Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem.1
SMA disorders are inherited in an autosomal recessive pattern. Deletions or mutations in the SMN1 gene on chromosome 5q13.2 result in deficiency of survival motor neuron (SMN) protein.2 However, phenotypic expression varies due to individuals carrying varying copies of the centromeric version of SMN, SMN2. Patients with SMA lack SMN1, the telomeric version, and thus depend on residual SMN2 production for motor neuron function and survival.4,5
Epidemiology including risk factors
Few studies have recently assessed the epidemiology of SMA. Generally, the incidence is around 10 per 100,000 live births and the prevalence is around 1-2 per 100,000 persons.6,7,8 The carrier frequency of disease-causing SMN1 mutations is estimated to be between 1/100 to 1/40.9
Because SMA is a genetic disease, there are no lifestyle related risk factors. Rather, risk factors that relate to increased inheritance of the gene mutation include family history and Caucasian race.9
The role of SMN protein is not fully understood but has been shown to play a key role in the maintenance of motor neurons and homeostatic cellular pathways.3 Research suggests that the SMN protein in the cytoplasm transports mRNA through axons and aids with vesicle release in the synapse. Furthermore, SMN protein in the nucleus aids in the formation of the spliceosome.10,11 Lastly, SMN protein has been reported to modulate apoptosis by blocking caspases and other regulators of cell survival.12 The lack of these functions then results in characteristic degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
All SMA patients have symmetric proximal muscle weakness that is greater in the lower limbs and decreased or absent deep tendon reflexes.13 However, the severity, onset, and clinical course are stratified into 5 subtypes of SMA, 0-IV. SMA is the most common monogenic cause of infant mortality.14
SMA type 0 (aka congenital SMA) has a prenatal onset and is associated with hypotonia, arthrogryposis, early respiratory failure, severe weakness, decrease fetal movements, and death at birth or within a few months.14 Infants with SMA type 0 generally have one copy of SMN2.15
SMA type I (aka Werdnig-Hoffman) presents in the first 6 months of age with symptoms including severe symmetric flaccid paralysis, inability to sit unsupported, limited head control, weak cry, poor suck and swallow reflexes, pooling of secretion, tongue fasciculations, and increase risk of failure to thrive.14 SMA type 1 infants will often assume a characteristic “frog-like” posture when supine due to severe hypotonic leg weakness. Without ventilatory support, most infants with SMA type I live to about two years of age.14 Infants with SMA type I generally have two or three copies of the SMN2 gene.15
SMA type II (aka Dubowitz) presents at 6-18 months of age with the ability to sit but hypotonia, areflexia, and progressive proximal weakness that disproportionately affects legs over arms. Muscular weakness often leads to scoliosis and restrictive lung disease. Other symptoms include joint contractures, ankylosis of the mandible, and polyminimyoclonus of the hands. Life expectancy is more variable but around 70% of SMA type II patients will survive until 25.14 Patients with SMA type II generally have three copies of the SMN2 gene.15
SMA type III (aka Kugelberg-Welander) presents after 18 months and patients are typically ambulatory but can require a wheelchair as the disease progresses. Symptoms generally include progressive proximal weakness disproportionately affected legs; however, patients do not typically suffer from restrictive lung disease or scoliosis and life expectancy is not affected.14 Patients with SMA type III generally have three or four copies of the SMN2 gene.15
SMA type IV (aka adult SMA) presents in adulthood and is the mildest phenotype. Patients are ambulatory and typically present with mild leg weakness and proximal weakness and an unaffected lifespan.14 Patients with SMA type IV generally have four to eight copies of the SMN215 gene.
Specific secondary or associated conditions and complications
The associated complications depend on the severity and type of SMA as outlined above. Typical complications include but are not limited to restrictive lung disease, failure to thrive, swallowing difficulties, aspiration, constipation, reflux, delayed gastric emptying, scoliosis, hip subluxation, contractures, and susceptibility to fractures.9
Essentials of Assessment
SMA should be suspected for any infant with unexplained proximal muscle weakness, motor difficulties or regression, and/or hypotonia. History will differ depending on SMA type as outlined above. Age of onset and symptom profile are key identifiers for SMA type.9
Physical examination should focus on neurological and musculoskeletal findings for diagnosis. Neurological findings may include proximal muscle weakness, lower extremity weakness, absent or diminished lower extremity reflexes, tongue fasciculations, and signs of lower motor neuron disease. Musculoskeletal findings may include scoliosis, contractures, or hip subluxation. A complete multisystem physical exam should be performed to assess secondary complications.9
Functional assessments may be appropriate for milder subtypes of SMA. The degree of weakness, functional impairment, and clinical course vary widely among subtypes of SMA and should be considered in evaluation.
