null Geneviève Bernard, MD, M.Sc., FRCP(c)
leukodystrophies • POLR3-related leukodystrophy • hypomyelination • neurodegenerative diseases • molecular genetics
I am a clinician-scientist with expertise in pediatric neurodegenerative diseases and I have built a cohesive and comprehensive research program on leukodystrophies. From bedside to bench and back to bedside, I assess patients’ needs, such as finding a precise diagnosis or improving their quality of life, and study them in the clinic and in the lab to develop targeted therapies to benefit my patients in real time. Leukodystrophies are a group of rare genetic diseases affecting previously healthy children, leading to progressive disability and death months to years following onset. No current treatment is available for most of these children, a situation exacerbated by the fact that an estimated 20-30% of patients remain without a precise diagnosis despite extensive clinical testing. Finding the cause of these diseases, the erroneous gene, is the first step towards finding a cure. My research program focuses on hypomyelinating leukodystrophies, specifically on one disorder called POLR3-related or 4H leukodystrophy. Children with this disease develop progressive difficulties in walking, talking, swallowing and seeing. 4H is caused by mutations (or alterations) in genes that are important for the survival of cells. Using 4H as my primary disease of interest, my comprehensive research program aims to describe these disorders by discovering gene mutations that cause the illness, characterizing how these mutations lead to disease on a molecular level (pathophysiology), describing how leukodystrophies evolve over time and impact patients and families and their quality of life, and find disease-modifying therapies. Together, this will improve medical care, ensure that we have sufficient data for upcoming therapeutic trials, and lead to effective treatments.
Perrier S, Gauquelin L, Fallet-Bianco C, Dishop MK, Michell-Robinson MA, Tran LT, Guerrero K, Darbelli L, Srour M, Petrecca K, Renaud DL, Saito M, Cohen, S, Leiz S, Alhaddad B, Haack TB, Tejera-Martin I, Monton FI, Rodriguez Espinosa N, Pohl D, Nageswaran S, Grefe A, Glamuzina E, Bernard G. Expanding the phenotypic and molecular spectrum of RNA polymerase III-related leukodystrophy. Neurol Genet, 2020 May 11;6(3):e425. doi: https://doi.org/10.1212/NXG.0000000000000425. PMID: 32582862.
Gauquelin L, Cayami FK, Sztriha L, Yoon G, Tran LT, Guerrero K, Hocke F, Fung EL, D’Arrigo S, Vasco G, Thiffault I, Niyazov DM, Person R, Lewis K, Wassmer E, Prescott T, Fallon P, McEntagart M, Rankin J, Webster R, Phlilppi H, van de Warrenburg B, Timmann-Braun D, Dixit A, Searle C, DDD study, Goizet C, Wolf NI, Bernard G. Clinical spectrum of POLR3-related leukodystrophy caused by POLR1C mutations. Neurology Genetics. Dec 2019; 5(6):e369. doi: 10.1212/NXG.0000000000000369. PMID: 32042905.
Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS, Gauquelin L, Tran LT, Forget D, Gauthier MS, Waisfisz Q, Smith DEC, Simons C, van der Knaap MS, Marquardt I, Lemes A, Guerrero Mierzewska H, Weschke B, Koehler W, Coulombe B, Wolf NI, Bernard G. Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-tRNA synthetase, cause a Hypomyelinating Leukodystrophy. Am J Hum Genet 2018, Apr 5;102(4):676-684. doi: 10.1016/j.ajhg.2018.02.011. PMID: 29576217.
Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates III JR, Coulombe B, Bernard G. Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623. PMID: 26151409.
Wolf NI, Vanderver A, van Spaendonk RML, Schiffmann R, Brais B, Bugiani M, Sistermans EA, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; On behalf of the 4H Research Group. Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology 2014 Nov 18;83(21):1898-905. doi: 10.1212/WNL.0000000000001002. PMID: 25339210.