Objectives: Leukodystrophies (LD) is a heterogeneous group of neurogenetic disorders that primarily affect the brain’s white matter. Despite progress in clinico-MRI (magnetic resonance imaging) classification and genomics, many cases remain unexplained with an unknown biochemical or molecular basis. Our objective was to identify genes involved in the ultrarare forms of undetermined leukodystrophies
Background: We have used whole exome sequencing in 80 families with undetermined leukoencephalopathies, collected in the LEUKOFRANCE network. In three families, we found mutations in the endoplasmic reticulum lipid desaturase DEGS1 gene. Clinical presentation among the four affected patients included absence of motor acquisitions with dystonia and nystagmus, severe spasticity, profound failure to thrive in two cases, and early onset progressive spasticity in two cases.
Methods: MRI showed hypomyelination in the deep white matter with thinning of the corpus callosum and progressive thalami and cerebellar atrophy in the most severe cases associated in one case with a demyelinating neuropathy. Due to the large clinical severity found among the three families, we asked for additional DEGS1 mutated patients through our European network for leukodystrophies and the GeneMatcher platforms. Fifteen additional patients from 10 unrelated families were identified. DEGS1 converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. A marked increase of the substrate DhCer and DhCer/Cer ratios in patient’s fibroblasts and muscle was demonstrated. Finally, a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with fingolimod (FTY720, Gilenyaâ) demonstrated the potential therapeutic interest of this molecule reducing the critical DhCer/Cer imbalance and the severe locomotor disability.
Conclusion: This new group of neurodegenerative disorders confirm the deleterious effect of sphingolipid imbalance, alreading involved in demyelinating leukodystrophies, such as Krabbe’s disease and metachromatic leukodystrophy, among others. In addition, this study highlights the interest of using freely accessible information exchange platforms, such as GeneMatcher after exome sequencing, for rapid identification of sufficient cases to delineate a disease spectrum and improve management
