Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

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.

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

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

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.