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. 2020 Mar 3;94(9):e921–e931. doi: 10.1212/WNL.0000000000008762

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

Christiano RR Alves 1, Ren Zhang 1, Alec J Johnstone 1, Reid Garner 1, Pann H Nwe 1, Jennifer J Siranosian 1, Kathryn J Swoboda 1,✉
PMCID: PMC7238944  PMID: 31882526

Abstract

Objective

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.

Methods

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 (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).

Results

Patients 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.

Conclusions

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.

graphic file with name NEUROLOGY2019992271FFU1.jpg

Spinal muscular atrophy (SMA) is characterized by motor neuron degeneration and progressive muscle atrophy and weakness. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene that result in reduced functional SMN protein expression. However, a paralog gene, SMN2, undergoes alternative splicing, including the removal of exon 7, and produces ≈10% functional SMN protein.1,2 The number of SMN2 copies inversely correlates with phenotypic severity.3–5 Historically, SMA subtype classification is based on age at onset and the maximum motor abilities achieved: infants with type 1 have onset in early infancy and never sit; those with type 2 have later infantile onset but never walk; and those with type 3 have more variable childhood onset and achieve the ability to walk.5–7 Because patients commonly lose function as the disease progresses (i.e., patients with type 3 may lose the ability to walk, and patients with type 2 lose the ability to sit unsupported), designating them as nonsitters, sitters, and walkers in longitudinal studies is also important to accurately capture their functional status. Identifying simple biomarkers to track SMA disease onset, progression, and therapeutic response remains a major research gap.

The phosphocreatine/creatine kinase system plays a crucial bioenergetic role in tissues with high metabolic demand by transferring the N-phosphoryl group from phosphocreatine to adenosine diphosphate. This resynthesizes adenosine triphosphate through a reversible reaction catalyzed by creatine kinase.8–10 This system stabilizes adenosine triphosphate concentrations at ≈3 to 6 mmol.9 Although low concentrations of creatine are found in cardiac and smooth muscle, brain, and other tissues, skeletal muscle stores >90% of total body creatine.11 Creatine is converted nonenzymatically into creatinine (Crn). This is an irreversible process and results in turnover of ≈1.7% of the total creatine per day.11 Therefore, creatine metabolism is essential to maintain skeletal muscle function, and most detectable serum Crn is a waste product from skeletal muscle creatine metabolism. Patients with SMA have low Crn concentrations compared to age-matched healthy controls on routine clinical laboratory studies; however, the potential role of Crn as a biomarker of muscle denervation and motor function in patients with SMA has not been systematically studied. Here, we sought to determine whether changes in Crn concentrations are associated with muscle denervation, motor function, and SMA subtype. We tested and considered potential confounding factors, including age, sex, and lean mass, in our analysis.

Methods

Study approval and participants

Written informed consent and parental consent were obtained from all participants under Institutional Ethics Review Boards at the University of Utah (protocol 8751) and Massachusetts General Hospital (protocol 2016P000469). We queried the Project Cure SMA Longitudinal Population Data Repository for all participants with Crn values in association with motor function, compound motor action potential (CMAP) amplitude, motor unit number estimation (MUNE), and dual-energy x-ray absorptiometry, collected from 2000 to 2016 under University of Utah Institutional Review Board No. 8751 and Partners Institutional Review Board No. 2016-P000469. The Project Cure SMA Longitudinal Population Data Repository is housed within the Research Electronic Data Capture Web Application at the Newborn Screening Translational Research Network. We identified 1,130 Crn observations from 238 patients with SMA evaluated between 2000 and 2016. To test for associations between Crn and maximum CMAP and between Crn and MUNE, we used 616 and 362 observations collected at the same time point for CMAP and MUNE data, respectively. To correct for lean mass, we used 573 Crn observations from a subset of 156 participants with available DEXA whole body–derived lean mass data. The second cohort included 22 presymptomatic infants followed up prospectively from birth through death or 2 years of age. Specifically, they included 10 patients with SMA with 2 SMN2 copies and 12 patients with SMA with 3 SMN2 copies, identified in the setting of an older sibling with SMA type 1 or 2, respectively (clinicaltrials.org, NCT00528268, STOP SMA database, Institutional Ethics Review Board at the University of Utah, protocol 8751). We did not include patients receiving nusinersen, AVXS-101, or RO7034067 in this study.

