PMID- 34693554 OWN - NLM STAT- MEDLINE DCOM- 20220114 LR - 20240320 IS - 1531-8249 (Electronic) IS - 0364-5134 (Print) IS - 0364-5134 (Linking) VI - 91 IP - 1 DP - 2022 Jan TI - Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy. PG - 101-116 LID - 10.1002/ana.26256 [doi] AB - OBJECTIVE: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP. METHODS: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5(c/-) ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. RESULTS: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5(c/-) mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia. INTERPRETATION: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116. CI - (c) 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. FAU - Bacq, Alexandre AU - Bacq A AUID- ORCID: 0000-0003-0179-145X AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. FAU - Roussel, Delphine AU - Roussel D AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. FAU - Bonduelle, Thomas AU - Bonduelle T AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. AD - Epilepsy and Neurology Department, Bordeaux University Hospital Center, Bordeaux, France. FAU - Zagaglia, Sara AU - Zagaglia S AUID- ORCID: 0000-0003-3508-3523 AD - Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, UK. AD - Chalfont Centre for Epilepsy, Bucks, UK. FAU - Maletic, Marina AU - Maletic M AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. FAU - Ribierre, Theo AU - Ribierre T AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. FAU - Adle-Biassette, Homa AU - Adle-Biassette H AD - Pathological Anatomy Department, University of Paris, AP-HP, Lariboisiere Hospital, DMU, DREAM, UMR 1141, INSERM, Paris, France. FAU - Marchal, Cecile AU - Marchal C AD - Epilepsy and Neurology Department, Bordeaux University Hospital Center, Bordeaux, France. FAU - Jennesson, Melanie AU - Jennesson M AD - Department of Pediatrics, American Memorial Hospital, Reims University Hospital Center, Reims, France. FAU - An, Isabelle AU - An I AD - Epileptology Unit and Reference Center of Rare Epilepsies, Pitie-Salpetriere Hospital, AP-HP, Paris, France. CN - Genomics England Research Consortium FAU - Picard, Fabienne AU - Picard F AUID- ORCID: 0000-0001-9120-1761 AD - EEG and Epilepsy Unit, Department of Clinical Neurosciences, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland. FAU - Navarro, Vincent AU - Navarro V AUID- ORCID: 0000-0003-0077-8114 AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. AD - Epileptology Unit and Reference Center of Rare Epilepsies, Pitie-Salpetriere Hospital, AP-HP, Paris, France. FAU - Sisodiya, Sanjay M AU - Sisodiya SM AD - Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, UK. AD - Chalfont Centre for Epilepsy, Bucks, UK. FAU - Baulac, Stephanie AU - Baulac S AUID- ORCID: 0000-0001-6430-4693 AD - Sorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, AP-HP, Pitie-Salpetriere Hospital, Paris, France. LA - eng GR - MC_EX_MR/M009203/1/MRC_/Medical Research Council/United Kingdom GR - 682345/ERC_/European Research Council/International GR - MR/M009203/1/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - MC_PC_14089/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211116 PL - United States TA - Ann Neurol JT - Annals of neurology JID - 7707449 RN - 0 (DEPDC5 protein, human) RN - 0 (Depdc5 protein, mouse) RN - 0 (GTPase-Activating Proteins) RN - 0 (NPRL2 protein, human) RN - 0 (NPRL3 protein, human) RN - 0 (Tumor Suppressor Proteins) SB - IM MH - Adolescent MH - Adult MH - Animals MH - Electrocardiography MH - Electroencephalography MH - Epilepsies, Partial/*complications/genetics MH - Female MH - GTPase-Activating Proteins/*genetics MH - *Heart MH - Humans MH - Male MH - Mice MH - Middle Aged MH - Mutation MH - Sudden Unexpected Death in Epilepsy/*etiology MH - Tumor Suppressor Proteins/genetics MH - Young Adult PMC - PMC9299146 COIS- Nothing to report. FIR - Ambrose, J C IR - Ambrose JC FIR - Jackson, R IR - Jackson R FIR - Ryten, M IR - Ryten M FIR - Arumugam, P IR - Arumugam P FIR - Jones, L J IR - Jones LJ FIR - Savage, K IR - Savage K FIR - Baple, E L IR - Baple EL FIR - Kasperaviciute, D IR - Kasperaviciute D FIR - Sawant, K IR - Sawant K FIR - Bleda, M IR - Bleda M FIR - Kayikci, M IR - Kayikci M FIR - Scott, R H IR - Scott RH FIR - Boardman-Pretty, F IR - Boardman-Pretty F FIR - Lahnstein, L IR - Lahnstein L FIR - Siddiq, A IR - Siddiq A FIR - Boissiere, J M IR - Boissiere JM FIR - Lawson, K IR - Lawson K FIR - Sieghart, A IR - Sieghart A FIR - Boustred, C R IR - Boustred CR FIR - Leigh, S E A IR - Leigh SEA FIR - Smedley, D IR - Smedley D FIR - Brittain, H IR - Brittain H FIR - Leong, I U S IR - Leong IUS FIR - Smith, K R IR - Smith KR FIR - Caulfield, M J IR - Caulfield MJ FIR - Lopez, F J IR - Lopez FJ FIR - Sosinsky, A IR - Sosinsky A FIR - Chan, G C IR - Chan GC FIR - Maleady-Crowe, F IR - Maleady-Crowe F FIR - Spooner, W IR - Spooner W FIR - Craig, C E H IR - Craig CEH FIR - Mason, J IR - Mason J FIR - Stevens, H E IR - Stevens HE FIR - Daugherty, L C IR - Daugherty LC FIR - McDonagh, E M IR - McDonagh EM FIR - Stuckey, A IR - Stuckey A FIR - de Burca, A IR - de Burca A FIR - Moutsianas, L IR - Moutsianas L FIR - Sultana, R IR - Sultana R FIR - Devereau, A IR - Devereau A FIR - Mueller, M IR - Mueller M FIR - Thomas, E R A IR - Thomas ERA FIR - Elgar, G IR - Elgar G FIR - Murugaesu, N IR - Murugaesu N FIR - Thompson, S R IR - Thompson SR FIR - Foulger, R E IR - Foulger RE FIR - Need, A C IR - Need AC FIR - Tregidgo, C IR - Tregidgo C FIR - Fowler, T IR - Fowler T FIR - Odhams, C A IR - Odhams CA FIR - Tucci, A IR - Tucci A FIR - Furio-Tari, P IR - Furio-Tari P FIR - Patch, C IR - Patch C FIR - Walsh, E IR - Walsh E FIR - Hackett, J M IR - Hackett JM FIR - Perez-Gil, D IR - Perez-Gil D FIR - Watters, S A IR - Watters SA FIR - Halai, D IR - Halai D FIR - Polychronopoulos, D IR - Polychronopoulos D FIR - Welland, M J IR - Welland MJ FIR - Hamblin, A IR - Hamblin A FIR - Pullinger, J IR - Pullinger J FIR - Williams, E IR - Williams E FIR - Henderson, S IR - Henderson S FIR - Rahim, T IR - Rahim T FIR - Witkowska, K IR - Witkowska K FIR - Holman, J E IR - Holman JE FIR - Rendon, A IR - Rendon A FIR - Wood, S M IR - Wood SM FIR - Hubbard, T J P IR - Hubbard TJP FIR - Riesgo-Ferreiro, P IR - Riesgo-Ferreiro P FIR - Zarowiecki, M IR - Zarowiecki M FIR - Ibanez, K IR - Ibanez K FIR - Rogers, T IR - Rogers T EDAT- 2021/10/26 06:00 MHDA- 2022/01/15 06:00 PMCR- 2022/07/20 CRDT- 2021/10/25 06:58 PHST- 2021/10/20 00:00 [revised] PHST- 2021/03/13 00:00 [received] PHST- 2021/10/21 00:00 [accepted] PHST- 2021/10/26 06:00 [pubmed] PHST- 2022/01/15 06:00 [medline] PHST- 2021/10/25 06:58 [entrez] PHST- 2022/07/20 00:00 [pmc-release] AID - ANA26256 [pii] AID - 10.1002/ana.26256 [doi] PST - ppublish SO - Ann Neurol. 2022 Jan;91(1):101-116. doi: 10.1002/ana.26256. Epub 2021 Nov 16.