Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

Stephen J Kolb, Christopher S Coffey, Jon W Yankey, Kristin Krosschell, W David Arnold, Seward B Rutkove, Kathryn J Swoboda, Sandra P Reyna, Ai Sakonju, Basil T Darras, Richard Shell, Nancy Kuntz, Diana Castro, Susan T Iannaccone, Julie Parsons, Anne M Connolly, Claudia A Chiriboga, Craig McDonald, W Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B Shieh, Erika Finanger, Merit E Cudkowicz, Michelle M McGovern, D Elizabeth McNeil, Richard Finkel, Edward Kaye, Allison Kingsley, Samantha R Renusch, Vicki L McGovern, Xueqian Wang, Phillip G Zaworski, Thomas W Prior, Arthur H M Burghes, Amy Bartlett, John T Kissel, NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators, Stephen J Kolb, Christopher S Coffey, Jon W Yankey, Kristin Krosschell, W David Arnold, Seward B Rutkove, Kathryn J Swoboda, Sandra P Reyna, Ai Sakonju, Basil T Darras, Richard Shell, Nancy Kuntz, Diana Castro, Susan T Iannaccone, Julie Parsons, Anne M Connolly, Claudia A Chiriboga, Craig McDonald, W Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B Shieh, Erika Finanger, Merit E Cudkowicz, Michelle M McGovern, D Elizabeth McNeil, Richard Finkel, Edward Kaye, Allison Kingsley, Samantha R Renusch, Vicki L McGovern, Xueqian Wang, Phillip G Zaworski, Thomas W Prior, Arthur H M Burghes, Amy Bartlett, John T Kissel, NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators

Abstract

Objective: This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).

Methods: This prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits.

Results: Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high-frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts.

Interpretation: By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

Figures

Figure 1
Figure 1
Motor function assessments in SMA and healthy infants in the first 6 months of life. (A) Motor function testing paradigm. All infants were tested using the TIMPSI. After the TIMPSI, a mandatory rest period of 20 minutes was followed by either the CHOP‐INTEND or AIMS assessment. Infants who scored less than 41 on the TIMPSI were tested using the CHOP‐INTEND, otherwise the infant was tested using the AIMS test. (B) Results of infant motor function tests for all infants as a function of the age at the time of enrollment visit. For the SMA cohort, the SMN2 copy number for each infant is indicated by the color as indicated in the key by each graph. For the healthy cohort the SMN1 copy number for each infant is indicated by the color as indicated in the key by each graph.
Figure 2
Figure 2
Ulnar compound muscle action potential is significantly reduced in SMA infants compared to healthy infants. Ulnar CMAP peak amplitude (mV) in SMA and healthy control infants as a function of the age at the time of enrollment visit. For the SMA cohort, the SMN2 copy number for each infant is indicated by the color as indicated in the key by each graph. For the healthy cohort, the SMN1 copy number for each infant is indicated by the color as indicated in the key by each graph.
Figure 3
Figure 3
Peripheral blood SMN mRNA and protein levels in SMA and healthy control infants. (A) Full‐length SMN mRNA levels from whole blood measured using ddPCR expressed as a ratio of SMN to HPRT. (B) SMN protein levels detected in PBMCs measured by SMN‐ECL ELISA expressed as pg/107 cells. For the SMA cohort, the SMN2 copy number for each infant is indicated by the color as indicated in the key by each graph. For the healthy cohort, the SMN1 copy number for each infant is indicated by the color as indicated in the key by each graph.

