Lactic Acidosis LSFC Consortium

Leigh syndrome French Canadian Type (LSFC)

Leigh syndrome French Canadian Type (LSFC) is an inherited metabolic disorder that usually kills children before 4 years of age. First described in 1993 by Dr Morin & colleagues, LSFC is characterized by an energy deficit and deadly lactic acidosis episodes commonly referred to as “crises”. The current incidence of this disease is 1/2000 and it is highly prevalent in the north-eastern region of Quebec where the number of carriers is estimated at 1/23.  In 2003, Dr Rioux & colleagues identified the mutations responsible for the LSFC in the LRPPRC gene thereby enabling prenatal screening. This is a unique screening program offered population-wide for the carrier detection and disease prevention.

The challenge is now to translate this information into treatment. Currently, therapeutic options for LSFC children undergoing crisis are practically nonexistent due to our lack of understanding of the (1) function of the normal LRPPRC protein, and (2) circulating factors triggering the crisis and precipitating death.


The Consortium

With the genetic discoveries as the starting point, a collaborative group of scientists was formed to obtain a better biologic understanding of this lethal metabolic disease and to identify therapeutic strategies to improve survival of LSFC patients undergoing a lactic acidosis crisis as well as to prevent and attenuate the detrimental consequences for children that survive the crisis, predominantly major brainstem injuries.  Our team includes pediatricians who treat children with inborn errors of metabolism such as the LSFC and works in close partnership with the Lactic Acidosis Association to insure rapid translation of research results to the target population. Anticipated findings of the proposed research go beyond LSFC patients as they may apply to other conditions involving mitochondrial energetic defects including common chronic diseases such as diabetes and heart failure.

The Consortium receives financial support from the Lactic Acidosis Parents’ Association and from the Canadian Institutes of Health Research. Consortium members are:

John D. Rioux, PhD | Canada Research Chair in Genetics and Genomic Medicine. Dr. Rioux’s group was responsible for mapping the LSFC gene and for identifying the mutations causing this disease. He founded and leads the Consortium.

Christine Des Rosiers, PhD | Professor of Nutrition and Biochemistry at Université de Montréal. Dr. Des Rosiers has gained international recognition for her work on metabolic phenotyping. She oversees the Metabolomics Biomarker Project at the Montreal Heart Institute and is co-leader of the Consortium.

Eric Shoubridge | Full Professor of Human Genetics and Neurology and Neurosurgery at McGill University. Dr. Shoubridge aims to determine the function of the LRPPRC protein in lactic acidosis. Specifically, he is interested in the role of LRPPRC in the mitochondria and why the A354V mutation in the LRPPRC gene causes serious disease.

Catherine Laprise | Professor of Genetics at Université du Québec à Chicoutimi. Dr. Laprise directs the lactic acidosis biobank in Saguenay. She also contributes to the transcriptomic study, a project aimed at identifying predictors of acidotic crises and is developing a project on neurons with other Consortium members.

Yan Burelle | Associate Professor of Pharmacy at Université de Montréal and a FRSQ Junior Research Fellow II. Dr. Burelle aims to establish the effects of mutations in the LRPPRC protein on mitochondrial function and the vulnerability of nerve cells to stress stimuli. In collaboration with other Consortium members, he also tests the efficacy of new therapeutic agents.

Bruce Allen | Associate Professor of Medicine at Université de Montréal and Montreal Heart Institute.

Chantal Bémeur | Assistant Professor of Nutrition at Université de Montréal.


Selected Publications

Cuillerier A et al. Loss of Hepatic Lrpprc Alters Mitochondrial Bioenergetics, Regulation of Permeability Transition and Trans-Membrane Ros Diffusion. Hum Mol Genet. 2017 May 31. doi: 10.1093/hmg/ddx202. [Epub ahead of print] [PMID: 28575497]

Thompson Legault et al. A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome. Cell Rep. 2015 Nov 3;13(5):981-9. doi: 10.1016/j.celrep.2015.09.054. Epub 2015 Oct 22. [PMID: 26565911]

Sasarman F et al. LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. Mol Biol Cell. 2010 Apr 15;21(8):1315-23 [PMID: 20200222]

Mootha VK et al. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):605-10 [PMID: 12529507]

Lee N et al. A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16. Am J Hum Genet. 2001 Feb;68(2):397-409 [PMID: 11156535]



First International Colloquium on Leigh's Syndrome French Canadian Type (LSFC) | Poster


Relevant Links

Association de l’acidose lactique du Saguenay-Lac-St-Jean

Génome Québec: Working for the Prevention of Lactic Acidosis