Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy
Devesh C. Pant, … , Odile Boespflug-Tanguy, Aurora Pujol
Devesh C. Pant, … , Odile Boespflug-Tanguy, Aurora Pujol
Published January 8, 2019
Citation Information: J Clin Invest. 2019;129(3):1240-1256. https://doi.org/10.1172/JCI123959.
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Research Article Neuroscience

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

Abstract

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients’ fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

Authors

Devesh C. Pant, Imen Dorboz, Agatha Schluter, Stéphane Fourcade, Nathalie Launay, Javier Joya, Sergio Aguilera-Albesa, Maria Eugenia Yoldi, Carlos Casasnovas, Mary J. Willis, Montserrat Ruiz, Dorothée Ville, Gaetan Lesca, Karine Siquier-Pernet, Isabelle Desguerre, Huifang Yan, Jingmin Wang, Margit Burmeister, Lauren Brady, Mark Tarnopolsky, Carles Cornet, Davide Rubbini, Javier Terriente, Kiely N. James, Damir Musaev, Maha S. Zaki, Marc C. Patterson, Brendan C. Lanpher, Eric W. Klee, Filippo Pinto e Vairo, Elizabeth Wohler, Nara Lygia de M. Sobreira, Julie S. Cohen, Reza Maroofian, Hamid Galehdari, Neda Mazaheri, Gholamreza Shariati, Laurence Colleaux, Diana Rodriguez, Joseph G. Gleeson, Cristina Pujades, Ali Fatemi, Odile Boespflug-Tanguy, Aurora Pujol

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Figure 3

Brain MRIs according to clinical severity and followup.

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Brain MRIs according to clinical severity and followup. (A) MRIs of pati...
(A) MRIs of patients with distinct clinical severity at the age of 6 years. Patient 7 (top row) shows the mildest presentation, with walking acquisition and spastic paraplegia. In FLAIR sequences, mild hyperintensities of the periventricular white matter (WM), with normal CC and internal capsule were observed. In T1 sagittal sequences, normal cerebellum and CC were observed. Patient 9 (bottom row) was able to hold the head but developed dystonia and spasticity with failure to thrive (–4 SD). Despite this severe clinical presentation, the FLAIR sequences show an abnormal hypersignal of the WM only in the periventricular and deep regions that are atrophic. The CC and the cerebellar vermis are atrophic. (B) Sequential MRIs of patient 16. At 6 months, all the WM structures including the cerebellum, the brainstem, and the CC appear unmyelinated. The CC is thin on the T1 sagittal section. A progression in the myelination has occurred at 2.5 years of age but the posterior part of the internal capsules is not myelinated, with periventricular hypersignals and an isosignal of the deep and subcortical WM and atrophic thalami. At 4 years of age the internal capsules and the deep and subcortical WM show normal myelinated signal, whereas the thalami and cerebellar vermis appeared as hypersignals and atrophic.