Increased α-tocopherol metabolism in horses with equine neuroaxonal dystrophy

Erin N. Hales, Hadi Habib, Gianna Favro, Scott Katzman, R. Russell Sakai, Sabin Marquardt, Matthew H. Bordbari, Brittni Ming-Whitfield, Janel Peterson, Anna R. Dahlgren, Victor Rivas, Carolina Alanis Ramirez, Sichong Peng, Callum G. Donnelly, Bobbi Sue Dizmang, Angelica Kallenberg, Robert Grahn, Andrew D. Miller, Kevin D Woolard, Benjamin MoellerBirgit Puschner, Carrie J. Finno

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with a vitamin E deficiency within the first year of life. Vitamin E consists of 8 isoforms metabolized by the CYP4F2 enzyme. No antemortem diagnostic test currently exists for eNAD/EDM. Hypothesis/Objectives: Based on the association of α-tocopherol deficiency with the development of eNAD/EDM, we hypothesized that the rate of α-tocopherol, but not γ-tocopherol or tocotrienol metabolism, would be increased in eNAD/EDM-affected horses. Animals: Vitamin E metabolism: Proof of concept (POC) study; eNAD/EDM-affected (n = 5) and control (n = 6) horses. Validation study: eNAD/EDM-affected Quarter Horses (QHs; n = 6), cervical vertebral compressive myelopathy affected (n = 6) horses and control (n = 29) horses. CYP4F2 expression and copy number: eNAD/EDM-affected (n = 12) and age- and sex-matched control (n = 11-12) horses. Methods: The rates of α-tocopherol/tocotrienol and γ-tocopherol/tocotrienol metabolism were assessed in equine serum (POC and validation) and urine (POC only) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative reverse-transcriptase PCR (qRT-PCR) and droplet digital (dd)-PCR were used to assay expression and genomic copy number of a CYP4F2 equine ortholog. Results: Metabolic rate of α-tocopherol was increased in eNAD/EDM horses (POC,P <.0001; validation, P =.03), with no difference in the metabolic rate of γ-tocopherol. Horses with eNAD/EDM had increased expression of the CYP4F2 equine orthologue (P =.02) but no differences in copy number. Conclusions and Clinical Importance: Increased α-tocopherol metabolism in eNAD/EDM-affected QHs provides novel insight into alterations in vitamin E processing in eNAD/EDM and highlights the need for high-dose supplementation to prevent the clinical phenotype in genetically susceptible horses.

Original languageEnglish (US)
Pages (from-to)2473-2485
Number of pages13
JournalJournal of Veterinary Internal Medicine
Volume35
Issue number5
DOIs
StatePublished - Sep 1 2021

Keywords

  • ataxia
  • cytochrome P450
  • equine degenerative myeloencephalopathy
  • genetics
  • vitamin E

ASJC Scopus subject areas

  • veterinary(all)

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