Mary Schroth, MD, FAAP, FCCP, Chief Medical Officer, Cure SMA, for assistance in the preparation of this report.
Spinal muscular atrophy (SMA) is a group of inherited neuromuscular disorders characterized by loss of nerve cells in the spinal cord called lower motor neurons or anterior horn cells. Lower motor neurons originate in the brainstem or the spinal cord and relay nerve impulses from upper motor neurons, located in the brain, to the muscles they control. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that is typically more pronounced in muscles closest to the trunk of the body (proximal muscles) such as the shoulders, hips and back. However, neurons controlling most voluntary muscles can be affected, including those that control muscles involved in feeding, swallowing and breathing.
SMA is divided into subtypes (SMA types 0 to 4) based on age of symptom onset and maximum motor function achieved, with a lower number representing a younger age of onset and more severe disease. SMA is inherited as an autosomal recessive genetic disorder and is associated with mutations in the survivor motor neuron 1 (SMN1) gene. SMN1 is located on chromosome 5 in the long arm (q) region. Thus, SMA with a SMN1 gene deletion is often referred to as 5q SMA, distinguishing this form of SMA from other genetic forms of SMA.
Newborn screening facilitates early identification of infants with SMA and thus early implementation of treatment. Infants identified by SMA newborn screening are urgently referred for confirmatory testing, discussion of treatments and care. Early treatment prior to the onset of symptoms provides the best outcomes.
Although the management of SMA was previously centered around symptom management and supportive care, since 2016, therapies that can improve the course of the disease (disease-modifying therapies) have emerged and have shown promising results. Currently three SMN-enhancing treatments have U.S. Food and Drug Administration (FDA) approval.
The signs and symptoms of SMA are a consequence of lower motor neuron loss. The features of lower motor neuron disease include muscle weakness and atrophy, hypotonia, decreased or absent reflexes (hypo- or areflexia) and twitching of muscle fibers (fasciculations). Although SMA is a disease spectrum, the five subtypes are determined based on their age of symptom onset and maximum motor function achieved. This classification for SMA was established prior to the availability of genetic testing and prior to the availability of disease modifying treatments.
SMA type 0, also known as prenatal SMA, is the most severe form of the disease and develops before birth. The first sign may be a decrease or loss of fetal movement during late pregnancy. Symptoms of SMA type 0 are apparent at birth and include severe weakness and hypotonia. In addition, joint deformity and tightening (contractures) and congenital heart defects are common. As a result, infants do not achieve developmental motor milestones. Because of severe respiratory muscle weakness, affected infants rapidly progress to respiratory failure often by the first month of life.
SMA type 1, also known as infantile SMA or Werdnig-Hoffmann disease, is the most common type of SMA affecting approximately 60% of infants born with SMA and is also a severe form of the disease. Infants with SMA type 1 usually appear normal at birth but experience severe weakness before 6 months of age. Developmentally they do not achieve independent sitting and may achieve very few developmental motor milestones. Because of lower motor neuron loss, affected infants have poor suck and swallow reflexes and respiratory muscle weakness. Historically without intervention, affected children die before two years of age due to progressive respiratory muscle weakness and respiratory failure.
SMA type 2, also known as intermediate SMA or Dubowitz disease, comprises about 30% of infants born with SMA. The disease usually manifests between 6 and 18 months of age. Affected children can sit independently at some point in their development. However, this ability is usually lost by the mid-teens or later and affected individuals never achieve independent standing and walking. Additional associated symptoms include difficulty swallowing (dysphagia) and respiratory difficulties. Trembling (tremor) of the fingers is also common. In addition, weakness of the muscles supporting the spine leads to curvature of the spine (scoliosis). Historically, life expectancy is reduced in patients with SMA type 2 but many reach adulthood.
SMA type 3, also known as juvenile SMA or Kugelberg-Welander disease, accounts for about 10% of infants born with SMA. The age of onset is variable and can be as early as 18 months or as late as teenage years. Although affected individuals have hip and leg weakness and may fall frequently, they are able to walk independently at some point in their development. However, the ability to walk and stand may be lost as they grow and with disease progression, and many become wheelchair dependent. Long-term prognosis depends on the degree of motor function attained as a child, and respiratory muscle weakness is typically mild or absent. SMA type 3 is associated with a normal life expectancy.
SMA type 4, also known as late-onset SMA, occurs in less than 1% of people with SMA. Symptoms are less severe than in other subtypes and onset typically occurs in adulthood and most commonly after 35 years of age. All motor developmental milestones are achieved and most individuals with SMA type 4 can walk throughout their life. Patients with SMA type 4 have a normal life expectancy.
The following resources from Cure SMA provides a description of symptoms, as well as videos to assist with early diagnosis:
SMA is caused by deletion or mutation in the SMN1 gene, which encodes a protein known as survival motor neuron (SMN). This protein plays an important role in the functioning and maintenance of motor neurons. Approximately 95-98% of affected individuals have deletions in the SMN1 gene and 2-5% have a point mutation in the SMN1 gene that results in a decreased production of the SMN protein.
