The study by Vaz et al. published in Brain in 2019 established a novel firm link between disrupted etherlipid biosynthesis and complex forms of hereditary spastic paraplegia (HSP) through the identification of recessive mutations in the PCYT2 gene (Synofzik and Schule, 2017; Darios et al., 2020; Rickman et al., 2020). Before, genetic causes of HSP had been found in genes with diverse functional roles (Shribman et al., 2019) including chaperone activity, axonal transport, mitochondrial function and many others. However, mutations in genes involved in complex lipid metabolism have increasingly been implicated in the pathology of HSP (CYP7B1, CYP2U1, DDHD1, DDHD2, BSCL2, ERLIN2, FA2H and PNPLA6/NTE, SELENOI/EPT1, SERAC1)(Windpassinger et al., 2004; Rainier et al., 2008; Goizet et al., 2009; Alazami et al., 2011; Schuurs-Hoeijmakers et al., 2012; Tesson et al., 2012; Cao et al., 2013; Synofzik et al., 2014; Ahmed et al., 2017; Roeben et al., 2018), thus presenting a converging and possibly even treatable mechanistic theme in pathophysiology of manifold HSP and spastic ataxias (Synofzik and Schule, 2017; Darios et al., 2020; Rickman et al., 2020). Phosphatidylethanolamine (PE) is a glycerophospholipid that, together with phosphatidylcholine, makes up more than 50% of the total phospholipids in eukaryotic cell membranes (McMaster, 2018). PE is particularly enriched in the brain where it constitutes 45% of the phospholipid fraction. PE is the product of two major biochemical processes: the CDP-ethanolamine pathway (Kennedy pathway) and the decarboxylation of phosphatidylserine in mitochondria (Vance, 2015; McMaster, 2018). CTP: phosphoethanolamine cytidylyltransferase, encoded by PCYT2, performs a crucial role within the CDP-ethanolamine pathway. It catalyses the conversion of CTP and phosphoethanolamine into CDP-ethanolamine, an intermediate that is subsequently converted into PE by ethanolamine phosphotransferase (McMaster, 2018).