References

    1. Pearn JH. The gene frequency of acute Werdnig‐Hoffmann disease (SMA type 1). A total population survey in North‐East England. J Med Genet 1973;10:260–265.
    1. Sugarman EA, Nagan N, Zhu H, et al. Pan‐ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet 2012;20:27–32.
    1. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997;16:265–269.
    1. Coovert DD, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 1997;6:1205–1214.
    1. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999;96:6307–6311.
    1. Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999;8:1177–1183.
    1. Burnett BG, Munoz E, Tandon A, et al. Regulation of SMN protein stability. Mol Cell Biol 2009;29:1107–1115.
    1. Kashima T, Manley JL. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet 2003;34:460–463.
    1. Zerres K, Rudnik‐Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 1995;52:518–523.
    1. Munsat T, Davies K. Spinal muscular atrophy. 32nd ENMC International Workshop. Naarden, The Netherlands, 10‐12 March 1995. Neuromuscul Disord 1996;6:125–127.
    1. McAndrew PE, Parsons DW, Simard LR, et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet 1997;60:1411–1422.
    1. Feldkotter M, Schwarzer V, Wirth R, et al. 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. Am J Hum Genet 2002;70:358–368.
    1. Elsheikh B, Prior T, Zhang X, et al. An analysis of disease severity based on SMN2 copy number in adults with spinal muscular atrophy. Muscle Nerve 2009;40:652–656.
    1. Monani UR, Sendtner M, Coovert DD, et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(‐/‐) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet 2000;9:333–339.
    1. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol 2011;68:979–984.
    1. Arnold WD, Burghes AH. Spinal muscular atrophy: development and implementation of potential treatments. Ann Neurol 2013;74:348–362.
    1. Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007;22:1027–1049.
    1. Oskoui M, Levy G, Garland CJ, et al. The changing natural history of spinal muscular atrophy type 1. Neurology 2007;69:1931–1936.
    1. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014;83:810–817.
    1. Kaufmann P, O'Rourke PP. Central institutional review board review for an academic trial network. Acad Med 2015;90:321–323.
    1. Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A 2010;152A:1608–1616.
    1. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009;85:408–413.
    1. Krosschell KJ, Maczulski JA, Scott C, et al. Reliability and validity of the TIMPSI for infants with spinal muscular atrophy type I. Pediatr Phys Ther 2013;25:140–148; discussion 9.
    1. Glanzman AM, Mazzone E, Main M, et al. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord 2010;20:155–161.
    1. Piper MC, Darrah J. Motor assessment of the developing infant. In: Company WS, editor; Philadelphia, 1994.
    1. Blanchard Y, Neilan E, Busanich J, et al. Interrater reliability of early intervention providers scoring the Alberta infant motor scale. Pediatr Phys Ther 2004. Spring;16(1):13–18.
    1. Rutkove SB, Gregas MC, Darras BT. Electrical impedance myography in spinal muscular atrophy: a longitudinal study. Muscle Nerve 2012;45:642–647.
    1. Sumner CJ, Kolb SJ, Harmison GG, et al. SMN mRNA and protein levels in peripheral blood: biomarkers for SMA clinical trials. Neurology 2006;66:1067–1073.
    1. Kolb SJ, Gubitz AK, Olszewski RF Jr, et al. A novel cell immunoassay to measure survival of motor neurons protein in blood cells. BMC Neurol 2006;6:6.
    1. Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J 1996;15:3555–3565.
    1. Finkel RS, Crawford TO, Swoboda KJ, et al. Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLoS One 2012;7:e35462.
    1. Kobayashi DT, Shi J, Stephen L, et al. SMA‐MAP: a plasma protein panel for spinal muscular atrophy. PLoS One 2013;8:e60113.
    1. Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol 2005;57:704–712.
    1. Finkel RS. Electrophysiological and motor function scale association in a pre‐symptomatic infant with spinal muscular atrophy type I. Neuromuscul Disord 2013;23:112–115.
    1. Rutkove SB, Shefner JM, Gregas M, et al. Characterizing spinal muscular atrophy with electrical impedance myography. Muscle Nerve 2010;42:915–921.
    1. Kobayashi DT, Decker D, Zaworski P, et al. Evaluation of peripheral blood mononuclear cell processing and analysis for Survival Motor Neuron protein. PLoS One 2012;7:e50763.
    1. Li J, Geisbush TR, Arnold WD, et al. A comparison of three electrophysiological methods for the assessment of disease status in a mild spinal muscular atrophy mouse model. PLoS One 2014;9:e111428.

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