Biomarkers for spinal muscular atrophy (SMA), including compound muscle action potential (CMAP) amplitude and neuromuscular ultrasound, provide valuable insights into motor neuron integrity and therapeutic efficacy. Ongoing research continues to refine these biomarkers and identify potential new biomarkers that may lead to early detection and may optimize therapeutic strategies.

The copy numbers of the SMN1 and SMN2 genes are key biomarkers for diagnosis, prognosis, and initial treatment selection in SMA. The more copies of SMN2 that someone has, generally the less severe their SMA phenotype. However, other genetic modifiers can also impact it. Patients with 0 copies of SMN1 and 1 to 4 copies of SMN2 should begin disease-modifying therapy as soon as possible. Those with 5 or more copies of SMN2 may never have symptoms, so watchful waiting is currently recommended.

There is a therapeutic window before the irreversible loss of motor neurons, so a goal is to detect changes toward active disease before clinical symptoms develop. I think that biomarkers could come into play there and when considering combination therapy in children who are symptomatic after receiving gene therapy.

The biomarkers that we are currently using in the clinic that are the most helpful are the ones that are most easily accessible. For example, CMAP amplitude can be evaluated relatively easily, and an increase in amplitude or its preservation over time has some correlation with treatment response. However, there can be some preservation of CMAP amplitude even in the setting of ongoing motor unit loss because of collateral sprouting, so it is not a perfect biomarker. Neuromuscular ultrasound is a noninvasive way to monitor muscle thickness over time and to look for changes in the echointensity. Neuromuscular ultrasound is more sensitive for detecting fasciculations compared with electromyography.

A third biomarker, which is used in clinical trials and is also being used more now in clinical practice, is neurofilament, a nonspecific marker of axonal degeneration. A decrease in neurofilament levels seems to be associated with treatment response, and, although it is not perfect, it is helpful. Eventually, neurofilament may also help clinicians determine who may need dual therapy in addition to helping them monitor the clinical status of patients. However, neurofilament may be less useful at distinguishing treatment response in older patients.

Other biomarkers are very interesting but are still in the early stages of development and are currently not in use in clinical practice. SMN protein levels have been evaluated in clinical trials and have demonstrated mixed results in terms of whether they correlate with treatment response, so further evaluation is needed. Finally, several different muscle-specific microRNAs have been shown to be dysregulated in SMA and may have some utility in monitoring treatment response and in detecting the transition from presymptomatic to symptomatic SMA due to their potential association with disease severity and stage.