Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

Abstract

ObjectiveThis study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).MethodsThis 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.ResultsEnrollment 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.InterpretationBy 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.

Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1–3

“…A negative correlation was observed between the SMN2 copy number and disease severity, which is consistent with the results of previous studies ( 5 , 13 , 25 , 26 ). Prior research has indicated a correlation between SMN2 copy number and the survival status of patients with SMA Type 1 ( 27 ).…”

Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1–3

“…A negative correlation was observed between the SMN2 copy number and disease severity, which is consistent with the results of previous studies ( 5 , 13 , 25 , 26 ). Prior research has indicated a correlation between SMN2 copy number and the survival status of patients with SMA Type 1 ( 27 ).…”

Update on Biomarkers in Spinal Muscular Atrophy

“… 146 However, SMA infants, the youngest cohort to be studied at the time of publication, have also shown increasing EIM measures over time. 31 Of the EIM outcome measures, only high-frequency reactance slope was able to discriminate between SMA infants and controls, contrary to previous studies in older children. 146 , 147 This may have been due to differing impedance spectral characteristics between infants and older children that were not clarified until after this study was conducted.…”

Use of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance

“…The INCEPTUS study supported the CHOP INTEND’s use as a sound measurement tool with excellent reliability, validity, and stability across the 21 months of the observational clinical study. INCEPTUS baseline CHOP INTEND scores were similar to baseline measures of other SMA-1 and XLMTM natural history studies [8, 41]. In regards to responsiveness, the INCEPTUS slope change of –0.070 indicates a fairly stable untreated cohort.…”

“…The majority of the scores fall within the 30-to 40-point range (Fig. 3), which is consistent with SMA [14,41] and XLMTM [8] natural history studies and indicates profound neuromuscular impairment. BSID was initiated only when a score of 45 was obtained on the CHOP INTEND or participants gained the ability to sit unassisted.…”

Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1–3

“…A negative correlation was observed between the SMN2 copy number and disease severity, which is consistent with the results of previous studies ( 5 , 13 , 25 , 26 ). Prior research has indicated a correlation between SMN2 copy number and the survival status of patients with SMA Type 1 ( 27 ).…”

Update on Biomarkers in Spinal Muscular Atrophy

“… 146 However, SMA infants, the youngest cohort to be studied at the time of publication, have also shown increasing EIM measures over time. 31 Of the EIM outcome measures, only high-frequency reactance slope was able to discriminate between SMA infants and controls, contrary to previous studies in older children. 146 , 147 This may have been due to differing impedance spectral characteristics between infants and older children that were not clarified until after this study was conducted.…”

Use of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance

“…The INCEPTUS study supported the CHOP INTEND’s use as a sound measurement tool with excellent reliability, validity, and stability across the 21 months of the observational clinical study. INCEPTUS baseline CHOP INTEND scores were similar to baseline measures of other SMA-1 and XLMTM natural history studies [8, 41]. In regards to responsiveness, the INCEPTUS slope change of –0.070 indicates a fairly stable untreated cohort.…”

“…The majority of the scores fall within the 30-to 40-point range (Fig. 3), which is consistent with SMA [14,41] and XLMTM [8] natural history studies and indicates profound neuromuscular impairment. BSID was initiated only when a score of 45 was obtained on the CHOP INTEND or participants gained the ability to sit unassisted.…”

Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1–3

“…A negative correlation was observed between the SMN2 copy number and disease severity, which is consistent with the results of previous studies ( 5 , 13 , 25 , 26 ). Prior research has indicated a correlation between SMN2 copy number and the survival status of patients with SMA Type 1 ( 27 ).…”

Update on Biomarkers in Spinal Muscular Atrophy

“… 146 However, SMA infants, the youngest cohort to be studied at the time of publication, have also shown increasing EIM measures over time. 31 Of the EIM outcome measures, only high-frequency reactance slope was able to discriminate between SMA infants and controls, contrary to previous studies in older children. 146 , 147 This may have been due to differing impedance spectral characteristics between infants and older children that were not clarified until after this study was conducted.…”

Use of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance

“…The INCEPTUS study supported the CHOP INTEND’s use as a sound measurement tool with excellent reliability, validity, and stability across the 21 months of the observational clinical study. INCEPTUS baseline CHOP INTEND scores were similar to baseline measures of other SMA-1 and XLMTM natural history studies [8, 41]. In regards to responsiveness, the INCEPTUS slope change of –0.070 indicates a fairly stable untreated cohort.…”

“…The majority of the scores fall within the 30-to 40-point range (Fig. 3), which is consistent with SMA [14,41] and XLMTM [8] natural history studies and indicates profound neuromuscular impairment. BSID was initiated only when a score of 45 was obtained on the CHOP INTEND or participants gained the ability to sit unassisted.…”