Serum creatinine is a biomarker of progressive denervation in spinal muscular atrophy

• Published in: Neurology Vol. 94; no. 9; p. e921
• Main Authors: Alves, Christiano R R, Zhang, Ren, Johnstone, Alec J, Garner, Reid, Nwe, Pann H, Siranosian, Jennifer J, Swoboda, Kathryn J
• Format: Journal Article
• Language: English
• Published: United States 03.03.2020
• Subjects: Action Potentials - physiology; Biomarkers - blood; Cell Count; Child; Creatinine - blood; Disease Progression; DNA Copy Number Variations - genetics; Female; Humans; Infant; Male; Motor Neurons - pathology; Muscle, Skeletal - physiology; Muscular Atrophy, Spinal - blood; Muscular Atrophy, Spinal - diagnosis; Muscular Atrophy, Spinal - genetics; Nerve Degeneration - blood; Nerve Degeneration - diagnosis; Predictive Value of Tests; Severity of Illness Index; Survival of Motor Neuron 2 Protein - genetics
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000008762

Identifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA. We examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 ( ) copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE). Patients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93-2.49; < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52-1.82; < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31-1.58; < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 copies had 1.8-fold (95% CI 1.57-2.11; < 0.0001) higher Crn levels compared to patients with SMA with 2 copies and 1.4-fold (95% CI 1.24-1.58; < 0.0001) higher Crn levels compared to patients with SMA with 3 copies. Patients with SMA with 3 copies had 1.4-fold (95% CI 1.21-1.56; < 0.0001) higher Crn levels than patients with SMA with 2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters ( < 0.0001) and positive associations between Crn and maximum CMAP ( < 0.0001) and between Crn and MUNE ( < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, copies, HFMS, CMAP, and MUNE. These findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.