Epileptic encephalopathy caused by ARV1 deficiency: refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins

Smrithi Salian, Marcello Scala, Thi Tuyet Mai Nguyen, Mariasavina Severino, Andrea Accogli, Elisabetta Amadori, Annalaura Torella, Michele Pinelli, Beth Hudson, Megan Boothe, Anna Hurst, Tawfeg Ben-Omran, Martin J Larsen, Christina R Fagerberg, Lene Sperling, Ieva Miceikaite, Lucas Herissant, Martine Doco-Fenzy, Mélanie Jennesson, Vincenzo NigroPasquale Striano, Carlo Minetti, Rani K Sachdev, Emma Elizabeth Palmer, Valeria Capra, Philippe M Campeau

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Abstrakt

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.

OriginalsprogEngelsk
TidsskriftClinical Genetics
Vol/bind100
Udgave nummer5
Sider (fra-til)607-614
ISSN0009-9163
DOI
StatusUdgivet - nov. 2021

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