Motor function, maximum CMAP, MUNE, SMN1 and SMN2 copy numbers, lean mass, and Crn levels

Maximum ulnar CMAP amplitude and MUNE were obtained by recording from the abductor digiti minimi muscle after ulnar nerve stimulation at the wrist as previously described.12,13 Motor function was assessed with the Hammersmith Functional Motor Scale (HFMS; score range 1–20) as previously described.14 SMN1 and SMN2 copy numbers were determined by quantitative PCR as previously described.15,16 Crn and lean mass data were available from clinical laboratory data obtained in association with research visits in the Project Cure SMA Longitudinal Population Data Repository (University of Utah Institutional Review Board No. 8751 and Partners Institutional Review Board No. 2016-P000469). We did not include healthy controls in this study, but expected normal levels of serum Crn are >0.5 mg/dL (range 0.5–1.2 mg/dL).

Statistical analysis

Generalized linear mixed model (GLMM) with random intercept was applied using SAS 9.4 (SAS Institute Inc, Cary, NC). Log transformation was applied to all continuous variables to match the assumptions of the GLMM. Data were controlled for age. Sex was not a significant confounding factor in our model. To correct for lean mass, we performed additional analysis adding Ln(lean mass) to the model. Stepwise deletion was applied for missing values. To compare Crn levels among patients with SMA types 1, 2, and 3, the model was Ln(Crn) = A + B1(i) × SMA type + B2 × Ln(patient age) + mixed term + error term, where type 3 was used as reference. To compare Crn levels among participants with 2, 3, and 4 SMN2 copies, the model was Ln(Crn) = A + B1(i) × SMN2 + B2 × Ln(patient age) + mixed term + error term, where 4 SMN2 copies was used as reference. Patients with SMA were divided into 3 categories based on the functional motor performance: walkers, sitters, and nonsitters. To compare Crn levels among walkers, sitters, and nonsitters, the model was Ln(Crn) = A + B(i) × (nonsitter/sitter/walker) + Ln(patient age) + mixed term + error term, where the walkers group was used as reference. Differences in Crn levels were reported as fold-change, 95% confidence interval (CI), and p values. To test a potential relationship between Crn and maximum CMAP and between Crn and MUNE, the model was Ln(Crn) = A + B1 × Ln(CMAP) or Ln(MUNE) + B2 × Ln(patient age) + mixed term + error. Adjustment for SMN2 copies was also performed with the model Ln(Crn) = A + B1 × Ln(CMAP) or Ln(MUNE) + B2 × Ln(patient age) + B3(i) × SMN2 copy number + mixed term + error, where SMN2 copies was treated as categorical variable with participants with 4 SMN2 copies as reference. Critical value was set as p < 0.05.

Data availability

All data relevant to this study are contained within the article.

Results

SMA clinical subtype, SMN2 dose, motor function, and severity of denervation are associated with Crn levels

The age at enrollment and the distribution of sex, race, SMA type, and SMN2 copies are presented in the table. To determine whether Crn is associated with SMA disease severity, we first compared Crn among patients with SMA types 1, 2, and 3. Mixed-effect model revealed significant differences in Crn among SMA types after correction for age (p < 0.0001; figure 1, A–D). On average, patients with SMA type 3 had 2.2-fold (95% CI 1.93–2.49; p < 0.0001) higher Crn levels compared to 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. Moreover, 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. We further investigated whether there was an association between Crn and SMN2 copies. We found significant differences in Crn among participants with 2, 3, and 4 SMN2 copies after correcting for Ln(age) (p < 0.0001; figure 2, A–D). 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.

Table.

Characteristics of patients with SMA

graphic file with name NEUROLOGY2019992271TT1.jpg

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Figure 1. Comparison of (A) serum creatinine concentrations among patients with SMA types 1, 2, and 3 using mixed effect-model and individual data from patients with SMA types (B) 1, (C) 2, and (D) 3.

Figure 1

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SMA = spinal muscular atrophy.

Figure 2. Comparison of (A) serum creatinine concentrations among patients with SMA with 2, 3, and 4 SMN2 copies using mixed-effect model and individual data from patients with SMA with (B) 2, (C) 3, and (D) 4 SMN2 copies.

Figure 2

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SMA = spinal muscular atrophy; SMN2 = survival motor neuron type 2.

