Longitudinal multi-omics profiling of spinal muscular atrophy

Area of Science:

• Neurology
• Biochemistry
• Genetics

Background:

• Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by SMN1 gene variants.
• Current treatments like nusinersen show variable patient responses, necessitating objective biomarkers.
• Identifying reliable indicators is crucial for personalized SMA management and therapy monitoring.

Purpose of the Study:

• To identify novel cerebrospinal fluid (CSF) and plasma biomarkers for SMA diagnosis.
• To assess the utility of these biomarkers in tracking disease progression and treatment response.
• To discover biomarkers differentiating SMA patients based on SMN2 gene copy number.

Main Methods:

• Targeted metabolomics and proteomics analyses were performed on plasma and CSF samples.
• Samples were collected from treatment-naive SMA patients and controls, and from patients post-treatment.
• Differential analysis identified significantly altered molecules and proteins.

Main Results:

• SMA plasma showed elevated acylcarnitines, biogenic amines, and decreased glycerophospholipids compared to controls.
• Biomarkers achieved high diagnostic accuracy (AUCs >0.9) for SMA detection, with NEFH and creatinine being prominent.
• 26 neurology-related proteins were altered in SMA patient CSF; 11 plasma proteins differentiated patients by SMN2 copy number.

Conclusions:

• This study identified specific biomarkers in plasma and CSF for SMA diagnosis and monitoring.
• These findings support personalized SMA management and the development of targeted therapies.
• Biomarker discovery aids in assessing treatment effectiveness and understanding disease heterogeneity.