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Publication Detail
Cardiac investigations in sudden unexpected death in DEPDC5-related epilepsy
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I, Genomics UK Research Consortium , Picard F, Navarro V, Sisodiya SM, Baulac S
  • Publisher:
    Wiley-Blackwell
  • Publication date:
    01/01/2022
  • Journal:
    Annals of Neurology
  • Status:
    Published online
  • Country:
    United States
  • Print ISSN:
    0364-5134
  • Language:
    eng
Abstract
OBJECTIVE: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the 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 sixteen patients with pathogenic variants in DEPDC5, NPRL2 or NPRL3. Two novel Depdc5 mouse strains, a HA-tagged Depdc5 mouse strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ) were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. RESULTS: Holter, echocardiography and ECG exams provided no evidence for altered clinical cardiac function in the patient cohort, of whom three DEPDC5-patients succumbed to a SUDEP and six 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 EEG-ECG records on Depdc5c/- 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. This article is protected by copyright. All rights reserved.
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Clinical & Experimental Epilepsy
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