39
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Natural history of infantile-onset spinal muscular atrophy : NeuroNEXT SMA Infant Biomarker Study

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 1
      Annals of Neurology
      Wiley-Blackwell

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d4090124e604">Objective</h5> <p id="P1">Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d4090124e609">Methods</h5> <p id="P2">A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d4090124e614">Results</h5> <p id="P3">Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of <i>SMN2</i> indicated a median age of 8 months at death (95%CI: 6,17). </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d4090124e622">Interpretation</h5> <p id="P4">These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide “real world”, prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. </p> </div>

          Related collections

          Most cited references17

          • Record: found
          • Abstract: found
          • Article: not found

          The survival motor neuron protein in spinal muscular atrophy.

          The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Developmental milestones in type I spinal muscular atrophy

            Highlights • This paper reports patterns of natural progression in type I SMA. • The HINE is used to capture motor developmental milestones in SMA. • Motor developmental milestones are rarely acquired in type I SMA infants.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              An analysis of disease severity based on SMN2 copy number in adults with spinal muscular atrophy.

              To evaluate the effect of SMN2 copy number on disease severity in spinal muscular atrophy (SMA), we stratified 45 adult SMA patients based on SMN2 copy number (3 vs. 4 copies). Patients with 3 copies had an earlier age of onset and lower spinal muscular atrophy functional rating scale (SMAFRS) scores and were more likely to be non-ambulatory. There was, however, no difference between the groups in quantitative muscle strength or pulmonary function testing. Functional scale may be a more discriminating outcome measure for SMA clinical trials.
                Bookmark

                Author and article information

                Journal
                Annals of Neurology
                Ann Neurol.
                Wiley-Blackwell
                03645134
                December 2017
                December 2017
                : 82
                : 6
                : 883-891
                Affiliations
                [1 ]the NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators
                Article
                10.1002/ana.25101
                5776712
                29149772
                5e65d1bd-14f2-4ca0-b58a-85a43b7681a2
                © 2017

                http://doi.wiley.com/10.1002/tdm_license_1.1

                History

                Comments

                Comment on this article