Table 1.
Prognostic and diagnostic molecular biomarkers of SMA.
| Reference | Measured Biomarker | Analyzed Bodily Fluid | Number of Participants | Type of Diagnosis (Number of Patients) | Method Used for Measurement of Biomarkers | Biomarkers in SMA Compared to HCs | Correlation of Biomarkers with Scores on Scales for the Assessment of Motor Functions | Type of Biomarker |
|---|---|---|---|---|---|---|---|---|
| [56] | NfL and pNfH | CSF and serum | 39 | Adult SMA patients (33) HCs (6) |
Single molecular array | Unchanged | Negative correlation between serum pNfH concentrations and RULM score, upper and lower extremity strength, and total strength | Pharmacodynamic, prognostic |
| [57] | IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-31, TNF-α, and IFN-γ |
Serum, CSF | 44 | SMA 1 (4) SMA 2 (13) SMA 3 (16) HCs (11) |
Multiplex immunoassay | In serum: ↑IL-1b, ↑IL-4, ↑IL-6, ↑IL-10, ↑IFN-γ, ↑IL-17A, ↑IL-22, ↑IL-23, ↑IL-31, ↑IL-33, ↑TNF-α | No correlation with the HFMSE score | Diagnostic |
| [51] | Whole miRNAome | Serum | 27 | SMA 2 (10) SMA 3 (10) HCs (7) |
miRNA next-generation sequencing | 42 miRNAs differentially expressed; 14 miRNAs upregulated and 28 downregulated |
Prognostic | |
| [48] | Whole proteome | CSF | 17 | SMA 1 (10) HCs (7) |
2D-PAGE, MS, WB |
↓APOA1 ↑Hemoglobin sub. β ↑Hemoglobin sub. α ↓Transthyretin 2D-PAGE analyses showed 39 protein differences |
Not analyzed | Diagnostic |
| [58] | CHIT1 | CSF | 109 | SMA 1 (7) SMA 2 (33) SMA 3 (39) HCs (30) |
ELISA | ↑CHIT1 | No association with HFMSE and CHOP-INTEND scores | Diagnostic, pharmacodynamic |
| [55] | Urinary metabolic profiling | Urine | 491 | Pre-symptomatic (5) SMA 1 (9) SMA 2 (8) SMA 3 (7) DMD (18) HCs (444) |
1H-NMR-based metabolic profiling combined with sophisticated algorithms based on machine learning |
Urinary metabolic profiling | Not analyzed | Diagnostic, prognostic |
| [49] | Whole proteome | Extracellular vesicles released from fibroblasts |
6 | SMA 1 (1) SMA 2 (2) HCs (3) |
MS, WB | 116 differentially expressed proteins (↓94, ↑21) ↑IGFBP3 ↓Plastin 3 ↓PTK7 ↓TCP1 ↑FETUA ↑FXA |
Not analyzed | Diagnostic |
| [39] | NfL in CSF and serum | CSF and serum | 115 | SMA 1 (4) SMA 2 (7) SMA 3 (3) SMA 2–3 (4) HCs (97), only serum samples |
Single-molecule array (SiMoA) assay | ↑NfL in serum | A negative correlation of serum NfL with CHOP-INTEND score | Pharmacodynamic, prognostic |
| [45] | In CSF: NfL, total tau, p-tau181, Qalb, OCB, CSF white cells In serum: creatinine |
CSF, serum | 21 | SMA 2 (3) SMA 3 (6) HCs (12) |
ELISA | ↓Creatinine | A positive relationship between creatinine and HFMSE score and RULM | Diagnostic, prognostic |
| [52] | Whole miRNAome | Serum | 88 | SMA 1 (3) SMA 2 (21) SMA 3 (26) SMA 4 (1) HCs (37) |
Quantitative real-time PCR | ↑miR-181a-5p ↑miR-324-5p ↑miR-451a |
Not analyzed | Diagnostic |
| [59] | HSPA7 mRNA, HSP70B protein, pNfH protein | Blood and serum | 52 | Pre-symptomatic (9) SMA 1 (22) SMA 2 (14) SMA 3 (2) HCs (5) |
Enzyme-linked lectin assay (for p-NfH), ELISA (for HSP70B), real-time PCR, whole-blood RNA sequencing | ↑HSPA7 mRNA; Positive association of HSP70B protein with pNfH | Not analyzed | Diagnostic, prognostic |
| [53] | Whole blood transcriptomic screen |
Whole blood | 65 | SMA 3 (31) HCs (34) |
L1000 profiling technology and RT-PCR | -Seven downregulated and three upregulated KEGG pathways -Most significantly downregulated pathway “Regulation of Actin Cytoskeleton” (including the expression of key genes in this pathway; ROCK1, RHOA, and ACTB) -↓270 genes, ↑287 genes |