To determine whether Crn is associated with motor function, we divided patients with SMA types 2 and 3 into 3 categories based on the HFMS performance: walkers, sitters, and nonsitters. Mixed-effect model revealed significant differences in Crn levels among these categories after correction for age (p < 0.0001; figure 3, A–D). Walkers had 2.2-fold (95% CI 1.91–2.51; p < 0.0001) higher Crn levels than nonsitters and 1.5-fold (95% CI 1.35–1.66; p < 0.0001) higher Crn levels than sitters. Sitters had 1.5-fold (95% CI 1.33–1.66; p < 0.0001) higher Crn levels than nonsitters.

Figure 3. Comparison of (A) serum creatinine concentrations among patients with SMA divided in nonsitters, sitters, and walkers on the basis of functional motor scale using mixed-effect model and individual data from (B) nonsitters, (C) sitters, and (D) walkers.

Figure 3

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SMA = spinal muscular atrophy.

We observed significant associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001) after correcting for age. In addition, we found significant associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001) after correcting for age and SMN2 copies. To determine whether Crn is associated with maximum CMAP and MUNE in the most severe cases of denervation, we performed independent analyses including only patients with SMA type 1. As previously reported for all patients with SMA, these additional analyses in patients with SMA type 1 showed significant associations between Crn and maximum CMAP (p = 0.0005) and between Crn and MUNE (p < 0.0001) after correction for age. Together, these data demonstrate that SMA disease severity is associated with the degree of decrease in Crn levels.

SMA disease severity is associated with decreased Crn levels after correction for lean mass

To determine whether change in Crn concentrations in patients with SMA is a simple consequence of muscle atrophy, we considered lean mass as a confounding factor in the mixed-effect model and performed additional analyses. After correcting for both age and lean mass, we found significant associations between Crn and SMA types (p < 0.0001), SMN2 copies (p < 0.018), and HFMS score (p < 0.0001). Patients with SMA type 3 had 1.8-fold (95% CI 1.49–2.07; p < 0.0001) higher Crn levels compared to patients with SMA type 1 and 1.4-fold (95% CI 1.28–1.63; p < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.21–1.52; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.3-fold higher Crn levels compared to patients with SMA with 2 SMN2 copies (95% CI 1.08–1.47; p = 0.006). There was no significant difference in Crn between patients with SMA with 4 SMN2 copies and those with 3 SMN2 copies (95% CI −0.232-0.033; p = 0.139). Patients with SMA with 3 SMN2 copies had 1.2-fold higher Crn levels than patients with SMA with 2 SMN2 copies (95% CI 1.02–1.29; p = 0.018). Walkers had 1.8-fold higher Crn levels than nonsitters (95% CI 1.43–2.13; p < 0.0001) and 1.3-fold higher Crn levels than sitters (95% CI 1.12–1.53; p = 0.0009). Sitters had 1.4-fold higher Crn levels than nonsitters (95% CI 1.22–1.60; p < 0.0001).

We also observed significant associations between Crn and maximum CMAP (95% CI 0.073–0.139; p < 0.0001) and between Crn and MUNE (95% CI 0.087–0.167; p < 0.0001) after correcting for age and lean mass. Moreover, similar data were observed for the association between Crn and MUNE (95% CI 0.08–0.18; p < 0.0001) after correction for age, lean mass, and SMN2 copies, and SMN2 copies was not identified as a confounding factor for maximum CMAP data in this analysis (p = 0.209). These data suggest that decreased Crn is associated with the severity of denervation and is not simply a consequence of reduced whole-body lean mass.

Crn levels decrease in infants in association with symptom onset in the first year of life

We further investigated a cohort of 22 presymptomatic infants to determine whether Crn levels decrease in association with symptom onset. In 10 patients with SMA with 2 SMN2 copies followed up from birth who had early severe denervation closely associated with symptom onset, both CMAP (p < 0.0001) and Crn (p < 0.0001) decreased precipitously from birth to 3 months of age (figure 4, A and B and figure 5, A–J). A cohort of 12 patients with SMA with 3 SMN2 copies demonstrated a more variable age at onset and pattern of denervation in the first year of life (p = 0.001); still, most (8 of 12) had decreased Crn (p < 0.0001) in association with symptom onset in the first year of life (figure 6, A and B and figure 7, A–L). More important, these data demonstrated a decrease in Crn that preceded the decrease in CMAP values, indicating that this biomarker may be a more sensitive biomarker of early denervation in infants with 3 SMN2 copies, at a time when compensatory reinnervation may result in stable CMAP values.

