Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

Abstract

Abstract5q-associated spinal muscular atrophy (SMA) is a rare genetic disease caused by mutations in the SMN1 gene, resulting in a loss of functional SMN protein and consecutive degeneration of motor neurons in the ventral horn. The disease is clinically characterized by proximal paralysis and secondary skeletal muscle atrophy. New disease-modifying drugs driving SMN gene expression have been developed in the past decade and have revolutionized SMA treatment. The rise of treatment options led to a concomitant need of biomarkers for therapeutic guidance and an improved disease monitoring. Intensive efforts have been undertaken to develop suitable markers, and numerous candidate biomarkers for diagnostic, prognostic, and predictive values have been identified. The most promising markers include appliance-based measures such as electrophysiological and imaging-based indices as well as molecular markers including SMN-related proteins and markers of neurodegeneration and skeletal muscle integrity. However, none of the proposed biomarkers have been validated for the clinical routine yet. In this narrative review, we discuss the most promising candidate biomarkers for SMA and expand the discussion by addressing the largely unfolded potential of muscle integrity markers, especially in the context of upcoming muscle-targeting therapies. While the discussed candidate biomarkers hold potential as either diagnostic (e.g., SMN-related biomarkers), prognostic (e.g., markers of neurodegeneration, imaging-based markers), predictive (e.g., electrophysiological markers) or response markers (e.g., muscle integrity markers), no single measure seems to be suitable to cover all biomarker categories. Hence, a combination of different biomarkers and clinical assessments appears to be the most expedient solution at the time.

Evaluation of risdiplam efficacy in 5q spinal muscular atrophy: A systematic comparison of electrophysiologic with clinical outcome measures

“…Finally, the consecutive accrual may be prone to selection bias. Various putative biomarker sources for SMA have been under investigation, including clinical, electrophysiologic, imaging, molecular, and digital biomarkers [10,[25][26][27]. Other than imaging technologies [28][29][30][31][32], electrophysiologic recordings, including CMAP measurements, motor unit number estimation (MUNE), and MUNIX, assess the functional status of the motor unit pool and are therefore important in the diagnostic process and monitoring of disease progression in motor neuron disorders.…”

“…Most recently, risdiplam, an oral, well-tolerated small molecule SMN2 splicing modifier, was approved for the treatment of SMA patients, based on positive results from randomized placebo-controlled clinical trials in patients with type 1, type 2, or non-ambulant type 3 SMA, up to an age of 25 years [7][8][9]. The rise of several cost-intensive innovative treatment options for SMA has led to a concomitant need of reliable biomarkers for meeting the challenges of therapeutic guidance and improved disease monitoring [10]. However, biomarkers appropriate to measure, monitor, or even predict the response to disease-modifying drugs such as risdiplam are still lacking to date.…”

“…Alongside molecular and imaging markers, appliance-based measures such as electrophysiologic recordings appear most promising to be developed as potential biomarkers for SMA in routine clinical practice [10]. The compound muscle action potential (CMAP) represents the summated action potentials of all stimulated motor endplates of a skeletal muscle upon supramaximal electrostimulation, and thus reflects the functional status of the involved motor unit pool.…”

Efficacy and safety of onasemnogene abeparvovec for the treatment of patients with spinal muscular atrophy type 1: A systematic review with meta-analysis

“…The clinical variability is partly attributed to the number of copies of the SMN2 gene in patients. However, there is an increasing body of evidence suggesting that additional factors play a role in the manifestation of the disease [ 6 ].…”

Troponin T is elevated in a relevant proportion of patients with 5q-associated spinal muscular atrophy

“…As there has no biomarker been validated of these new therapeutic options for the clinical routine yet, clinical scales remain the most relevant outcome parameter to date 10 . Major efforts for identifying suitable biomarkers have been undertaken but none have been implemented into clinical routine yet.…”