A Cross-sectional and Longitudinal Evaluation of Serum Creatinine as a Biomarker in Spinal Muscular Atrophy

Abstract Objective Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by proximal muscle weakness and atrophy. The proliferation of disease-modifying therapy has prompted the development of biomarkers to facilitate clinical observations. We explored the association between disease severity and serum creatinine (Crn) levels in patients with SMA over an up to 2-year treatment period with nusinersen. Methods We measured serum Crn and assessed function performance using Hammersmith Functional Motor Scale-Expanded (HFMSE), Medical Research Council Scale (MRC), 6-Minute Walk Test (6MWT), ulnar Compound Muscle Action Potential (CMAP) and forced vital capacity (FVC) in a cohort of 28 adolescent and adult patients with SMA. We investigated the association between Crn and disease severity by partial rank correlation and linear mixed model after correction for age, gender, and BMI. The prediction of functional performance was analyzed using linear models. Results 28 SMA patients with 185 visits and 28 gender- and age-matched healthy controls (HCs) were included. Compared with HCs, SMA patients had significantly lower Crn values ​​(67.4 ± 14 vs 23.7 ± 14.8 umol/L, p<0.0001). Crn has a positive correlation with HFMSE (p<0.0001, r = 0.884), MRC (p<0.0001, r = 0.827), FVC (p = 0.002, r = 0.730), and ulnar CMAP (p<0.0001, r = 0.807) after correction for age, sex, and BMI. The Crn level in patients with SMN2 copy number ≥ 4 is nearly twice (34.1 ± 3.75 vs 17.2 ± 2.52 umol/L, p = 0.00145) as high as that in patients with SMN2 copy number < 4. The Crn level in the ambulants is more than twice (32 ± 2.33 vs 12.9 ± 2.38 umol/L, p<0.0001) as high as that in the non-ambulants. Crn could explain up to 83.5% of the variance of functional performance of the HFMSE, MRC, and 6MWT, which is significantly higher than that of traditional biomarkers. Conclusions These findings suggest that Crn can reflect the disease severity in adolescents and adults with SMA, making it a promising candidate biomarker for SMA.