Molecular genetic testing is the gold standard for SMA diagnosis by detecting homozygous deletions of exon 7 of SMN1. If the clinical picture suggests SMA but only a single deletion is identified, sequencing of SMN1 to look for point mutations should be pursued.16 SMN2 detection is often performed at the same time to aid in prognostic evaluation as higher SMN2 copies are associated with less severe phenotypes.17 SMA was added to the Recommended Uniform Screening Panel (RUSP) for newborns in the United States in 2018, and several states have begun newborn screening for SMA.18
Imaging for musculoskeletal, respiratory, or gastrointestinal complications may be appropriate depending on patient presentation and can be considered for further workup.
Supplementary assessment tools
Electromyography (EMG) and muscle biopsy are not often pursued due to genetic testing but were once a standard part of diagnosis. EMG typically shows denervation changes without reinnervation for SMA I or neurogenic patterns with increased amplitude, prolonged duration, and diminished recruitment for SMA II and III. Muscle biopsy would show a neurogenic pattern. Furthermore, nerve conduction studies may show diminished motor action potentials. Lastly, creatinine kinase is typically normal although may be very mildly elevated.17
Early predications of outcomes
Early predictions of outcomes depend on the SMA type and number of copies of the SMN2 gene. Earlier the onset and fewer copies of SMN2 are correlated with mores severe outcomes.
Environmental factors that can lead to neurological, musculoskeletal, gastrointestinal, and respiratory deficits should be assessed and avoided.
Social role and social support system
Families of children affected by SMA may benefit from a greater social support system to cope with this difficult diagnosis. Patients affected by SMA commonly reported emotional difficulties, fatigue, and a perceived lack of societal support.19
Depending on severity of weakness, accommodations in school or the workplace may be appropriate for patients and caregivers of those with SMA.
Rehabilitation Management and Treatment
Available or current treatment guidelines
Current treatment includes novel therapies as well as symptom management. Disease-modifying therapies are now available which have been shown to improve life span and decrease morbidity.20 These include nusinersen, onasemnogene abeparvovec, and risdiplam. Nusinersen is an intrathecally delivered antisense oligonucleotide that promotes functional SMN2 production.21 Onasemnogene abeparvovec is a onetime intravenous injection gene therapy that ultimately results in delivering the SMN1 gene into cells and allowing the body to produce functioning SMN protein.22 Risdiplam is an oral medication that modifies SMN2 splicing and increasing functional SMN protein levels.23 For children over the age of 2, treatment with nusinersen or risdiplam is suggested as the efficacy in this group of onasemnogene abeparvovec is unknown. The choice among treatments options should be individualized and consider cost (which can be extraordinary), risk profiles, avenues of administration, unknown effects, and availability. Furthermore, some children may be too debilitated to benefit from these treatment modalities.
Symptom management with supportive therapies and early palliative care specialists is the standard for those without disease-modifying therapy. This may include but is not limited to non-invasive ventilation (most commonly BiPAP), tracheostomy, permanent invasive ventilation, gastrostomy, fundoplication, modified diets, physiotherapy, physical therapy, bracing, orthotics, or wheelchairs to improve quality of life.9
Coordination of care
An interdisciplinary approach including physiatrists, pediatricians, geneticists, gastroenterologists, pulmonologists, neurologists, orthopedic surgeons, social workers, psychologists, and other specialists as necessary is recommended.27
Patient and family education
As this is a genetic disease, genetic counseling to patients and family members is important to make properly informed decision in the future. SMA’s autosomal recessive inheritance patterns should be explained to affected families. Preconception counseling should be offered to affected individuals and screening for planned reproductive partner.26 The American College of Medical Genetics recommends offering carrier testing to all couples regardless of race or ethnicity and the American College of Obstetricians and Gynecologists recommends that screening for SMA should be offered to all women who are considering pregnancy or are pregnant.28,29,30
External resources include the following:
Novel disease-modifying therapies are at the forefront of SMA treatment and should continue to be explored and tested.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
SMA phenotypes vary significantly from SMA type 0 to type IV. At its most severe form, patients typically do not live long after birth while at its least severe patients may be largely unaffected. Screening and carrier testing should be offered to all individuals. Supportive management with a large interdisciplinary team is recommended for optimizing treatment. Disease-modifying treatment may cost in the millions USD and varies in approach and frequency of treatment.