Not analyzed | Diagnostic |
| [60] | NfL | Serum | 106 | SMA 2 (20) SMA 3 (26) SMA 2/3 (46) HCs (14) |
NfL Advantage kit from Quanterix | No difference | Higher levels of NfL were associated with poorer motor performance (as measured by the HFMSE and ALSFRS-R). No correlation between NfL levels and motor scale scores | Pharmacodynamic, prognostic |
| [47] | Creatinine | Serum | 238 | SMA 1 (49) SMA 2 (97) SMA 3 (92) |
Creatinine data from Project Cure SMA Longitudinal Population Data Repository | Decrease in creatinine levels with disease severity (SMA 3 > SMA 2 > SMA 1) | A positive association with the HFMS score | Diagnostic, prognostic |
| [61] | pNfH, NfL | CSF | 21 | SMA 3 (12) HCs (9) |
ELISA | No difference | No association with the HFMSE score | Pharmacodynamic, prognostic |
| [62] | NfL, total tau, GFAP | CSF | 23 | SMA 1 (12) HCs (11) |
ELISA | ↑NfL ↑total tau ↑GFAP |
A negative correlation of NfL and total tau levels with the CHOP-INTEND score | Prognostic, diagnostic, pharmacodynamic |
| [63] | pNfH | Plasma | 155 | SMA 1 (121) HCs (34) |
Protein Simple platform | ↑pNfH | A negative association between pNfH and the CHOP-INTEND score | Prognostic, diagnostic, pharmacodynamic |
| [64] | SMN protein | Peripheral blood nuclear cells (CD3+, CD19+, and CD33++ cells) |
39 | SMA 1 (4) SMA 2 (17) SMA 3 (4) HCs (14) |
Imaging flow cytometry | ↓SMN protein | A positive correlation between SMN-spot+ cell percentage and the HFMS | Prognostic, diagnostic |
| [36] | SMN mRNA and protein | Blood | 53 | Infantile-onset SMA (26) HCs (27) |
ECL immunoassay, Droplet Digital PCR | ↓SMN mRNA and protein | A positive association of SMN mRNA with TIMPSI No association with the CHOP-INTEND score |
Prognostic, diagnostic |
| [65] | SMN protein | Exosomes released from fibroblasts and serum | 2 | SMA 3 (1) HCs (1) |
WB | ↓SMN protein | Not analyzed | Diagnostic |
| [66] |
SMN1, SMN2-FL, SMN2-Δ7, GAPDH and 18S mRNA, SMN protein |
PBMCs, skin-derived fibroblasts | 443 | SMA 1 (18) SMA 2 (60) SMA 3 (52) SMA 4 (5) HCs (293) |
ELISA, real-time PCR | ↓SMN protein | Correlation between SMN protein concentration in fibroblasts and HFMSE | Prognostic, diagnostic |
| [67] | SMN protein | Whole blood | 52 | SMA 1 (5) SMA 2 (22) SMA 3 (22) HCs (3) |
ECL immunoassay | ↓SMN protein | Not analyzed | Diagnostic |
| [68] | SMN mRNA, SMN protein | Blood | 131 | SMA 1 (7) SMA 2 (14) SMA 3 (15) HCs (95) |
In-house ELISA, multiplex qRT-PCR | A positive association between SMN protein and SMN mRNA levels in patients with SMA 1 and SMA 2 | Not analyzed | Diagnostic |
| [69] | SMN protein | Fibroblasts | SMA 1 (1) HC |
Imaging flow cytometry technique | ↓SMN protein | Not analyzed | Diagnostic | |
| [50] | Analysis of nearly 1000 plasma proteins | Plasma | 288 | BforSMA samples: SMA 1 (17) SMA 2 (49) SMA 3 (42) HCs (22) PNCRN samples: SMA 1 (35) SMA 2 (66) SMA 3 (57) |
Multiplex immunoassay | Development of commercial SMA-MAP biomarker panel (APOB, APCS, ASHG, AXL, CCL2, CD93, CFH, CDH13, CHI3L1, CLEC3B, COMP, CRP, CTSD, DPP4, ENG, ERBB2, FBLN1, IGF1, IGFBP6, LEP, LUM, MB, PEPD, PGF, SPP1, THBS4, TNXB) | A positive association of AXL, CD93, CDH13, COMP, DPP4, LUM, MB, PEPD, SPP1, and THBS4, and negative association of CHI3L1, APCS, and LEP with the MHFMS | Prognostic, diagnostic |
| [70] | GRP75/Mortalin, Calreticulin |
Biopsy of skeletal muscle (m. quadratus femoris) | 6 | SMA 2/3 (3) HCs (3) |
Quantitative fluorescent WB | ↑Calreticulin | Not analyzed | Prognostic |
