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

Abstract

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.

Whole‐blood dysregulation of actin‐cytoskeleton pathway in adult spinal muscular atrophy patients

“…26 Other exploratory biomarkers include immunoassays to detect circulating levels of lightor heavy-chain neurofilaments, a marker of axonal damage, 27 and serum creatinine, which we recently demonstrated to be a simple biomarker of progressive denervation in SMA. 28 No studies to date have examined these potential biomarkers specifically in adult SMA patients. Additional biomarkers to better assess acute and chronic denervation, whole body lean mass, metabolic status, and other measures of health and well-being in adult SMA patients are also needed.…”

“…This cross‐sectional study applied an unbiased approach to screen plasma from a cohort of infantile and childhood‐onset SMA type 1, 2, and 3 patients and age‐ and gender‐matched controls to identify 97 proteins and 59 metabolites that correlated with SMA phenotypes across a wide spectrum of disease severity 26 . Other exploratory biomarkers include immunoassays to detect circulating levels of light‐ or heavy‐chain neurofilaments, a marker of axonal damage, 27 and serum creatinine, which we recently demonstrated to be a simple biomarker of progressive denervation in SMA 28 . No studies to date have examined these potential biomarkers specifically in adult SMA patients.…”

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

“…Few biomarkers of muscle activity are known such as creatinine, a waste product from the phosphorylation of adenosine diphosphate by creatine that mostly occurs in skeletal muscles. Levels of creatinine are relatively lower in patients with SMA than controls [ 143 ], as reported in a longitudinal study of a 238 SMA patient cohort. Indeed, in these SMA patients, creatinine levels correlated closely with maximum CMAP and MUNE values, even after correction for confounding factors such age and lean mass (muscle atrophy).…”

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

“…Patients with SMA have been shown to have lower values of creatinine compared to age-matched controls [ 109 ]. In the skeletal muscles is stored most creatine of the body, and its metabolism is essential to maintain the muscle function; creatinine is a product of muscle creatine metabolism.…”