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.


When Jake was just eight months old he crawled off the blanket where his mother, Tanja, had put him and began rubbing his forehead on the carpet. He continued to rub his forehead even when it became raw and bloody. This was when Tanja first suspected something was wrong with her son. The self-injuring behaviour worsened so severely that by the age of seven years Jake went to live in a specially designed care home: he was self-injuring thousands of times a day.

Although Jake had been diagnosed with Autism at the age of eighteen months, his parents questioned the diagnosis - they didn’t see that type of behaviour in other autistic children. So they continued to search for answers. Their diagnostic odyssey would last over sixteen years, until clinician-researchers at TIDE-BC, determined that Jake has an extremely rare PAK3 genetic mutation.


When Nolin was just three years old he became the first person in the world to be diagnosed with NANS deficiency, a genetic disorder that causes severe neonatal epilepsy, bone abnormalities, and developmental arrest. The problem lies in the body’s inability to make enough sialic acid, a sugar which provides building blocks for many processes in the body.

The diagnosis, made by the clinician-researchers at TIDE-BC, had a profound effect not only on Nolin’s access to care but also in providing support for his parents, Darlene and Frank.

NANS deficiency is a truly devastating condition. Nolin is missing a critical enzyme that affects the development of many of the body’s tissues and cells. As a result, he cannot hold up his head, sit, stand, eat orally, talk or see very well. He needs 24 hours of care, a feeding tube, is prone to airway infections and blood complications, in short, he is completely dependent on others.

Nolin is described along with 8 other individuals with NANS deficiency, a novel inborn error of metabolism, in a recent Nature Genetics article.

Together with the dieticians in BC Children's Hospital, we've created an exciting line-up of diet apps. These apps are designed to support families and children who suffer very rare disorders like: Maple Syrup Urine Disease, Pyridoxine dependent epilepsy, Phenylketonuria and 12 others.

You can read more about these apps and try them out via this link:



Logan is an 18-year old who loves to play hockey, swim with dolphins and take the occasional spin around Orlando Speedway. As part of his recent graduation events he participated in a seven day hiking trip in the Rocky Mountains, in a trail rider with his classmates and father close by. The fact that Logan has neurodegenerative disease which severely restricts his independent mobility does not stop him. As his father, Rick, says, “We just adapt and find a way to make it happen.”

Logan Miller has an ultra-rare disease – the cause of which has, for the past 14 years, remained undiagnosed. Now researchers believe they may be close to a diagnosis. In fact, the decision to enroll Logan into the genomics study has brought the Miller family the closest they’ve been to understanding their son’s disease since it first became apparent he was not developing at the same pace as his peers. He went on to suffer memory loss, muscle weakness and eye movement problems.

“We enrolled him because Logan has always wanted a diagnosis, and we want to know, not least because his illness is progressive,” said Debbie Miller, Logan’s mother. “This study seemed a good fit.”

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

Study Team: Dr. Sylvia Stockler (PI), Dr. Clara van Karnebeek (Co-PI), Dr. Kathryn Selby, Dr. Aspasia Michoulas, Dr. Mary Connolly, Sravan Jaggumantri, Alex Fergusan, Keiko Ueda, Chris Simonson, Francesca Zanotto
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.

Via the international PDE Consortium, TIDE has taken the lead in treating this metabolic epilepsy and continues to play a fundamental role in evidence generation. Soon the TIDE team will launch of an international REDCAp database to capture natural history and treatment outcome data to allow studies on new treatments (including arginine supplementation), ultimately to improve outcomes of affected individuals worldwide.
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).

Pyridoxine dependent epilepsy (PDE) is another rare condition, and data on a new metabolic treatment (lysine restricted diet) was recently published by the TIDE group showing positive effects (ie, a decrease in toxic biomarkers and improvement neurodevelopment and seizure control). Consequently, Dr. van Karnebeek, together with an international PDE consortium, has published guidelines for this new treatment. She spearheads the CIMDRN PDE registry, the aim of which is to capture Canadian patients with this condition and to assess their long term outcomes; this data will be merged with data from patients around the world.

CIMDRN will also collect data from numerous treatable IEM identified via universal newborn screening. Dr. Hilary Vallance, the director of the BC Neonatal Screening Program, plays an important role in CIMDRN data collections for long term follow-up of patients identified by Canadian newborn screening programs. Approximately 15 children are born a year in BC with conditions investigated by CIMDRN.

Funded by the Canadian Institutes for Health Research (CIHR), CIMDRN integrates nearly all biochemical genetics centers in Canada, and includes investigators with expertise in clinical care of patients with IEMs, as well as epidemiology, health services and policy and health economics.

Overall, the partnership between TIDE and centers within the CIMDRN framework will enable data gathering on treatments and health outcomes for a large group of highly specialized patients and provide the necessary evidence to improve outcomes and health care services for children with IEM and their families, thereby enabling a personalized approach in the care of rare diseases.
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.
To this family, I contribute my knowledge and skills for the efficient development and use of computational methods with which to identify pathogenic variants in timely manner. My ability to understand clinical, experimental and computational methods proved to be important in bridging the clinical and computational work. Specifically, I have devised optimal delivery of easy-to-understand bioinformatics candidate variant lists to clinicians, which had accelerated our team’s understanding and discovery tremendously. As well, I have uncovered many new pathogenic variants, which are currently at various stages of experimental validations.