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Mathilde came into the world with chubby cheeks and a full head of auburn hair. But she was a very sick baby, and was immediately transferred on January 19, 2013 to the Neonatal Intensive Care Unit at the Montreal Children鈥檚 Hospital of the UU直播 Health Centre (MCH-MUHC). By the time she arrived, she was sicker than initially expected; Mathilde鈥檚 small head was of particular concern to doctors. She underwent neurological tests, and sadly, they came back abnormal: her brain hadn鈥檛 developed properly and her brain white matter (or myelin) was found to be atypical. Doctors confirmed she was suffering from an unidentified kind of genetic leukoencephalopathy, a family of diseases affecting both the nerve cells and the white matter. Mathilde passed away when she was two-and-a-half months old, surrounded by the people who loved her most.

Thanks to an international effort led by physician-scientists at Rady Children鈥檚 Institute for Genomic Medicine (RCIGM)-San Diego in California, Dr. Genevi猫ve Bernard鈥檚 team at the Research Institute of the UU直播 Health Centre (RI-MUHC) and UU直播 was able to confirm the diagnosis for Mathilde: she died from VARS-related disorder, an extremely rare neurodevelopmental condition. Their findings, which were recently published in Nature Communications, are paving the way for the first step in developing potential therapies for this rare neurodegenerative condition.

Investigators performed advanced genetic tests on blood samples from seven children with neuro-developmental disabilities who were evaluated by doctors in San Diego, Montreal and Cairo. This led to the discovery of mutations in the VARS gene, which had not previously been linked to human disease.

鈥淭hese children showed epileptic seizures and abnormalities evident on brain MRI scans,鈥� said lead study鈥檚 author Joseph Gleeson, MD, director of neurodevelopmental genetics at RCIGM and professor of neuroscience and pediatrics at UC San Diego School of Medicine. 鈥淎lthough no treatment currently exists for this condition, the results are important as the first step in guiding research directed at targeted therapies.鈥�

The genetic mutations identified in the study led to a defect in the enzyme responsible for generating proteins containing the amino acid valine, which is necessary for cellular health. Genetic variations that damage these types of enzymes are associated with a variety of human diseases including microcephaly and neuropathy.

In this study, the team found that enzymatic activity was significantly reduced in cells from their young patients. The findings suggest that children with this disorder may benefit from treatments to support the synthesis of new valine-containing proteins in the brain.

The cause of genetic disabilities in many children is rarely identified. This limits the ability of doctors to develop precise treatment plans. Both whole exome and whole genome testing were conducted as part of this study. These tests search an individual鈥檚 genetic code for imperfections that are the source of disease.

"Trying new approaches to understand these diseases is important. Having an answer about what鈥檚 making their child so sick helps families grieve," added study co-author Genevi猫ve Bernard, MD, MSc, FRCPc, pediatric neurologist and a researcher with the Child Health and Human Development Program of the RI-MUHC.

鈥淭he diagnosis gave us some closure,鈥� said Mathilde鈥檚 father, Gabriel. Because their daughter鈥檚 disease was so rare, they agreed to take part in further research into the disorder. 鈥淚t felt good to know that our daughter could help other children and the scientific community at large.鈥�

Patient evaluation and testing for this study was conducted at Rady Children鈥檚 Hospital-San Diego, the Montreal Children鈥檚 Hospital of the UU直播 Health Centre and the National Research Center in Cairo. Medical research institutions in Amsterdam, Hong Kong, Qatar and Egypt also played a supporting role in confirming the biologic impact of the mutation in the VARS gene.

鈥淔or ultra-rare conditions such as this one, collaboration among multiple research institutions is crucial to confirm that changes identified in the genetic code may be common to multiple children with similar clinical symptoms,鈥� said study co-author Jennifer Friedman, MD, neurologist at Rady Children鈥檚 Hospital and professor at UC San Diego School of Medicine.

鈥淪uch cooperation and patient matching plays a critical role in the identification of new genes and provision of diagnoses to geographically dispersed individuals with the same rare disorder,鈥� Dr. Friedman added.

In future experiments, the researchers hope to test whether dietary supplementation with valine or gene therapy may help to restore the altered protein in the brain of these children.

by J. Friedman et al. was pubished in Nature Communications.

This research was made possible in part by support provided by The UU直播 and G茅nome Qu茅bec Innovation and Centre Compute Canada. This work was partly supported by grants from the Canadian Institutes of Health Research (CIHR), la Fondation du Grand D茅fi Pierre Lavoie, Fondation les Amis d鈥橢liott, Fondation Lueur d鈥橢spoir pour Ayden, et le R茅seau de M茅decine G茅n茅tique Appliqu茅 du Fonds de recherche en sant茅 du Qu茅bec.

About Rady Children鈥檚 Institute for Genomic Medicine:

The Institute is leading the way in advancing precision healthcare for infants and children through genomic and systems medicine research. Discoveries at the Institute are enabling rapid diagnosis and targeted treatment of critically ill newborns and pediatric patients at Rady Children鈥檚 Hospital-San Diego and partner hospitals. The vision is to expand delivery of this integrated translational research process to enable the practice of precision pediatric medicine at children鈥檚 hospitals across California, the nation and the world. RCIGM is a subsidiary of Rady Children鈥檚 Hospital and Health Center. Learn more at . Follow us on and LinkedIn.

About the Research Institute of the MUHC

The of the UU直播 Health Centre (RI-MUHC) is a world-renowned biomedical and healthcare research centre. The Institute, which is affiliated with the Faculty of Medicine of UU直播, is the research arm of the 鈥� an academic health centre located in Montreal, Canada, that has a mandate to focus on complex care within its community. The RI-MUHC supports over 420 researchers and close to 1,200 research trainees devoted to a broad spectrum of fundamental, clinical and health outcomes research at the Glen and the Montreal General Hospital sites of the MUHC. Its research facilities offer a dynamic multidisciplinary environment that fosters collaboration and leverages discovery aimed at improving the health of individual patients across their lifespan. The RI-MUHC is supported in part by the Fonds de recherche du Qu茅bec 鈥� Sant茅 (FRQS).