Project ID NS-MH2023_22


Co Supervisor 1A IoPPN/Basic and Clinical NeuroscienceWebsite

Co Supervisor 1B FoLSM/Randall Centre for Cell & Molecular BiophysicsWebsite

Diet-based nonpharmacological intervention for the control of epileptic co-morbidity in the EPG5-related spectrum of neurological disorders

Mutations in EPG5 cause Vici Syndrome, a neurodevelopmental disease associated with subsequent neurodegeneration. EPG5 encodes for a protein that regulates autophagy, by controlling the fusion between autophagosomes and lysosomes. Autophagy is an essential housekeeping mechanism that controls neuronal health.

Our recent work on more than 100 patients and on relevant animal models has evidenced how milder EPG5 variants are involved in a wider variety of neurological syndromes. A frequent co-morbidity of EPG5-associated disorders is epilepsy.

Our work in animal models has suggested that the epilepsy phenotype in EPG5 deficiency is associated with the primary function of EPG5 in controlling the autophagy flux and that it thus can be rescued by caloric restriction, which enhances autophagy.

In this project the student will pursue the following aims

To gather detailed information on the clinical aspects of epilepsy in our patient cohort

To search wider genomic databases of neurodevelopmental and neurodegenerative disorders (including those associated with epilepsy and movement disorders) for variants of interest in EPG5 and in other relevant autophagy modulators (e.g. WDR45, SNX14, RAB7, SNAP29).

To attempt a diet-based approach using caloric restriction and special diets (ketogenic) in available EPG5 animal models (Drosophila and mouse)

These aims will be developed according top the time frame below.
Year 1. Aim 1 alongside Drosophila experiments for Aim 3.
Year 2. Aim 2: Search of genomic databases start of mouse experiments for Aim 3.
Year 3. End of mouse experiments for Aim 3. Thesis write up.

The expected outcome of this translational project is a novel approach for epilepsy prevention and management in patients with EPG5-associated disorders.

This approach would be also easily applicable by extension to many other neurodegenerative diseases with a primary defect in autophagy and that display epilepsy as a co-morbidity.

Representative Publications

Byrne S, Jansen L, U-King-Im JM, Siddiqui A, Lidov HG, Bodi I, Smith L, Mein R, Cullup T, Dionisi-Vici C, Al-Gazali L, Al-Owain M, Bruwer Z, Al Thihli K, El-Garhy R, Flanigan KM, Manickam K, Zmuda E, Banks W, Gershoni-Baruch R, Mandel H, Dagan E, Raas-Rothschild A, Barash H, Filloux F, Creel D, Harris M, Hamosh A, Kölker S, Ebrahimi-Fakhari D, Hoffmann GF, Manchester D, Boyer PJ, Manzur AY, Lourenco CM, Pilz DT, Kamath A, Prabhakar P, Rao VK, Rogers RC, Ryan MM, Brown NJ, McLean CA, Said E, Schara U, Stein A, Sewry C, Travan L, Wijburg FA, Zenker M, Mohammed S, Fanto M*, Gautel M*, Jungbluth H*. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain 2016 Mar;139(Pt 3):765-81. doi: 10.1093/brain/awv393.

Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H. The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy. Autophagy. 2022 Mar;18(3):496-517. doi:10.1080/15548627.2021.1943177. PMID: 34130600