title: Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study.
abstract: BACKGROUND
  Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets.
  
  
  OBJECTIVE
  To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches.
  
  
  METHODS
  A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2-12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures.
  
  
  RESULTS
  A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS.
  
  
  CONCLUSIONS
  In this cross-sectional study, "BforSMA" (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with disease progression, and assess potential impact on clinical trial design.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00756821.
authors.affiliation: Department of Neurology and Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. finkel@email.chop.edu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Petra
authors.initials: P
authors.lastname: Kaufmann
authors.forename: Peter
authors.initials: P
authors.lastname: Juhasz
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Li
authors.forename: Felicia
authors.initials: F
authors.lastname: Trachtenberg
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Forrest
authors.forename: Dione T
authors.initials: DT
authors.lastname: Kobayashi
authors.forename: Karen S
authors.initials: KS
authors.lastname: Chen
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Joyce
authors.forename: Thomas
authors.initials: T
authors.lastname: Plasterer
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood / Q000652:urine; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D003430:Cross-Sectional Studies; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D055432:Metabolomics / Q000379:methods; D009043:Motor Activity / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D010641:Phenotype; D010865:Pilot Projects; D040901:Proteomics / Q000379:methods; D012720:Severity of Illness Index; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D053719:Tandem Mass Spectrometry
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D005230:Fatty Acids, Nonesterified; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein