More SMA Biomarkers Are Needed to Gauge Disease Progression, Therapy Response

A review of current molecular and electrophysiological biomarkers in spinal muscular atrophy (SMA) concluded that more exploration is necessary to find noninvasive, yet accurate, measures of disease progression and therapy response.

As disease-modifying treatments are utilized and developed for spinal muscular atrophy (SMA), clinically meaningful biomarkers are necessary to provide insight into the effects of therapy and disease progression ahead of clinical detection. A recent review provides updates on current biomarkers relevant to the genetic motor neuron disease while highlighting the need for additional progress to understand variability in therapy effectiveness and optimize treatment response.

SMA, a degenerative motor neuron disorder, is caused by homozygous deletion or mutation of the SMN1 gene, which causes a deficiency in SMN protein. The SMN2 gene can produce some SMN, but not enough to compensate for the lack of functioning SMN1. Therefore, the number of SMN2 copies a patient has typically correlates with disease severity. The less SMN2 copies a patient has, the more severe their disease.

In recent years, the treatment landscape has evolved and 3 treatments are now available for SMA (nusinersen, risdiplam, and onasemnogene abeparvovec). But a feasible way to evaluate SMN levels in surviving patients is lacking, notes the review, which was published in Biomarker Insights.

“The ideal biomarker for SMA is one that is noninvasive, yet able to reflect systemic SMN levels, particularly those within protected nervous tissue. It must also be accurate and reliable,” the authors wrote. “However, a single biomarker may be useful but not fulfill insights into all areas — disease progression, prognosis, and response to therapy — thus, a combination of biomarkers may provide greater insight and more accurate clinical assessment.”

The review stratifies biomarkers by their points of diagnosis and treatment:

  • Diagnostic: markers of disease phenotype prior to diagnosis
  • Prognostic: markers of disease phenotype prior to treatment
  • Disease progression: markers of disease phenotype after treatment initiation
  • Predictive: markers of treatment response prior to treatment initiation
  • Pharmacodynamic: markers of treatment response after treatment initiation

Regarding molecular biomarkers, number of SMN2 copies is a known option and the best way to predict clinical outcomes in untreated patients. More SMN2 copies typically correlates with less severe disease, lower mortality, and a lesser need for ventilatory support. However, a patient’s number of SMN2 copies does not change with treatment and therefore is not useful to gauge disease progression or treatment response. Treatment for SMA must begin as soon as possible in affected infants, so newborn screening to detect SMN1 and quantify SMN1 and SMN2 is increasingly common.

SMN and mRNA protein levels can provide insight into current disease state but are not effective for monitoring disease progression and response to therapy over time. And while measuring these levels in the blood makes SMN and mRNA protein levels more accessible, blood SMN and mRNA protein levels may not be reflective of the levels in motor neurons or central nervous system tissue.

Elevated neurofilaments (NFs)—cytoskeletal proteins released from neurons after they sustain injury—are a marker found in both blood and cerebrospinal fluid (CSF). They have been shown to be elevated in patients with SMA patients compared with healthy populations and can predict disease severity ahead of treatment. NF levels have also been found to decline quickly within months of treatment initiation in infants, making them a promising biomarker possibility. Even so, studies have found that NFs are a less useful biomarker in adults, and the correlation between lowering NF levels and improving motor function is not consistent.

Spinal muscular atrophy multi-analyte panel (SMA-MAP) protein analytes are potentially useful in distinguishing between infants with SMA and healthy infants. Certain analytes in particular have been shown to be reliable in this respect. In the Biomarkers for SMA study, for example, dipeptidyl peptidase-IV, osteopontin, and tetranectin showed increased plasma levels and had positive correlations with the Modified Hammersmith Functional Motor Scale (MHFMS), which measures disease severity. On the other hand, the analytes fetuin-A and vitronectin showed decreased plasma levels and had negative correlations with the MHMFS. Other studies have pointed to certain analytes being useful, but research has not led to conclusions on (SMA-MAP) protein analytes on the whole as a biomarker.

Creatine kinase (CK) is an enzyme that allows phosphate to transfer to creatine, which is a rapidly mobilizable energy reserve in muscle; and creatinine (Crn) is a metabolic waste product of the CK system that is known to correlate with disease severity in other denervating moron neuron diseases. Both may be useful predictive and pharmacodynamic biomarkers. In children and adolescents, serum Crn levels (corrected for age and lean mass) are inversely correlated with disease severity. Baseline levels of serum CK and Crn can also distinguish nusinersen treatment responders from non-responders in adults, with higher levels of both being higher in responders.

Electrophysiology and imaging biomarkers are also useful in gauging motor function and can be predictive of treatment effect. These include compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number index (MUNIX), motor unit size index (MUSIX), and electrical impedance myography (EIM). Electrophysiology methods vary in their invasiveness but are reliable for assessing muscle health and strength, and they may be able to detect changes before clinical symptoms arise.

Overall, despite the growing variety of biomarkers that can be used to identify and monitor SMA, more work needs to be done to allow for consistent, accurate measurements of SMA progression and response to treatment.

“No single biomarker may necessarily be sufficient to monitor disease progression and treatment efficacy, but there is great potential in a combination of robust biomarkers that together allow for more accurate clinical assessment,” the authors conclude. Overall, more pre-clinical studies and clinical research and collaboration is necessary to determine what factors—or combinations of factors—can serve as biomarkers in SMA.


Pino M, Rich K, Kolb S. Update on biomarkers in spinal muscular atrophy. Biomark. Insights. Published online August 14, 2021. doi:10.1177/11772719211035643