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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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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DiagnClinic
In our second newsletter of 2013, we focus on the value of collaborative medicine to provide individualized patient care. Initiatives such as the TIDE Complex Diagnostic Clinic (TCDC), unite the expertise of over 25 clinical and laboratory specialists to provide a causal diagnosis for children with complex neurologic conditions who remain a mystery despite endless clinic visits and the “million dollar” work up. The TCDC is meticulously prepared and run: during one morning, 3 to 4 patients are each evaluated by several specialists, who participate in the clinic on a rotational basis. The children’s cases are then discussed during multidisciplinary rounds to formulate a differential diagnosis and plan for investigations.

In a manuscript recently submitted by the TCDC team for publication in the journal Genetics in Medicine, we report our experience with 7 clinics held over the first 16 months since its establishment in 2011. For the 24 children assessed in these clinics (seen by up to 10 specialist services prior to the TCDC), the diagnostic yield was higher than expected with confirmed and working diagnoses in 9 (38%) and 11 (46%) children respectively. Costs savings resulted from fewer trips to the hospital and fewer tests resulting from more streamlined evaluations.
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Mason was just 2 months old when he was put on anti-seizure medication. It quickly became evident that he was unresponsive to the medication and only responded to the vitamin B-6 (pyridoxine) and folinic acid therapy. However, once diagnosed with pyridoxine dependent epilepsy (PDE), a metabolic form of epilepsy, Mason began treatment which changed the course of both his life and his mother’s. Without realizing it, Mason has helped lead the way for other children suffering from the same inborn error of metabolism. His treatment -a lysine restricted diet- is a medical therapy pioneered though TIDE-BC. Mason was among the first patients with PDE worldwide to be successfully treated by by this medical diet in conjunction with vitamin B6, a therapy which has been developed and studied by the TIDE-BC team in collaboration with German neurologists.

READ MASON'S FULL STORY HERE

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TIDE has presented it's first year results in december 2012. This interim evaluation comes at 15 months of full TIDE operations, reporting deliverables and milestones achieved during the first term of our 36-month research and care program. While this is a very short period over which to demonstrate improvement of child health and bridge the ring-road between CFRI/CMMT and the hospital, most outcomes integral to supporting TIDE’s vision have been achieved and even exceeded during this time.
The key achievements shown in the interim evaluation lay the foundation for TIDE’s most sustainable activities into the future. Our team rides this wave of innovation and collaboration with only one mission: to improve the health and wellbeing of children and youth in British Columbia.

The evaluation report is downloadable here as pdf file (53 pages, 5MB).

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During a meeting with TIDE BC & Child Health BC on September 28th, the TIDE BC Protocol (for diagnostic evaluation of Children with Intellectual Disability/Global Developmental Delay of unknown cause) was finalized based on the valuable input of a large group of BC pediatricians. The Protocol has been send to the first group of pediatricians this week and can be viewed and downloaded on this site in the "TIDE for Physicians" section. TIDE-BC is continuing to work closely with Child Health BC and currently working with the BC Pediatric Society to further the roll out of the TIDE-BC protocol to pediatricians throughout the province.
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During the Canadian Association of Paediatric Health Centres Conference (held in Vancouver Oct 28-31, 2012) TIDE BC presented four posters highlighting several of TIDE’s accomplishments


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TIDE-BC is demonstrating an impact for families. Five-year old Nathan’s life has improved immensely, as has his family’s. At the age of three, suffering from developmental delay, autism and seizures but undiagnosed despite having seen 15 specialists, TIDE-BC first tier testing revealed creatine in Nathan’s urine. He was referred to TIDE-BC at BCCH where he was diagnosed with Creatine Transporter Deficiency, one of the rare yet treatable disorders causing intellectual disability for which the TIDE program promotes active screening.

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Translating Research into Better Care
Drs. Clara van Karnebeek and Ramona Salvarinova presented on behalf of the TideX team the first report of a newly discovered inborn error of metabolism, carbonic anhydrase 5A (CA5A) deficiency at the September 2012 International Society for the Study of Inborn Errors of Metabolism (SSIEM) meeting. This enzyme is pivotal for normal cell function. The impact for patients is significant as the genetic condition is treatable. The list of treatable intellectual disabilities has now expanded to 82. Early recognition of the disease, which causes life-threatening symptoms at birth, allows intervention to prevent brain damage. This discovery is a breakthrough, as it allows us to better understand how the body produces energy and neutralizes toxins.

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Within 1 year of establishing its research and clinical care program, TIDE-BC:
  • discovers a new Treatable Intellectual Disability which expands our understanding of intermediary metabolism (read more...)
  • is the 1st world-wide to report promising results of new therapy for a metabolic epilepsy (read more…)
  • publishes on the www.treatable-id.org App as clinical tool to improve care for diseases (read more…)
The above is proof that TIDE succeeds in the missions they set out to accomplish in 2011:
  1. bridging the Ringroad & Translation of Knowledge into Better Care;
  2. increasing the number of treatable intellectual disabilities, from 81 in 2011 to 82 (and counting) in 2012;
  3. establishing global leadership in the field or rare metabolic diseases.
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It has been six months since TIDE BC was officially launched and Dr. Clara van Karnebeek and her TIDE BC partners have already presented some of their ground-breaking work at the Garrod Association Conference, held in the first week of May, in Winnipeg. The Garrod Association is made up of members of the Canadian Association Of Centers For The Management of Hereditary Metabolic Disorders and represents over one hundred top-tier clinicians, researchers and decision-makers in the field of inherited metabolic disorders. Dr van Karnebeek presented both the methods and the progress made so far in TIDE BCs evidence-based diagnostic protocol that is used to quickly identify children with treatable forms of global developmental delay/intellectual disability, also known as treatable IEMs.

First presented was TIDE BCs multi-level diagnostic method, with the supporting Web App also detailed:

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TIDE BC's preliminary success in finding patients with treatable IEMs was highlighted.

In the first 6 months, 130 patients were enrolled in the TIDE BC program, with 25% of these patients having a confirmed, and 17%, a probable, diagnosis. Of these, 10 patients were identified with a treatable metabolic condition and are now on track for a treatment program that supports their ability to achieve a greater level of development and intellectual ability. What is clear from these early results is that this novel approach has the potential to improve outcomes of many children who would have unnecessarily developed significant developmental and intellectual disabilities.
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TIDE Lab
Seventeen of the 81treatable causes of intellectual disability included in the TIDE-BC protocol can be diagnosed through the analysis of amino acids in plasma. The Biochemical Genetics Laboratory at BC Children’s Hospital routinely measures amino acids in >2000 plasma samples per year to investigate children for these, and related metabolic disorders. At an analysis time of almost 4 hours per sample, the current HPLC method has reached capacity.
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