The SMN2 gene is a paralog of SMN1 and also encodes the SMN protein and can partially compensate for the loss of the SMN1 gene. However, most SMN protein produced by the SMN2 gene is not functional, which means that the SMN2 gene can only partially compensate for the loss of the SMN1 gene. For this reason, an individual with SMA who has more copies of the SMN2 gene will produce more functional SMN protein and may be better able to compensate for the loss of the SMN1 gene, therefore leading to less severe disease. Generally, more copies of SMN2 are associated with milder SMA disease, although there are exceptions.
SMA is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a pathogenic gene variant for the disease from each parent. If an individual receives one normal gene and one variant gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the variant gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close blood relative (consanguineous) are more likely to have the same harmful gene variant and, therefore, to have an affected child.
The incidence of SMA is approximately 1 in 10,000 live births. SMA affects females and males equally.
The evaluation of a patient with suspected SMA, such as an infant with unexplained weakness and hypotonia while appearing bright eyed and socially engaging, begins with a complete patient history and physical examination. If the clinical evaluation shows signs of lower motor neuron disease (see Signs & Symptoms section) and suggests SMA, the diagnosis is confirmed with genetic testing to detect pathogenic variants in the SMN1 gene and if there are no copies of SMN1, then reflex testing for SMN2 copy number should be competed. If the patient is symptomatic and one copy of SMN1 is identified, then gene sequence analysis should be obtained to evaluate for a possible SMN1 point mutation.
No other tests are needed to diagnose SMA, although additional testing may be initially performed to exclude other conditions that could have a similar clinical presentation. This can include genetic testing associated with other diseases, metabolic or biochemical tests or evaluation of the transmission of electrical signals from nerves to muscles (electromyography; EMG). Muscle biopsy may be considered when the above testing does not reveal a diagnosis.
Newborn screening for SMA is being implemented throughout the United States. As of January 2021, 39 states screen for SMA representing 86% of all infants born in the U.S. Newborn screening facilitates early identification of infants with SMA and thus early implementation of treatment. Infants identified by SMA newborn screening are urgently referred for confirmatory testing, discussion of treatments and care. Early treatment prior to the onset of symptoms provides the best outcomes. Newborn screening will not identify 3-5% of infants with SMA due to having a point mutation in the SMN1 gene. These infants will progress to develop symptoms and require rapid diagnosis and treatment.
Carrier testing for SMA is also available using a molecular genetic test in which the number of copies of the SMN1 gene is determined. The American College of Obstetricians and Gynecologists recommends offering carrier screening for SMA to all women who are considering pregnancy or are currently pregnant.
The treatment of SMA requires a multidisciplinary team approach and should notably include neurologists, medical geneticists, physical therapists, speech pathologists, pulmonologists, respiratory therapists, medical social workers, nutritionists, psychologists and specialized nurses. There are two main components to SMA management: treatment that slows the progression of the disease (disease-modifying therapy) and therapy that helps manage symptoms and improves quality of life (supportive therapy). Genetic counseling is recommended for affected individuals and their families.
The symptomatic management of SMA includes physical therapy, occupational therapy, monitoring respiratory function and intervening as clinically indicated, nutritional status monitoring and intervention, spine curvature monitoring and intervention and use of orthotics and adaptive equipment as needed. Respiratory support for SMA type 1 (infants symptomatic prior to 6 months of age) includes providing breathing support called BiPAP (bi-level positive airway pressure) to manage hypoventilation and a mechanical insufflation-exsufflation device to support weak cough. Supportive management has been shown to increase comfort and life expectancy. Earlier in the disease, some affected infants might only require ventilation support at night. Children with progressive respiratory insufficiency might require more invasive interventions to breathe, such as surgical placement of a breathing tube through the neck (tracheostomy). For infants and children with dysphagia, nutrition support may require gastrostomy tube placement to provide nutrition safely. Children with SMA may also require surgical intervention for musculoskeletal issues such as scoliosis and/or hip dislocation.
Research efforts have led to therapies that can improve the course of SMA. The first disease-modifying therapy was approved by the U.S. Food and Drug Administration (FDA) in 2016. These therapies have shown promising results, notably developmental motor milestone achievement and improved survival in treated individuals. As the impact of these treatments are being studied, keep in mind that these treatments are not cures.
In 2016, nusinersen (Spinraza) was approved by the FDA as the first drug to treat children and adults with SMA. Nusinersen is an injection administered into the fluid surrounding the spinal cord (intrathecal administration). Nusinersen acts by modifying the splicing of the SMN2 gene product, mRNA, so that more full length and functional SMN protein is produced.
In 2019, the FDA approved onasemnogene abeparvovec-xioi (Zolgensma) for the treatment of children less than two years of age with SMA. Onasemnogene abeparvovec-xioi is a gene therapy that delivers a fully functional copy of human SMN1 gene into the target motor neuron cells via a viral vector, AAV9. A one-time intravenous administration of the medication results in increased SMN protein in all cells including motor neurons.
In 2020, the FDA approved risdiplam (Evrysdi) to treat patients two months of age and older with SMA. Risdiplam is the first orally administered drug approved for the treatment of SMA. It has a mechanism of action is also to modify splicing of the SMN2 mRNA resulting in increased SMN protein.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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