Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Spinal muscular atrophy (SMA) is a rare autosomal disease caused by genetic defects of the survival motor neuron 1 (SMN1) gene. The degeneration and loss of motor neurons in the spinal cord are hallmarks of SMA and lead to progressive weakness and atrophy of skeletal muscle. Weakness is typically symmetrical and mostly observed in the proximal muscles. Deep tendon reflexes may also be compromised, depending on the time of presentation of the disease.1 Weakness of the respiratory muscles and muscles involved in swallowing may lead to breathing and feeding difficulties.2
SMA Genetic Testing
The standard diagnostic testing for SMA is molecular genetic testing.2,3 This widely available and cost-effective test is used to confirm the homozygous deletion in the SMN1 gene, present in 95% of SMA patients.1,4 Sensitivity and specificity of SMA genetic testing reaches 95% and 100%, respectively.5 For the remaining 5% of patients that do not show a homozygous deletion in SMN1 gene, SMA testing for the deletion alone will not be sufficient, since these patients will typically combine a deletion with a point mutation, one in each allele.6 Genetic studies can be recommended in addition to their use as diagnostic tools. SMA genetic testing can in fact be performed in the scope of a prenatal, newborn, or carrier screening.
Different laboratory methodologies can detect homozygous deletions and deletions of the SMN1 gene. These methods include restriction fragment length polymorphism polymerase chain reaction (PCR), multiplex ligation probe amplification (MLPA), and real-time PCR.2 When a positive test for deletion is obtained, the SMN2 copy number must be determined.
Sequencing of the SMN1 gene is required for about 5% of patients that show pathogenic variants.2 This sequencing testing, typically next generation sequencing or Sanger sequencing, also allows the identification of the copy number and sequence variants of the SMN1 gene.7,8
In case of a negative SMA genetic test result, clinicians focus on studying creatine kinase (CK) levels or performing nerve conduction and electrophysiological1 tests. CK levels are not indicative of SMA disease, but these have been shown to be elevated in SMA type 2 and SMA type 3 patients, indicative of muscle damage.
SMA Imaging Studies
Magnetic resonance imaging (MRI) is not a standard part of the SMA workup, but if it is ordered, it may allow monitoring of SMA patients that show progressive weakness.9,10 Brain MR imaging typically reveals cortical atrophy.11 Other pathological findings, such as delayed myelination of the subcortical white matter, have been associated with SMA type 1 presentations.12
Muscle MRI findings of patients with severe types of SMA will show muscular atrophy; however, these findings are not exclusively linked to SMA and can be related to other medical conditions. Intramuscular fat planes are found to vary in size depending on SMA severity.13,14
Other imaging techniques, such as ultrasound, have been studied as potential spinal muscular atrophy testing methods. In later stages of pregnancy, reduced fetal movements can be linked to aggressive manifestations of SMA. Fetal ultrasounds, however, may not detect these changes in fetal movement.15
Other SMA Testing Methods
Before molecular testing availability, other SMA testing methods were considered standard tools. Nowadays, electrodiagnostic options are still considered for patients when no mutation or deletion of the SMN1 gene is detected — that is, when atypical SMA is suspected.
Electrodiagnostic testing focuses on denervation assessment.3,16 By performing an electromyography (EMG), motor neuron function — more precisely, neuronal and axonal loss — can be evaluated.16 Reinnervation and enlargement of the amplitudes of the motor unit action potential (MUAPs) may be revealed during EMG testing.1,16,17 Compound muscle action potentials (CMAP) are typically affected while motor axonal loss with intact sensory nerve potentials is usually observed. Motor unit number estimation (MUNE) as well as neuromuscular transmission additionally can be evaluated with this test.1 Patients with severe SMA show a generalized decreased CMAP with reduced MUNEs.18
EMG, CMAP and MUNE evaluations can be combined to ascertain SMA severity as there is a good correlation with these electrophysiological parameters and SMA aggressiveness. In fact, CMAP size and functioning can be regarded as a potential prognostic biomarker.16 Age and functional ability of the patients also contribute to electrophysiological differences in SMA; patients with later disease onset can present with normal electrophysiological parameters.16,18
Prior to the development of genetic studies, muscle biopsies were considered a standard test for SMA. As relevant information on denervation can be obtained through tests such as the electrodiagnostic testings and considering the invasiveness of a biopsy procedure, other medical tests are preferred for the evaluation of SMA.16
When performed, muscle biopsies reveal atrophy, infiltration by fat cells,19 reduced cytoplasm, and few histological features that can be correlated with the aggressiveness of the disease.
