Abstract
Sjögren‐Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid peak in the white matter of patients with SLS, suggesting lipid accumulation in the brain as well. Using histopathology, mass spectrometry imaging, and lipidomics, we studied the morphology and the lipidome of a postmortem brain of a 65‐year‐old female patient with genetically confirmed SLS and compared the results with a matched control brain. Histopathological analyses revealed structural white matter abnormalities with the presence of small lipid droplets, deficient myelin, and astrogliosis. Biochemically, severely disturbed lipid profiles were found in both white and gray matter of the SLS brain, with accumulation of fatty alcohols and ether lipids. Particularly, long‐chain unsaturated ether lipid species accumulated, most prominently in white matter. Also, there was a striking accumulation of odd‐chain fatty alcohols and odd‐chain ether(phospho)lipids. Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome. Our data show that SLS is not a pure leukoencephalopathy, but also a gray matter disease. Additionally, the histopathological abnormalities suggest that astrocytes and microglia might play a pivotal role in the underlying disease mechanism, possibly contributing to the impairment of myelin maintenance.
Highlights
Sjögren-Larsson syndrome (SLS; OMIM #270200) is a neurometabolic disorder caused by fatty aldehyde dehydrogenase (FALDH) deficiency[1] due to biallelic mutations in ALDH3A2.2 Patients suffer from intellectual disability, spastic diplegia, ichthyosis, and retinopathy.[3,4] The FALDH deficiency results in accumulation of fatty aldehydes and fatty alcohols in plasma and skin.[5,6] FALDH is involved in the degradation of leukotrienes, which leads to increased levels of leukotriene B4 in patients.[7]
Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome
Our study describes a comprehensive biochemical as well as histopathological evaluation of the postmortem brain of a patient with genetically confirmed SLS; the results contribute to our understanding of SLS, and illustrate the power of novel techniques to clarify the biochemical abnormalities of the brain in neurometabolic disorders
Summary
Sjögren-Larsson syndrome (SLS; OMIM #270200) is a neurometabolic disorder caused by fatty aldehyde dehydrogenase (FALDH) deficiency[1] due to biallelic mutations in ALDH3A2.2 Patients suffer from intellectual disability, spastic diplegia, ichthyosis, and retinopathy.[3,4] The FALDH deficiency results in accumulation of fatty aldehydes and fatty alcohols in plasma and skin.[5,6] FALDH is involved in the degradation of leukotrienes, which leads to increased levels of leukotriene B4 in patients.[7]. Backbone, and one or two fatty acyl-groups linked via an ester bond They are subdivided in subclasses based on the nature of the head group (ie, phosphatidylethanolamine contains an ethanolamine head-group, whereas phosphatidylcholine contains a choline head group).[15] Ether phospholipids, including plasmalogens, constitute a special phospholipid class, characterized by the presence of an ether or a vinyl ether at the sn-1 position of the glycerol backbone instead of an ester (Figure 1).[16] The most abundant lipid species in the human brain, apart from cholesterol, are phospholipids with phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS) as the three most abundant classes.[17]. Show a severely disturbed lipid profile in the SLS brain with accumulation of various species of fatty alcohols, ether(phospho)lipids, and triacylglycerols in both white and gray matter, and confirm the presence of structural white matter abnormalities
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