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Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid
  1. Sanne Piepers1,
  2. Jan-Maarten Cobben2,
  3. Peter Sodaar1,
  4. Marc D Jansen1,
  5. Renske I Wadman1,
  6. Ann Meester-Delver3,
  7. Bwee Tien Poll-The4,
  8. Henny H Lemmink5,
  9. John H J Wokke1,
  10. W-Ludo van der Pol1,
  11. Leonard H van den Berg1
  1. 1Rudolf Magnus Institute of Neuroscience, Department of Neurology, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. 2Department of Paediatric Genetics, Emma Children's Hospital/Academic Medical Centre, Amsterdam, The Netherlands
  3. 3Department of Rehabilitation, Emma Children's Hospital/Academic Medical Centre, Amsterdam, The Netherlands
  4. 4Department of Paediatric Neurology, Emma Children's Hospital/Academic Medical Centre, Amsterdam, The Netherlands
  5. 5Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
  1. Correspondence to Dr S Piepers, Rudolf Magnus Institute of Neuroscience, Department of Neurology, University Medical Centre Utrecht, The Netherlands HP G 02.320, PO Box 85500, 3508 GA Utrecht, The Netherlands; s.piepers-2{at}umcutrecht.nl

Abstract

Background Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein production by histone deacetylase inhibiting drugs such as valproic acid (VPA) is an experimental treatment strategy for SMA.

Objective To investigate whether an SMN-specific ELISA could detect changes in SMN protein expression in peripheral blood mononuclear cells (PBMCs) after treatment with VPA.

Methods The authors developed a sensitive SMN-specific ELISA. Six patients with SMA types 2 and 3 participated in the study. Recombinant SMN calibration curves were used to calculate SMN protein levels in PBMCs before and after 4 months of VPA treatment.

Results The SMN ELISA was able to detect small differences in SMN protein concentrations, and differences in SMN protein levels in Epstein–Barr virus immortalised lymphocyte cell lines from SMA type 1 and 2 patients, carriers and healthy individuals (p<0.05). The mean SMN protein level in PBMCs from SMA patients was 22% (SD 15%) of the value in a healthy control. VPA treatment resulted in significantly increased SMN protein levels in five out of six SMA patients compared with baseline values (p<0.05), but did not restore SMN levels to normal values.

Conclusions SMN protein quantification by this SMN ELISA is a useful additional tool for evaluating the effects of experimental treatment in SMA.

  • Survival motor neuron protein
  • spinal muscular atrophy
  • HDAC inhibition
  • ELISA
  • motor neuron disease

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Footnotes

  • W-LvdP and LHvdB contributed equally.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the Ethics Committee of the Academical Medical Centre Amsterdam, The Netherlands.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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