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

被引:54
作者
Alves, Christiano R. R. [1 ]
Zhang, Ren [1 ]
Johnstone, Alec J. [1 ]
Garner, Reid [1 ]
Nwe, Pann H. [1 ]
Siranosian, Jennifer J. [1 ]
Swoboda, Kathryn J. [1 ]
机构
[1] Massachusetts Gen Hosp, Dept Neurol, Ctr Genom Med, Boston, MA 02114 USA
关键词
DOUBLE-BLIND; MULTICENTER; DYSTROPHY; CHILDREN; NUMBER;
D O I
10.1212/WNL.0000000000008762
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
ObjectiveIdentifying 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.MethodsWe 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 (SMN2) 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).ResultsPatients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93-2.49; p < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52-1.82; p < 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; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.8-fold (95% CI 1.57-2.11; p < 0.0001) higher Crn levels compared to patients with SMA with 2 SMN2 copies and 1.4-fold (95% CI 1.24-1.58; p < 0.0001) higher Crn levels compared to patients with SMA with 3 SMN2 copies. Patients with SMA with 3 SMN2 copies had 1.4-fold (95% CI 1.21-1.56; p < 0.0001) higher Crn levels than patients with SMA with 2 SMN2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters (p < 0.0001) and positive associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, SMN2 copies, HFMS, CMAP, and MUNE.ConclusionsThese 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.
引用
收藏
页码:E921 / E931
页数:11
相关论文
共 35 条
[1]   Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments [J].
Ackerley, S ;
Thornhill, P ;
Grierson, AJ ;
Brownlees, J ;
Anderton, BH ;
Leigh, PN ;
Shaw, CE ;
Miller, CCJ .
JOURNAL OF CELL BIOLOGY, 2003, 161 (03) :489-495
[2]   Creatine Supplementation in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial [J].
Alves, Christiano R. R. ;
Santiago, Bianca M. ;
Lima, Fernanda R. ;
Otaduy, Maria C. G. ;
Calich, Ana Luisa ;
Tritto, Aline C. C. ;
de Sa Pinto, Ana Lucia ;
Roschel, Hamilton ;
Leite, Claudia C. ;
Benatti, Fabiana B. ;
Bonfa, Eloisa ;
Gualano, Bruno .
ARTHRITIS CARE & RESEARCH, 2013, 65 (09) :1449-1459
[3]   Motor unit number estimation in infants and children with spinal muscular atrophy [J].
Bromberg, MB ;
Swoboda, KJ .
MUSCLE & NERVE, 2002, 25 (03) :445-447
[4]   Evaluation of SMN Protein, Transcript, and Copy Number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study [J].
Crawford, Thomas O. ;
Paushkin, Sergey V. ;
Kobayashi, Dione T. ;
Forrest, Suzanne J. ;
Joyce, Cynthia L. ;
Finkel, Richard S. ;
Kaufmann, Petra ;
Swoboda, Kathryn J. ;
Tiziano, Danilo ;
Lomastro, Rosa ;
Li, Rebecca H. ;
Trachtenberg, Felicia L. ;
Plasterer, Thomas ;
Chen, Karen S. .
PLOS ONE, 2012, 7 (04)
[5]   Assessing the safety and efficacy of MNK-1411 in patients with Duchenne muscular dystrophy in a multicenter, double-blind, placebo-controlled, multiple-dose study [J].
Due, B. ;
Becker, P. ;
Crawford, T. .
NEUROMUSCULAR DISORDERS, 2018, 28 :S65-S65
[6]   Spinal muscular atrophy-recent therapeutic advances for an old challenge [J].
Faravelli, Irene ;
Nizzardo, Monica ;
Comi, Giacomo R. ;
Corti, Stefania .
NATURE REVIEWS NEUROLOGY, 2015, 11 (06) :351-359
[7]   Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR:: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy [J].
Feldkötter, M ;
Schwarzer, V ;
Wirth, R ;
Wienker, TF ;
Wirth, B .
AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 70 (02) :358-368
[8]   Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study [J].
Finkel, Richard S. ;
Crawford, Thomas O. ;
Swoboda, Kathryn J. ;
Kaufmann, Petra ;
Juhasz, Peter ;
Li, Xiaohong ;
Guo, Yu ;
Li, Rebecca H. ;
Trachtenberg, Felicia ;
Forrest, Suzanne J. ;
Kobayashi, Dione T. ;
Chen, Karen S. ;
Joyce, Cynthia L. ;
Plasterer, Thomas .
PLOS ONE, 2012, 7 (04)
[9]   Advances in therapy for spinal muscular atrophy: promises and challenges [J].
Groen, Ewout J. N. ;
Talbot, Kevin ;
Gillingwater, Thomas H. .
NATURE REVIEWS NEUROLOGY, 2018, 14 (04) :214-224
[10]   In sickness and in health: the widespread application of creatine supplementation [J].
Gualano, Bruno ;
Roschel, Hamilton ;
Lancha, Antonio Herbert, Jr. ;
Brightbill, Charles E. ;
Rawson, Eric S. .
AMINO ACIDS, 2012, 43 (02) :519-529