Table 1.

Candidate biomarkers for SMA

Biomarker	Notes	References
Biomolecular candidates
SMN protein	Lower levels of circulating SMN protein correlate with more severe/ advanced disease.	[18, 39, 48, 57, 81, 104–106]
Neurofilament	Higher levels of NF indicate greater axonal degradation and more severe/advanced disease.	[78, 107–118, 167]
Muscle indicators	Creatinine, creatine kinase, and other markers of muscle damage are elevated in more advanced SMA.	[122–124]
Genetic candidates
SMN2 gene copy number or polymorphisms	Fewer copies of SMN2 gene correlate with less SMN protein and more severe/advanced disease.	[10, 13–16, 81–83]
Modifier genes	The expression of some non-SMN genes may modify the SMA phenotype.	[73, 84–89]
Gene transcription and
splicing regulators
Micro RNAs	Preclinical and clinical research suggests different miRNAs may be expressed differentially according to SMA severity.	[90–94]
Methylation factors	Methylation of SMN2 impacts its expression and may be a way to measure SMN protein production. Genome-wide methylation patterns and methylation of genes other than SMN1 and SMN2 may correlate with disease severity.	[95–99]
Long non-coding RNAs	Non-coding RNAs might impact gene expression, including activation of SMN2.	[100–103]
Imaging candidates
Muscle imaging approaches	MRI may be useful in determining the degree of SMA severity, muscle atrophy, and response to treatment.	[128–133]
Electrical impedance myography (EIM)	EIM measures action potentials on the surface of muscles following stimulation and has been shown to be sensitive to nuanced advancement of disease progression.	[75, 125–127]
Electrophysiological parameters
Compound muscle action potential (CMAP)	CMAP measurements indicate the degree to which a muscle responds to motor nerve stimulation. CMAP responses decline with disease onset.	[45, 75, 134–138, 175]
Motor unit number estimation (MUNE)	MUNEs are obtained through several methods, such as applying increasing levels of stimulus to estimate the number of motor units that remain.	[134, 135, 138, 175–179]
Repetitive nerve stimulation (RNS)	RNS measures of function of the neuromuscular junction and is an exploratory indicator of SMA disease state.	[180–182]