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Increased α-tocopherol metabolism in horses with equine neuroaxonal dystrophy.
Abstract: 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. Objective: 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. Methods: 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: 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.
© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.
Publication Date: 2021-07-31 PubMed ID: 34331715PubMed Central: PMC8478026DOI: 10.1111/jvim.16233Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The research investigated how vitamin E metabolism is altered in horses affected by an inherited neurogenerative disorder known as equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM). It proposed that the metabolism rate of a specific form of vitamin E called α-tocopherol, but not other forms, would be increased in affected horses.
Objective and Hypothesis
- The researchers aimed to understand the metabolism of Vitamin E in horses suffering from eNAD/EDM, an inherited neurodegenerative disorder. As previous findings highlighted that Vitamin E deficiency contributes to the development of this disease, they hypothesized that the metabolism rate of α-tocopherol, a specific isoform of Vitamin E would be higher in affected horses.
Methods
- The research involved observation and analysis of both eNAD/EDM-affected and healthy horses in Proof of Concept and validation studies. Additionally, horses with cervical vertebral compressive myelopathy, another form of neurodegenerative disorder, were also studied for validation.
- The metabolism rates of α-tocopherol/tocotrienol and γ-tocopherol/tocotrienol were analyzed in the serum and urine of the horses involved in the study through liquid chromatography tandem mass spectrometry (LC-MS/MS).
- The researchers also assessed the expression and genomic copy number of CYP4F2 equine ortholog, an enzyme involved in Vitamin E metabolism, using quantitative reverse-transcriptase PCR (qRT-PCR) and droplet digital (dd)-PCR.
Results
- The findings confirmed the original hypothesis – the metabolic rate of α-tocopherol was significantly increased in eNAD/EDM horses. However, there was no change in the metabolic rate of γ-tocopherol.
- They also found increased expression of the CYP4F2 equine ortholog enzyme in the horses with eNAD/EDM, but the copy number of this enzyme remained unchanged.
Conclusion
- The findings offer new insights into how vitamin E processing is altered in horses suffering from eNAD/EDM. It suggests the need for administering high-dose supplements of Vitamin E in genetically susceptible horses as a way to prevent the development of the disorder’s clinical phenotype. This possibly opens up new opportunities for the management and treatment of eNAD/EDM in horses.
Cite This Article
APA
Hales EN, Habib H, Favro G, Katzman S, Sakai RR, Marquardt S, Bordbari MH, Ming-Whitfield B, Peterson J, Dahlgren AR, Rivas V, Ramirez CA, Peng S, Donnelly CG, Dizmang BS, Kallenberg A, Grahn R, Miller AD, Woolard K, Moeller B, Puschner B, Finno CJ.
(2021).
Increased α-tocopherol metabolism in horses with equine neuroaxonal dystrophy.
J Vet Intern Med, 35(5), 2473-2485.
https://doi.org/10.1111/jvim.16233 Publication
Researcher Affiliations
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, New York, USA.
- Department of Pathology and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Michigan State University College of Veterinary Medicine, East Lansing, Michigan, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
MeSH Terms
- Animals
- Chromatography, Liquid / veterinary
- Horse Diseases
- Horses
- Neuroaxonal Dystrophies / genetics
- Neuroaxonal Dystrophies / veterinary
- Tandem Mass Spectrometry / veterinary
- Vitamin E
- alpha-Tocopherol
Grant Funding
- L40 TR001136 / NCATS NIH HHS
- K01OD015134-01A1 / NIH HHS
- UC Davis Center for Equine Health
- L40 TR001136 / NIH HHS
- 20143842021796 / National Institute of Food and Agriculture
- K01 OD015134 / NIH HHS
Conflict of Interest Statement
Authors declare no conflict of interest.
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Citations
This article has been cited 5 times.- Powers A, Peek SF, Reed S, Donnelly CG, Tinkler S, Gasper D, Woolard KD, Finno CJ. Equine neuroaxonal dystrophy/degenerative myeloencephalopathy in Gypsy Vanner horses. J Vet Intern Med 2024 May-Jun;38(3):1792-1798.
- Palmisano M, Kulp J, Bender S, Stefanovski D, Robinson M, Johnson A. Measurement of 8-hydroxy-2'-deoxyguanosine in serum and cerebrospinal fluid of horses with neuroaxonal degeneration and other causes of proprioceptive ataxia. J Vet Intern Med 2024 Mar-Apr;38(2):1207-1213.
- Brown KA, Bender SJ, Johnson AL. Clinical and histopathological features in horses with neuroaxonal degeneration: 100 cases (2017-2021). J Vet Intern Med 2024 Jan-Feb;38(1):431-439.
- Ma Y, Peng S, Donnelly CG, Ghosh S, Miller AD, Woolard K, Finno CJ. Genetic polymorphisms in vitamin E transport genes as determinants for risk of equine neuroaxonal dystrophy. J Vet Intern Med 2024 Jan-Feb;38(1):417-423.
- Donnelly CG, Johnson AL, Reed S, Finno CJ. Cerebrospinal fluid and serum proteomic profiles accurately distinguish neuroaxonal dystrophy from cervical vertebral compressive myelopathy in horses. J Vet Intern Med 2023 Mar;37(2):689-696.
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