Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders
Authors: Dafsari Hormos Salimi , Deneubourg Celine , Singh Kritarth , Maroofian Reza , Suprenant Zita , Kho Ay Lin , Ingham Neil J , Steel Karen P , Sheshadri Preethi , Baur Franciska , Hentrich Lea , Gerisch Birgit , Zamani Mina , Alvares Cesar , Siddiqui Ata , Dafsari Haidar S , Salari Mehri , Lang Anthony , Harris Michael , Abdelaleem Alice , Sadeghian Saeid , Azizimalamiri Reza , Galehdari Hamid , Shariati Gholamreza , Sedaghat Alireza , Zeighami Jawaher , Calame Daniel , Marafi Dana , Duan Ruizhi , Boehnke Adrian , Mohila Carrie , Steel Dora , Chopra Saurabh , Sharma Suvasini , Kohlschmidt Nicolai , Patzer Steffi , Saffari Afshin , Ebrahimi-Fakhari Darius , Eser Çavdartepe Büşra , Chang Irene J , Beckman Erika , Peters Renate , Fennell Andrew Paul , Lo Bernice , Averdunk Luisa , Distelmaier Felix , Baethmann Martina , Elmslie Frances , Joost Kairit , Nampoothiri Sheela , Yesodharan Dhanya , Mandel Hannah , Kimball Amy , Kline Antonie D. , Mignot Cyril , Keren Boris , Laugel Vincent , Õunap Katrin , Devadathan Kalpana , van Berkestijn Frederique M.C. , Silwal Arpana , Koene Saskia , Verma Sumit , Karim Mohammed Yousuf , Boubidi Chahynez , Aziz Majid , ElGhazali Gehad , Mattas Lauren , Miryounesi Mohammad , Hashemi-Gorji Farzad , Alavi Shahryar , Nouri Nayereh , Noruzinia Mehrdad , Kavousi Saeedeh , Kamath Arveen , Jayawant Sandeep , Saneto Russell , Haridy Nourelhoda A. , Kart Pinar Ozkan , Cansu Ali , Beneteau Claire , Stuurman Kyra E. , Wilke Martina , Barakat Tahsin Stefan , Tajsharghi Homa , Scardamaglia Annarita , Vallian Sadeq , Hız Semra , Shoeibi Ali , Boostani Reza , Hashemi Narges , Babaei Meisam , Alsaleh Norah Saleh , Lander Julie , Attié-Bitach Tania , Marzin Pauline , Wicher Dorota , Gold Jessica I , Monje Mariana H G , Krainc Dimitri , Mencacci Niccolò , Bakhtiari Somayeh , Kruer Michael , Argilli Emanuela , Sherr Elliott , Jamshidi Yalda , Karimiani Ehsan Ghayoor , Cheung Yiu Wing Sunny , Karin Ivan , Chung Wendy K , Lupski James R. , Kurian Manju A. , Dötsch Jörg , von Kleist-Retzow Jürgen-Christoph , Klopstock Thomas , Wagner Matias , Yip Calvin , Roos Andreas , Dionisi-Vici Carlo , Gautel Mathias , Duchen Michael R , Antebi Adam , Houlden Henry , Fanto Manolis , Jungbluth Heinz 
Published: June 2024

ABSTRACTAutophagy is a fundamental and evolutionary conserved biological pathway with vital roles in intracellular quality control and homeostasis. The process of autophagy involves the engulfment of intracellular targets by autophagosomes and their delivery to the lysosome for digestion and recycling. We have previously reported recessive variants inEPG5, encoding for the ectopic P-granules 5 autophagy protein with a crucial role in autophagosome-lysosome fusion, as the cause of Vici syndrome (VS), a severe multisystem neurodevelopmental disorder defined by a combination of distinct clinical features including callosal agenesis, cataracts, cardiomyopathy, immunodeficiency, and hypopigmentation. Here, we present extensive novel genetic, clinical, neuroradiological and pathological features from the largest cohort ofEPG5-related disorders reported to date, complemented by experimental findings from patient cells and models of EPG5 defects inCaenorhabditis elegansandMus musculus. We identified 200 patients with recessiveEPG5variants, 86 of them previously unpublished. The associated phenotypic spectrum ranged from antenatally lethal presentations and the classic VS phenotype (n=60) to much milder neurodevelopmental disorders with less specific manifestations (n=140). Myopathic features and epilepsy with variable progression were frequently observed. Novel manifestations included early-onset parkinsonism and dystonia with cognitive decline during adolescence, hereditary spastic paraplegia (HSPP), and myoclonus. Radiological findings included previously recognizedEPG5-related features with callosal abnormalities and pontocerebellar hypoplasia, and a range of novel features suggesting an emerging continuum with disorders of brain iron accumulation or copper metabolism as well as HSPPs. Genotype-phenotype studies suggested a correlation between predicted residual EPG5 expression and clinical severity, especially regarding disease progression and survival. The Epg5 p.Gln331Arg knock-in mouse, a model of milderEPG5-related disorders, showed an age-related motor phenotype and impaired autophagic clearance in several brain regions mirroring those also affected in humans. InCaenorhabditis elegans, epg-5knockdown gave rise to neurodevelopmental features and motor impairment comparable to defects in parkinsonism-related genes, abnormal mitochondrial respiration, and impaired mitophagic clearance early in life. Cellular assays revealed impaired PINK1-Parkin dependent mitophagic clearance in patient fibroblasts. Our findings expand the phenotypic spectrum ofEPG5-related disorders and indicate a life time continuum of disease that overlaps with other disorders of defective autophagy and intracellular trafficking. Our observations also suggest close links between early-onset neurodevelopmental and neurodegenerative conditions of later onset due to EPG5 defects, in particular dystonia and parkinsonism, highlighting the fundamental importance of dysfunctional autophagy in the pathophysiology of common neurodegenerative disorders.