Figure 4. Crn decreases in association with symptom onset and disease progression in the first year of life in patients with SMA with 2 SMN2 copies.

Figure 4

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Longitudinal maximum compound motor action potential (CMAP) and (B) serum creatinine (Crn) data in patients with spinal muscular atrophy (SMA) with 2 survival motor neuron 2 (SMN2) copies (n = 10). NP = negative peak.

Figure 5. Maximum CMAP and Crn data for each patient with SMA with 2 SMN2 copies.

Figure 5

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Each panel shows compound muscle action potential (CMAP) and creatinine (Crn) data for a different individual case (A-J) available in our data repository. NP = negative peak; SMA = spinal muscular atrophy; SMN2 = survival motor neuron 2.

Figure 6. Serum Crn decreases in association with symptom onset and disease progression in the first year of life in patients with SMA with 3 SMN2 copies.

Figure 6

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(A) Longitudinal maximum compound motor action potential (CMAP) and (B) creatinine (Crn) data in patients with spinal muscular atrophy (SMA) with 3 survival motor neuron 2 (SMN2) copies (n = 12). NP = negative peak.

Figure 7. Maximum CMAP and Crn data for each patient with spinal muscular atrophy with 3 SMN2 copies.

Figure 7

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Each panel shows compound motor action potential (CMAP) and creatinine (Crn) data for a different individual case (A-L) available in our data repository. NP = negative peak; SMN2 = survival motor neuron 2.

Discussion

Identifying prognostic and predictive biomarkers to track denervation in patients with SMA remains a high priority for SMA researchers and clinicians as we enter the era of newborn screening for SMA. Circulating SMN transcripts and protein levels are obvious candidates for monitoring the impact of therapies targeting SMN production. However, additional biomarkers are critically needed because (1) changes in SMN levels are not expected to change in response to therapies that do not increase peripheral SMN levels, (2) circulating SMN may not reflect the SMN expression in affected tissues, and (3) initial studies indicate significant fluctuation in circulating SMN levels, requiring further studies.5,17–19 In addition, plasma and CSF neurofilament levels have recently been identified as a potential treatment responsive biomarker in SMA and other neurodegenerative diseases.20–23 The Biomarkers for SMA (BforSMA) study, a cross-sectional study of children with SMA types 1, 2, and 3 who were 2 to 12 years and age and sex-matched controls, used unbiased transcriptomics, proteomics, and metabolomics to screen for biomarkers in plasma and urine.17 While no transcripts were identified as candidate biomarkers, at least 97 plasma proteins, 59 plasma metabolites, and 44 urine metabolites correlated with SMA phenotypes across a wide spectrum of disease severity in infantile and childhood-onset SMA. Here, we find that Crn is a potential biomarker to track SMA progression as we continue to seek better biomarkers to monitor disease onset, progression, and response to therapies.

This is the first longitudinal cohort study investigating the potential role of Crn as a biomarker of muscle denervation and disease severity in patients with SMA. Previous studies have demonstrated decreased Crn levels in other motor neuron diseases, including spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS). SBMA is an adult form of X-linked motor neuron disease caused by an expansion of a CAG sequence in the first exon of the androgen receptor gene.24–26 Recently, studies demonstrated that lower Crn concentrations not only were associated with prodromal symptoms such as hand tremor and muscle cramping in patients with SBMA but also decreased steadily years before the onset of weakness, suggesting that Crn is a predictive biomarker for SBMA.24,27 Notably, the authors also tested for potential associations between Crn concentrations and the onset of muscle weakness in individuals with ALS and Parkinson disease. Crn levels started to decline immediately before the onset of muscle weakness in patients with ALS, but a decrease in Crn did not precede clinical onset.27 No changes in Crn were apparent in those with Parkinson disease, a neurodegenerative disorder without direct involvement of motor neurons.27 Studies have also identified low Crn concentrations in association with increased disease severity in other childhood-onset neuromuscular diseases, including Duchenne and Becker muscular dystrophy.28,29