Cutting Edge/ Emerging and Unique Concepts and Practice
Novel disease-modifying therapies and uses continue to be heavily researched. Preliminary studies suggest that combining disease modifying therapies such as nusinersen and onasemnogene may be beneficial but further research needs to be done to determine the efficacy and feasibility of this approach.24,25
Gaps in the Evidence-Based Knowledge
- Updated epidemiology including incidence, prevalence, and carrier frequency are largely unknown and based off older studies.
- SMN protein function and precise role in neuronal longevity should be further researched.
- Efficacy of onasemnogene abeparvovec for children under the age of 2 is unknown.
- Long term effects of disease-modifying therapy are unknown.
- Efficacy and feasibility of combination therapy with disease-modifying agents is largely unknown.
- The pathophysiology of gastrointestinal and metabolic complications of SMA are largely unknown.
- Ross LF, Kwon JM. Spinal Muscular Atrophy: Past, Present, and Future. Neoreviews. 2019 Aug;20(8):e437-e451. doi: 10.1542/neo.20-8-e437. PMID: 31371553.
- Burr P, Reddivari AKR. Spinal Muscle Atrophy. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560687/
- SMN1 gene: Medlineplus genetics, MedlinePlus. (n.d.). https://medlineplus.gov/genetics/gene/smn1/.
- Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011 Aug;68(8):979-84. PMC free article PubMed Reference list
- Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, Burghes AH, Kissel JT. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009 Sep;85(3):408-13. PMC free article PubMed Reference list
- Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371:2120–33.
- Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002;110:301–7.
- Merlini L, Stagni SB, Marri E, Granata C. Epidemiology of neuromuscular disorders in the under-20 population in Bologna Province, Italy. Neuromuscul Disord. 1992;2:197–200.
- Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2020 Dec 3]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1352/
- Bowerman M, Becker CG, Yáñez-Muñoz RJ, Ning K, Wood MJA, Gillingwater TH, Talbot K., UK SMA Research Consortium. Therapeutic strategies for spinal muscular atrophy: SMN and beyond. Dis Model Mech. 2017 Aug 01;10(8):943-954. PMC free article PubMed Reference list
- D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011 Nov 02;6:71. PMC free article PubMed Reference list
- Anderton RS, Meloni BP, Mastaglia FL, Boulos S. Spinal muscular atrophy and the antiapoptotic role of survival of motor neuron. Mol Neurobiol. 2013;47:821–32. PubMed Reference list
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve 2015; 51:157
- Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015 Jun;62(3):743-66. PubMed Reference list
- Butchbach ME. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front Mol Biosci 2016; 3:7.
- Prior TW, Finanger E. Spinal muscular atrophy.GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1352/ (Accessed on March 03, 2017).
- Han JJ, McDonald CM. Diagnosis and clinical management of spinal muscular atrophy. Phys Med Rehabil Clin N Am. 2008 Aug;19(3):661-80, xii. PubMed Reference list
- Recommended uniform screening panel, HRSA. (n.d.). https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp
- Wan, H.W.Y., Carey, K.A., D’Silva, A. et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis 15, 70 (2020). https://doi.org/10.1186/s13023-020-1339-3
- Ludolph AC, Wurster CD. Therapeutic advances in SMA. Curr Opin Neurol. 2019 Oct;32(5):777-781. PubMed Reference list
- Claborn MK, Stevens DL, Walker CK, Gildon BL. Nusinersen: A Treatment for Spinal Muscular Atrophy. Ann Pharmacother. 2019 Jan;53(1):61-69. PubMed Reference list
- Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 02;377(18):1713-1722. PubMed Reference list
- Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, Denk N, Feng Z, Green L, Guerard M, Jablonski P, Jacobsen B, Khwaja O, Kletzl H, Ko CP, Kustermann S, Marquet A, Metzger F, Mueller B, Naryshkin NA, Paushkin SV, Pinard E, Poirier A, Reutlinger M, Weetall M, Zeller A, Zhao X, Mueller L. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Aug 09;61(15):6501-6517. PubMed Reference list
- Lee BH, Collins E, Lewis L, et al. Combination therapy with nusinersen and AVXS-101 in SMA type 1. Neurology 2019; 93:640.
- Matesanz SE, Curry C, Gross B, et al. Clinical Course in a Patient With Spinal Muscular Atrophy Type 0 Treated With Nusinersen and Onasemnogene Abeparvovec. J Child Neurol 2020; 35:717.
- Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Feb 24, 2000. PubMed Reference list
- Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A., Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007 Aug;22(8):1027-49. PubMed Reference list
- Prior TW, Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med 2008; 10:840.
- Prior TW. Spinal muscular atrophy: a time for screening. Curr Opin Pediatr 2010; 22:696.
- Committee on Genetics. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol 2017; 129:e41. Reaffirmed 2019.
Sunil K Jain, MD
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Martin Barylak, BS
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