Exome sequencing and the management of neurometabolic disorders” , download article here

The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource, download article here.

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A study is currently underway at TIDE, designed to evaluate the safety and efficacy of a novel treatment for glucose transporter deficiency syndrome (Glut1-DS), a rare genetic epilepsy caused by insufficient transport of sugar into the brain, often resulting in developmental delays. A ketogenic diet is standard treatment but in some cases this does not control the seizures and movement disorder. Triheptanoin/C7 oil could provide an alternative source of fuel for the brain, thereby improving brain function and development. In collaboration with Ultragenyx Inc, the company supplying the investigational drug, the study, designed by the TIDE team, is using innovative trial methodology for rare diseases and has obtained approvals from Health Canada and REB. The first patient was enrolled on April 15th and the next phase protocols for further clinical development of Triheptanoin are currently being planned. If successful, this personalized approach to treating Glut1-DS could serve as a model for eliminating seizures and side effects in other types of hard-to-treat epilepsies.

The study is actively recruiting GLUT1-DS patients across Canada Interested?
Please contact us via email: tide-bc@cw.bc.ca

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The Lysine –Restricted Diet as Novel Add-On Therapy for Pyridoxine Dependent Epilepsy: PDE Consortium’s Consensus Recommendations

Among the most recent TIDE publications are the consensus recommendations for lysine –restricted diet as new add-on therapy for PDE. This paper is the result of several international PDE Consortium Workshops (2010-2013), a platform uniting expert physicians and scientists in the field of this metabolic epilepsy. Published in JIMD Reports, these Recommendations aim to standardize the implementation and monitoring of patients using the new diet in addition to vitamin B6 treatment, with the goal of improving neurodevelopmental outcomes: about 75% of patients with PDE due to antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability despite receiving treatment for seizures. The 2012, a landmark paper by Dr. Clara van Karnebeek in collaboration with Canadian, German (Dr. Hans Hartmann and colleagues) and USA (Dr. Johan Van Hove and colleagues) centers, showed that adjunctive treatment with a lysine-restricted diet is safe, and prevents brain damage via lowering toxic lysine intermediates in the brain. Potential benefits included seizure control and improved psychomotor development in this patient population.
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CIMDRN-Eng-Burgundy
From the 3rd through 5th of April a group of investigators from the University of Ottawa (Dr. Beth Potter, PI, Sara Khangura, manager, the Canadian Inherited Metabolic Diseases Research Network (CIMDRN), Monica Hernandez, REDCap manager and Kylie Tingley, PhD student), representing CIMDRN, visited the Biochemical Diseases team at BC Children’s Hospital, with the objective of discussing a research initiative on PKU to TIDE researchers Drs, Sylvia Stockler, Clara van Karnebeek and Hilary Vallance, who are Vancouver-based co-PIs in CIMDRN. BCCH is among the first Canadian sites to have received ethics review board approval for enrolment of patients in an observational database designed to capture long term outcomes of patients with rare inborn errors of metabolism (IEM). During CIMDRN’s visit, Dr. Potter presented the Network objectives and goals to patients and their families at the BC CanPKU Day (a yearly event for PKU families) together with Dr. Sylvia Stockler, who presented an overview of ongoing clinical studies conducted at the Vancouver campus for and with patients with PKU. The Vancouver team has enrolled the first patients in the PKU database. Dr. Nataliya Yuskiv is coordinating patient enrollment.

PKU, as one of the most frequent, treatable intellectual disabilities, is a CIMDRN priority disease. In BC alone there are approximately 300 individuals, ranging in age from 0-50 years, diagnosed with PKU and every year approximately 4 children are born with this condition province-wide.

Other CIMDRN Initiatives
CIMDRN also includes databases for ultra-rare conditions. Guanidinoacetate methyltransferase deficiency (GAMT) is a treatable intellectual disability with only 80 patients known worldwide. Canada has 8 patients whose longitudinal outcomes will be captured by a CIMDRN database. The database is spearheaded by Dr. Sylvia Stockler who first described this disease in 1996 and recently conducted an international survey on treatments and long term outcomes including 48 patients with this disease (see report last tide newsletter).
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MajaTarailoGraovac
Who I Am
I am a geneticist who combines knowledge and training in biochemistry, medical genetics, cell biology, bioinformatics, arts and teaching to accelerate discovery of new pathogenic variants of known and unknown genes that lead to disease, using whole exome sequencing (WES) and whole genome sequencing (WGS) methods.