Typically, patients with SMA type 1 or 2 exhibit atrophic type I and II muscle fibers amidst normal muscle fibers.16,20 Hypertrophied fibers are usually type I and round-shaped.20 In type 3 SMA, groups of atrophic fibers are found between nonatrophic muscle fibers. Muscle fibers can be either of type I or II. Similar findings can be observed in SMA type 4.16 Despite this evidence, muscle biopsies cannot distinguish between SMA types.
Reviewed by Michael Sapko, MD on 7/1/2021
- D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6:71. doi:10.1186/1750-1172-6-71
- Brandsema JF, Gross BN, Matesanz SE. Diagnostic testing for patients with spinal muscular atrophy. Clin Lab Med. 2020;40(3):357-367. doi:10.1016/j.cll.2020.05.005
- Iftikhar M, Frey J, Shohan MJ, Malek S, Mousa SA. Current and emerging therapies for Duchenne muscular dystrophy and spinal muscular atrophy. Pharmacol Ther. 2021;220:107719. doi:10.1016/j.pharmthera.2020.107719
- Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015;62(3):743-766. doi:10.1016/j.pcl.2015.03.010
- Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027-1049. doi:10.1177/0883073807305788
- Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228-237. doi:10.1002/(SICI)1098-1004(200003)15:3<228:AID-HUMU3>3.0.CO;2-9
- Feng Y, Ge X, Meng L, et al. The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing. Genet Med. 2017;19(8):936-944. doi:10.1038/gim.2016.215
- Cao YY, Zhang WH, Qu YJ, et al. Diagnosis of spinal muscular atrophy: a simple method for quantifying the relative amount of survival motor neuron gene 1/2 using sanger DNA sequencing. Chin Med J. 2018;131(24):2921-2929. doi:10.4103/0366-6999.247198
- Verhaart IEC, Robertson A, Leary R, et al. A multi-source approach to determine SMA incidence and research ready population. J Neurol. 2017;264(7):1465-1473. doi:10.1007/s00415-017-8549-1
- Stam M, Haakma W, Kuster L, et al. Magnetic resonance imaging of the cervical spinal cord in spinal muscular atrophy. Neuroimage Clin. 2019;24:102002. doi:10.1016/j.nicl.2019.102002
- Hsu CF, Chen CY, Yuh YS, et al. MR findings of Werdnig-Hoffmann disease in two infants. AJNR Am J Neuroradiol. 1998;19(3):550-552.
- Polido GJ, Barbosa AF, Morimoto CH, et al. Matching pairs difficulty in children with spinal muscular atrophy type I. Neuromuscul Disord. 2017;27(5):419-427. doi:10.1016/j.nmd.2017.01.017
- Chan WP, Liu GC. MR imaging of primary skeletal muscle diseases in children. AJR Am J Roentgenol. 2002;179(4):989-997. doi:10.2214/ajr.179.4.1790989
- Liu GC, Jong YJ, Chiang CH, Yang CW. Spinal muscular atrophy: MR evaluation. Pediatr Radiol. 1992;22(8):584-586. doi:10.1007/BF02015357
- Parra J, Martínez-Hernández R, Also-Rallo E, et al. Ultrasound evaluation of fetal movements in pregnancies at risk for severe spinal muscular atrophy. Neuromuscul Disord. 2011;21(2):97-101. doi:10.1016/j.nmd.2010.09.010
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167. doi:10.1002/mus.24497
- Farrar MA, Vucic S, Johnston HM, Kiernan MCl. Corticomotoneuronal integrity and adaptation in spinal muscular atrophy. Arch Neurol. 2012;69(4):467-473. doi:10.1001/archneurol.2011.1697
- Arnold WD, Porensky PN, McGovern VL, et al. Electrophysiological biomarkers in spinal muscular atrophy: preclinical proof of concept. Ann Clin Transl Neurol. 2014;1(1):34-44. doi:10.1002/acn3.23
- Hsu CF, Chen CY, Yuh YS, Chen YH, Hsu YT, Zimmerman RA. MR findings of Werdnig-Hoffmann disease in two infants. AJNR Am J Neuroradiol. 1998;19(3):550-552.
- Fenichel GM, Engel WK. Histochemistry of muscle in infantile spinal muscular atrophy. Neurology. 1963;13:1059-1066. doi:10.1212/wnl.13.12.1059