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DOI 10.1002/ana.78013

Медицинская библиотека · Annals of neurology · 2025

Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism.

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, Alves Cesar, Siddiqui Ata, Dafsari Haidar S, Salari Mehri, Lang Anthony E, Harris Michael, Abdelaleem Alice, Sadeghian Saeid, Azizimalamiri Reza, Galehdari Hamid, Shariati Gholamreza, Sedaghat Alireza, Zeighami Jawaher, Calame Daniel, Marafi Dana, Duan Ruizhi, Boehnke Adrian, Clark Gary D, Rosenfeld Jill A, Mohila Carrie A, Steel Dora, Chopra Saurabh, Sharma Suvasini, Kohlschmidt Nicolai, Patzer Steffi, Saffari Afshin, Ebrahimi-Fakhari Darius, Çavdartepe Büşra Eser, 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 Hanna, 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 Saeideh, Kamath Arveen, Jayawant Sandeep, Saneto Russell, Haridy Nourelhoda A, Kart Pinar Ozkan, Cansu Ali, Joubert Madeleine, 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, Porter Julie, Attié-Bitach Tania, Marzin Pauline, Wicher Dorota, Gold Jessica I, Schuler Elisabeth, Kashgari Amna, Alanazi Rakan F, Eyaid Wafaa, Engelen Marc, Langeveld Mirjam, Stüve Burkhard, Li Yun, Yigit Gökhan, Wollnik Bernd, Monje Mariana H G, Krainc Dimitri, Mencacci Niccolò E, Bakhtiari Somayeh, Kruer Michael, Argilli Emanuela, Sherr Elliott, Jamshidi Yalda, Karimiani Ehsan Ghayoor, Cheung Yiu Wing Sunny, Karin Ivan, Zifarelli Giovanni, Bauer Peter, Chung Wendy K, Lupski James R, Kurian Manju A, Dötsch Jörg, von Kleist-Retzow Jürgen-Christoph, Klopstock Thomas, Wagner Matias, Yip Calvin, Roos Andreas, Carsetti Rita, Dionisi-Vici Carlo, Gautel Mathias, Duchen Michael R, Antebi Adam, Houlden Henry, Fanto Manolis, Jungbluth Heinz

СтатьяПеревод в очереди

Аннотация

OBJECTIVE

Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

METHODS

We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

RESULTS

Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes.

INTERPRETATION: Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy. ANN NEUROL 2025;98:932-950.

Для цитирования: 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, Alves Cesar, Siddiqui Ata, Dafsari Haidar S, Salari Mehri, Lang Anthony E, Harris Michael, Abdelaleem Alice, Sadeghian Saeid, Azizimalamiri Reza, Galehdari Hamid, Shariati Gholamreza, Sedaghat Alireza, Zeighami Jawaher, Calame Daniel, Marafi Dana, Duan Ruizhi, Boehnke Adrian, Clark Gary D, Rosenfeld Jill A, Mohila Carrie A, Steel Dora, Chopra Saurabh, Sharma Suvasini, Kohlschmidt Nicolai, Patzer Steffi, Saffari Afshin, Ebrahimi-Fakhari Darius, Çavdartepe Büşra Eser, 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 Hanna, 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 Saeideh, Kamath Arveen, Jayawant Sandeep, Saneto Russell, Haridy Nourelhoda A, Kart Pinar Ozkan, Cansu Ali, Joubert Madeleine, 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, Porter Julie, Attié-Bitach Tania, Marzin Pauline, Wicher Dorota, Gold Jessica I, Schuler Elisabeth, Kashgari Amna, Alanazi Rakan F, Eyaid Wafaa, Engelen Marc, Langeveld Mirjam, Stüve Burkhard, Li Yun, Yigit Gökhan, Wollnik Bernd, Monje Mariana H G, Krainc Dimitri, Mencacci Niccolò E, Bakhtiari Somayeh, Kruer Michael, Argilli Emanuela, Sherr Elliott, Jamshidi Yalda, Karimiani Ehsan Ghayoor, Cheung Yiu Wing Sunny, Karin Ivan, Zifarelli Giovanni, Bauer Peter, Chung Wendy K, Lupski James R, Kurian Manju A, Dötsch Jörg, von Kleist-Retzow Jürgen-Christoph, Klopstock Thomas, Wagner Matias, Yip Calvin, Roos Andreas, Carsetti Rita, Dionisi-Vici Carlo, Gautel Mathias, Duchen Michael R, Antebi Adam, Houlden Henry, Fanto Manolis, Jungbluth Heinz. Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism.. Annals of neurology. 2025. DOI: 10.1002/ana.78013.

Предметные рубрики MeSH

HumansAnimalsFemaleMiceMaleAutophagyMutationParkinsonian DisordersAdolescentNeurodevelopmental DisordersChildAdultNeurodegenerative DiseasesCaenorhabditis elegansAutophagy-Related ProteinsCohort StudiesAge of OnsetYoung AdultVesicular Transport ProteinsChild, PreschoolDisease Models, Animal
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