What I do for TIDE
I am leading Wasserman’s group in applied genome analysis efforts to develop efficient methods with which to utilize next generation sequencing (NGS) advances and facilitate their translation into clinical practice. As a member of TIDE’s computational research team, we have successfully established a computational pipeline for high throughput processing of sequencing data, variant calls, variant prioritization and optimal delivery of visual and understandable candidate variant lists for clinicians. Currently, using this pipeline in our trio-based analysis (father-mother-child), we are able to process raw fastq sequencing files and deliver an annotated list of variants to clinicians in 1-2 days (8-16 hours).

Special accomplishments for TIDE
At TIDE, we work as a family to combine our strengths for timely diagnosis of rare genetic diseases. We work around the clock with hopes of discovering new/optimal treatments thereby improving lives of patients and their families at BCCH and beyond.
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The TIDEX team publishes their new discovery: "Carbonic anhydrase VA deficiency as novel and treatable cause of hyperammonemia in the young child" in the American Journal of Human Genetics, February 2014 (click here for the Epub ahead of print).

newborn
Read more about the research of our UBC team in collaboration with colleagues in the USA, UK, and Australia, via the UBC Faculty of Medicine website ("Genetic discovery helps newborns beat a life-threatening condition").



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While it’s true that having a child will change your life in ways you cannot possibly imagine, for Krystal Shipley this saying was to have a very special meaning. Her now 3-year old son, Azyac, is thought to be the only person alive with a rare genetic condition called RMND1 deficiency, which causes a type of fatal mitochondrial disease. Diagnosed by the physicians at BC Children’s TIDE-BC program when he was two years old – Ayzac is also helping move medical science forward. “He’s my hero” Krystal said.

READ AYZAC'S FULL STORY HERE…


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This November, Dr. Sylvia Stocker and TIDE investigators Drs. Clara van Karnebeek, Theresa Newlove and Nataliya Yuskiv, together with an international team of investigators, have had a landmark paper on GAMT deficiency accepted for publication in Molecular Genetics and Metabolism. The article presents follow-up data on 48 GAMT-deficient patients. This is the largest cohort described in the 19 years since the discovery of this ultra-rare disease by Dr. Stockler and a team of pediatric neurologists, biochemists and physicists in Germany.

GAMT deficiency is an inborn error of creatine synthesis, which results in intellectual and motor disability, autism, and epilepsy. This paper details potentials and limitations of the currently available treatment modalities (creatine and ornithine supplements and dietary arginine restriction) and clinical outcomes monitored from several months up to 16 years. It discusses the influence of the age at treatment onset, making the case that it is much better to diagnose and initiate a treatment very early, e.g. within the first weeks/months of life.
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Recently, Dr. Carlo Marra, Pharmaceutical Sciences, UBC, together with Dr. van Karnebeek and colleagues at UBC, completed a paper detailing the health economic analysis of a new diagnostic screening method for early diagnosis of Niemann Pick type C (NP-C) disease in patients with intellectual disability (ID). The authors show that screening this patient population as early as possible for NP-C, using a novel oxysterol method, provides a cost benefit over selective testing done later in a child’s development using molecular analysis and invasive skin biopsies, which is current practice.
Most importantly, application of this innovative oxysterol methodology as a screening approach among intellectually disabled children, reduces diagnostic delay, which, in patients with NP-C, is critical given the neurodegenerative and potentially life-threatening nature of the disease: Early diagnosis of NP-C is essential, as it facilitates early treatment with Miglustat and prevention of brain damage and severe impairment. Considered rare and potentially fatal, NP-C has an estimated prevalence of roughly 1 in 120,000 live births, however, it is often missed or underdiagnosed due to the its heteroegenous clinical presentation.
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