Spinal Muscular Atrophy: Diagnosis

The diagnosis of Spinal Muscular Atrophy (SMA) presently relies on a combination of medical history, physical examination, electrodiagnostics, and genetic testing. Unfortunately, despite the widespread knowledge and diagnostic tools capable of achieving a definitive SMA diagnosis in a timely fashion, delays in diagnosis of months to years persist.1,2 With the advent of the first effective approved treatments for SMA, there is growing support for newborn screening programs to include SMA testing in order to allow early interventions.3 Pilot newborn screening may be a cost effective and successful way to idetify and enroll patients into SMA-specific early intervention programs yielding good patient outcomes.4,5

A history of early onset of weakness and physical examination showing hypotonia and can suggest a diagnosis of SMA but further testing will always be needed to confirm the diagnosis.6 While the weakness caused by SMA may appear symmetrically more proximal than distal on examination, this finding is not sufficiently pathognomonic to suffice as a diagnostic criterion.6,7 Likewise, sparing of sensory neurons or the absence of encephalopathy may be suggestive of the diagnosis of SMA but these findings may not be achievable in infantile-onset patients.7 Finally, a serum creatine kinase (CK) test should be performed in any patient in whom myopathy is suspected.8 Patients with SMA typically will not have the elevated serum creatine kinase (CK) found in patients with weakness due to muscle degeneration, and a normal CK finding in a patient with suspected SMA is considered complementary to definitive results of genetic and neurodiagnostic tests.6

In 2007, an International Conference on the Standard of Care for SMA proposed a diagnostic algorithm for SMA that stated “the first diagnostic test for a patient suspected to have [SMA] should be the SMN gene deletion test.”6 This algorithm was reaffirmed in 2018 with the elaboration that “[t]he gold standard of SMA genetic testing is a quantitative analysis of both SMN1 and SMN2 using multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR) or next generation sequencing (NGS)”7 Regardless of the particular means of genetic testing utilized, the “absence of both full SMN1 copies will provide diagnosis of SMA.”7 If a patient fits the clinical picture of SMA but testing reveals one or two apparently intact copies of SMN1, sequencing of all SMN1 genes is indicated, especially if there is a history of consanguinity.7 The additional information provided by SMN2 testing is advised not for its diagnostic value per se but as a prognostic consideration since SMN2 copy number can predict severity of the SMA phenotype.7,9

If SMN1 genetic testing fails to reveal a SMN1 genetic variant, electromyogram (EMG) and nerve conduction studies with repetitive stimulation should be performed.6 The expectation in all types of SMA would be that the EMG will reveal neurogenic changes consistent with motor neuron or axon loss (denervation) and resting fibrillation potentials.10 An EMG that is consistent with a lower motor neuron process as opposed to myopathic disease suggests the need for exploration of non-SMN1 causes, or so-called non-5q SMA, using genome wide sequencing or SMA genetic panels.10-12 Muscle and nerve biopsies are options after less invasive means have been exhausted.6


1. Lin CW, Kalb SJ, Yeh WS. Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review. Pediatr Neurol. 2015;53(4):293-300.

2. Belter L, Cook SF, Crawford TO, et al. An overview of the Cure SMA membership database: Highlights of key demographic and clinical characteristics of SMA members. J Neuromuscul Dis. 2018;5(2):167-176.

3. Glascock J, Sampson J, Haidet-Phillips A, et al. Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. J Neuromuscul Dis. 2018;5(2):145-158.

4. Kraszewski JN, Kay DM, Stevens CF, et al. Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. Genet Med. 2018;20(6):608-613.

5. Phan HC, Taylor JL, Hannon H, Howell R. Newborn screening for spinal muscular atrophy: Anticipating an imminent need. Seminars in perinatology. 2015;39(3):217-229.

6. 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.

7. Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscular disorders : NMD. 2018;28(2):103-115.

8. Dimberg EL. The office evaluation of weakness. Seminars in neurology. 2011;31(1):115-130.

9. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. American journal of human genetics. 2002;70(2):358-368.

10. Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167.

11. Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014;137(Pt 11):2879-2896.

12. Karakaya M, Storbeck M, Strathmann EA, et al. Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. Human mutation. 2018.