Because low Crn concentrations are commonly observed in chronic medical conditions associated with cachexia,30 we performed additional analysis considering diminished total body lean mass, measured by dual-energy x-ray absorptiometry, as a cofounding factor. Significant associations remain even after corrections for lean mass, suggesting that decreased Crn is not entirely attributable to muscle wasting but is a marker for the degree of denervation during SMA progression. The decrease in Crn in SMA type 1 is associated with a decline in maximum CMAP and MUNE during the most acute phase of denervation in these infants. This occurs before 6 months of age, by which time all infants have evident symptoms and signs of significant generalized weakness and hypotonia. Because Crn is an inexpensive and accessible measurement and commonly assessed as part of routine safety monitoring for prior and ongoing clinical trials, we suggest longitudinal analysis of Crn in these cohorts and in all patients with newly diagnosed SMA to investigate whether increases in Crn correspond to apparent improvements in motor function in response to novel molecular and genetic therapies (e.g., nusinersen, AVXS-101, and RO7034067).

Creatine metabolism plays a crucial bioenergetic role in maintaining muscle fiber homeostasis.9 Oral creatine supplementation can increase intramuscular creatine content.17 The therapeutic effects of creatine supplementation have been recognized and extensively studied in a broad range of diseases, including myopathies and neurodegenerative disorders.10,31–34 Randomized clinical trials have shown that short- and medium-term creatine supplementation can increase muscle strength and is well tolerated in patients with muscular dystrophies.33,34 While creatine supplementation seems an important nonpharmacologic strategy to improve muscle function, the effects of creatine supplementation in patients with SMA are still uncertain. In 2007, Wong et al.35 reported that 6 weeks of creatine supplementation did not improve motor function, muscle strength, or quality of life in patients with SMA. However, several serious methodologic limitations should be considered in this study, including lack of power, high dropout rate, and unbalanced baseline characteristics. Currently, a trial is analyzing the effects of creatine supplementation in people with SBMA.36 Considering our novel findings, carefully designed studies to assess the potential benefit of creatine supplementation as an adjunct therapy for select populations of patients with SMA may be worth revisiting.

This study is not without limitations. First, we used GLMM to investigate all longitudinal data. This model is appropriate to establish associations among the current variables, but it should not be used to make inferences. For example, a decrease of 50% in Crn may not indicate a decrease of 50% in maximum CMAP. Thus, while we recommend including Crn measurement as an additional candidate biomarker for motor function and severity of denervation, caution is needed in making inferences between Crn values and other variables. For instance, Crn may not be as sensitive as maximum CMAP in detecting the differences in severity of denervation between more significantly affected patients with SMA because it has a limited range. Moreover, direct comparison between Crn levels corrected by lean mass and Crn levels not corrected by lean mass should be avoided because the sample size and statistical power were different for each analysis.

These observations demonstrate that Crn is a potential prognostic biomarker for patients with SMA, particularly in newborns and in those with a higher SMN2 copy number. Crn levels correlate with SMA type, SMN2 copy number, motor function, and severity of denervation as approximated by ulnar CMAP and MUNE. Because Crn is a simple, inexpensive, and accessible measurement, we propose that Crn should be monitored routinely in longitudinal follow-up of all patients with SMA.

Acknowledgment

The authors are grateful to all the patients and families who participated in this study. They thank the Project Cure SMA Investigators Network for contribution of deidentified data for inclusion in the database and Dr. Thomas Prior for determining SMN2 copy number.

Glossary

ALS

amyotrophic lateral sclerosis

BforSMA

Biomarkers for SMA

CI

confidence interval

CMAP

compound muscle action potential

Crn

creatinine

GLMM

generalized linear mixed model

HFMS

Hammersmith Functional Motor Scale

MUNE

motor unit number estimation

SBMA

spinal and bulbar muscular atrophy

SMA

spinal muscular atrophy

SMN

survival motor neuron

Appendix. Authors

Appendix.

Appendix.

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Study funding

Financial support was provided to K.J.S. from National Institute of Child Health and Human Development R01HD054599 and Cure SMA.

Disclosure

C. Alves, R. Zhang, A. Johnstone, R. Garner, P. Nwe, and J. Siranosian report no disclosures relevant to the manuscript. K. Swoboda is on the scientific advisory board for Cure SMA; is a consultant for Biogen and AveXis; and receives clinical trial funding from AveXis and Biogen. Go to Neurology.org/N for full disclosures.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data relevant to this study are contained within the article.

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