| [71] | SMN2-FL transcripts, SMN-∆D7, SMN protein | Blood | 45 | SMA 3 | ELISA, real-time PCR | Not analyzed | A positive correlation between SMN2-FL transcripts and lower limb Medical Research Council (MRC) score and total MRC score |
Prognostic |
| [34] | Proteome, transcriptome, metabolome | Plasma (proteome, metabolome, amino acids, free fatty acids), urine (metabolome), whole blood (transcriptome) | 130 | SMA 1 (17) SMA 2 (49) SMA 3 (42) HCs (22) |
LC-MALDI-MS/MS Proteomics, Lipid LC/MS Metabolomics, GC/MS Metabolomics, Affymetrix Exon Array | Top 20 markers: (in plasma) TNXB, CILP2, COMP, Glu, CLEC3B, ADAMTSL4, THBS4, OMD, LUM, DPP4, PEPD, C10:0-fatty-acid, CDH13, Asp, Hyp, (in urine) Inositol, Uric acid, Pantothenic acid | 97 plasma proteins, 59 plasma metabolites, and 44 urine metabolites correlated with the MHFMS | Prognostic |
| [72] | SMN protein, SMN transcripts (SMN2-FL, SMN1-FL, SMN-∆D7), GAPDH transcript | Blood | 130 | SMA 1 (17) SMA 2 (49) SMA 3 (42) HCs (22) |
ELISA, real-time PCR | ↓SMN protein SMN2-FL (SMA 3 > SMA 2 > SMA 1) ↑SMN-∆7 (in SMA 2 and 3) ↓GAPDH (in SMA 2 and 3) |
No association with the MHFMS |
Prognostic, diagnostic |
| [73] |
SMN-FL, SMN-Δ7 mRNA |
Blood | 61 | SMA 2 (42) SMA 3 (19) |
Real-time PCR | ↓SMN-FL/SMNΔ7 ratio | Not analyzed | Prognostic |
| [54] | Transcriptome (Gene Expression Plate “Neurodegeneration”), α-synuclein (SNCA) protein |
Fibroblasts, spinal cord mRNA | 6 | SMA 1 (3) HCs (3) |
Real-time PCR, WB | ↓SMN1 mRNA, ↓SNCA mRNA, ↓SNCA protein, ↓SV2A mRNA and ↓SYN2 mRNA | Not analyzed | Diagnostic |
| [74] | SMN protein | PBMCs | 7 | SMA 1 (1) HCs (6) |
ELISA | ↓SMN protein | Not analyzed | Diagnostic |
| [75] | SMN mRNA and SMN protein | Blood | 86 | SMA 1 (6) SMA 2 (9) SMA 3 (14) Carriers (29) HCs (28) |
Cell immunoassay, quantitative reverse transcription PCR | ↑SMN-Δ7 mRNA in SMA 2 and 3 patients ↓SMN-7+ mRNA in SMA 1 patients ↓SMN protein in SMA 1 patients |
Diagnostic |
(↑) increase, (↓) decrease. The literature search was completed on 2 May 2023. Column “Type of biomarker” was determined based on comments given by the authors of a particular study, but also by observations from the authors of the other studies. 2D-PAGE, two-dimensional SDS-polyacrylamide gel electrophoresis; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; CHIT1, chitotriosidase 1; CHOP-INTEND, The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; CSF, cerebrospinal fluid; DMD, Duchenne muscular dystrophy; ECL, Electrochemiluminescence; ELISA, enzyme-linked immunosorbent assay; FL, Full Length; GFAP, Glial fibrillary acidic protein; HC, healthy control; HFMS, Hammersmith Functional Motor Scale; HFMSE, Hammersmith Functional Motor Scale Expanded; HSPA7, Heat Shock Protein Family A Member 7; HSP70B, heat shock 70 kDa protein 7; IFN, Interferon; IL, interleukin; MHFMS, Modified Hammersmith Functional Motor Scale; miRNA, micro RNA; MS, MALDI-TOF mass spectrometry; NfH, neurofilament heavy chain; NfL, neurofilament light chain; NMR, nuclear magnetic resonance; OCB, oligoclonal immunoglobulin G (IgG) bands; PBMC, peripheral blood mononuclear cells; pNfH, phosphorylated neurofilament heavy chain; pNfL, phosphorylated neurofilament light chain; p-tau181, tau protein phosphorylated at threonine 181; Qalb, CSF/serum quotient of albumin; RULM score, Revised Upper Limb Module score; SMA, spinal muscular atrophy; SMN, survival motor neuron; TIMPSI, Test of Infant Motor Performance Screening Items; TNF-α, tumor necrosis factor alpha; WB, Western blot.