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Brain. 2017 Mar 1;140(3):547-554. doi: 10.1093/brain/aww318.

A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.

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Medical Research (Level 4), University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
Department of Biology, College of Science, Sultan Qaboos University, Sultanate of Oman.
Department of Genetics, College of Medicine, Sultan Qaboos University, Sultanate of Oman.
Department of Paediatrics, Sultan Qaboos University Hospital, Sultanate of Oman.
Department of Pharmacology, Dalhousie University, Halifax, NS, B3H 4H7, Canada.
Faculty of Medicine, University of Southampton, UK.
West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TG, UK.
Department of Ophthalmology, Sultan Qaboos University Hospital, Sultanate of Oman.
Department of Radiology and Molecular Imaging, Sultan Qaboos University Hospital, Sultanate of Oman.
Department of Paediatrics, Sameal Hospital, Ministry of Health, Sultanate of Oman.
SLING, Life Sciences Institute, National University of Singapore, Singapore.
Department of Biochemistry, National University of Singapore, Singapore.
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.


Mutations in genes involved in lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative motor neuron disorders characterized by spastic paraparesis. Here, we report an unusual autosomal recessive neurodegenerative condition, best classified as a complicated form of hereditary spastic paraplegia, associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine. Phosphatidylethanolamine is a glycerophospholipid that, together with phosphatidylcholine, constitutes more than half of the total phospholipids in eukaryotic cell membranes. We determined that the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis. Additionally, due to central nervous system inaccessibility we undertook quantification of phosphatidylethanolamine levels and species in patient and control blood samples as an indication of liver phosphatidylethanolamine biosynthesis. Although this revealed alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients, overall phosphatidylethanolamine levels were broadly unaffected indicating that in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways. These studies define the first human disorder arising due to defective CDP-ethanolamine biosynthesis and provide new insight into the role of Kennedy pathway components in human neurological function.


EPT1 mutation; Kennedy pathway; hereditary spastic paraplegia; phospholipid biosynthesis; whole exome sequencing

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