Clara van Karnebeek
About the TIDE research program: www.tidebc.org
Early recognition of rare but treatable genetic diseases in children is the key to preventing certain forms of intellectual disability.
“Intellectual disabilities are no longer necessarily an unchangeable fate,” says Dr. van Karnebeek. “Today, new tools allow us to diagnose and treat specific genetic conditions causing developmental delay and intellectual disability, previously thought to be permanent.”
Dr. van Karnebeek’s research is aimed at discovering new inborn errors of metabolism, a class of genetic diseases that is particularly amenable to treatment. Her team uses a multidisciplinary approach involving the study of three “-omics” in patients: phenomics, their physical and biochemical properties, genomics, their genetic information, and metabolomics, their metabolite profiles. She established two large collaborative efforts, the Treatable Intellectual Disability Endeavor in BC (TIDEBC.org with Sylvia Stockler), and the international TIDEX Study aimed at harnessing these new technologies for the discovery of genetic defects in children who present with intellectual disabilities and providing clinicians the tools for early recognition and management.
Dr. van Karnebeek and her team already successfully identified a number of these defects, developed new treatments and were able to enhance identification of these diseases in BC Children’s Hospital. Over the past 4 years, more than 500 children with intellectual disability were systematically screened and 5% were identified to have treatable condition; treatment in these cases improved behavior, cognition and often changed the lives of the whole family.
These diagnostic tools – a protocol supported by the Treatable-ID.org App - are now used by physicians around the world, allowing them to recognize diseases in newborns and treat these vulnerable patients before they suffer important brain damage.
Dr. van Karnebeek’s team has discovered 11 novel human diseases, including carbonic anhydrase VA deficiency (presenting with a life-threatening hyperammonemia amenable to treatment with carglumic acid and medical diet) as well as NANS deficiency (a sialic acid metabolism defect presenting with skeletal and brain abnormalities and brain, for which therapy is being developed). In May 2016, the TIDEX genomics discovery study will be published in a major medical journal reporting a diagnostic yield of 90% in 41 families with unexplained neurometabolic phenotypes; most importantly the study demonstrates personalized medicine as a genomic diagnosis enables targeted therapy for improved outcomes in 44%.
MAJOR ACHIEVEMENTS & PUBLICATIONS
Canadian Organization for Rare Diseases Scientific Award - 2016
Michael Smith Foundation for Health Research Scholar Award - 2014
IG Maud Menten New Principal Investigator Finalist Prize (CIHR) – 2013
Digital Health Innovation Summit Award - 2012
Bluma Tischler Fellowship Research Award - 2011
Laura McRae Award for Excellence in Pediatrics - 2011
van Karnebeek CD, Bonafé L, Wen XY et al.NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genetics 2016,doi:10.1038/ng.3578
Tarailo-Graovac M, Shyr C, Ross C, et al, van Karnebeek CD.Exome sequencing and the management of neurometabolic disorders. New Engl J Med 2016:May 25th
Cameron JM, Shyr C, Zhang L, Drögemöller B, Ross CJ, Wasserman WW, Wevers RA, Rodenburg RJ, Gupte G, Preece MA, van Karnebeek CD. Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis. Molec Genet Metab 2016 Mar 4. pii: S1096-7192(16)30021-X. doi: 10.1016/j.ymgme.2016.03.001
Horvath G, Demos M, Shyr C, Matthews A, Zhang L, Race S, Stockler-Ipsiroglu S, Van Allen MI, Mancarci O, Toker L, Pavlidis P, Ross CJ, Wasserman WW, Trump N, Heales S, Pope S, Cross JH, van Karnebeek CDMSecondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: a potential treatment target?Molec Genet Metab 2016 Jan;117:42-48 (IF 2.6).
Langlois S, Tarailo-Graovac M, Sayson B, Drögemöller B, Swenerton A, Ross CJ, Wasserman WW, van Karnebeek CD. De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.Eur J Hum Genet.2015 Oct 21. doi: 10.1038/ejhg.2015.217. [Epub ahead of print] (IF 4.3).
Jaggumantri S, Dunbar M, Edgar V, Mignone C, Newlove T, Elango R, Collet JP, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. Treatment of Creatine Transporter (SLC6A8) Deficiency With Oral S-Adenosyl Methionine as Adjunct to L-arginine, Glycine, and Creatine Supplements.Pediatr Neurol.2015 Oct;53(4):360-363.e2. doi:
Boycott K, Hartley T, Adam S, Francois Bernier3, Karen Chong4,5, Bridget A. Fernandez6, Jan M. Friedman2, Michael T. Geraghty1, Stacey Hume7, Bartha Knoppers8, Anne-Marie Laberge9, Jacek Majewski10, Roberto Mendoza-Londono4, M. Stephen Meyn4,11, Jacques L. Michaud9, Tanya N. Nelson12, Julie Richer1, Bekim Sadikovic13, David L. Skidmore14, Tracy Stockley15, Sherry Taylor7, van Karnebeek CD, Zawati M, Lauzon J, Armour C (on behalf of the Canadian College of Medical Geneticists) The clinical application of genome-wide sequencing for monogenic diseases in Canada Position Statement of the Canadian College of Medical Geneticists. J Med Genet.2015 Jul;52(7):431-7. doi: 10.1136/jmedgenet-2015-103144
Sirrs S, van Karnebeek CD, Peng X, Shyr C, Tarailo-Graovac M, Mandal R, Testa D, Dubin D, Carbonetti G, Glynn SE, Sayson B, Robinson WP, Han B, Wishart D, Ross CJ, Wasserman WW, Hurwitz TA, Sinclair G, Kaczocha M. Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.Orphanet J Rare Dis.2015 Mar 28;10(1):38
van Karnebeek CD, Sly WS et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet.2014;94:453-61.
“UBC scientist helps physicians diagnose a life-threatening disease in newborns”, Feature by UBC Faculty of Medicine, February 14 2014. http://www.med.ubc.ca/ubc-scientist-helps-physicians-diagnose-a-life-threatening-disease-in-newborns/
Stockler-Ipsiroglu S, Nahdi S, van Karnebeek C. Introduction of the Tide Protocol to screen children for treatable intellectual disability: first evaluation of protocol use by community pediatricians in British Columbia. BCMJ (http://www.bcmj.org).2015 Nov, 57(9):387-393.
van Karnebeek, CDM, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab.2014 (ePub ahead of print).
Michelle K Demos, Clara DM van Karnebeek, Colin JD Ross, Shelin Adam, Yaoqing Shen, Shing Hei Zhan, Casper Shyr, Gabriella Horvath, Mohnish Suri, Alan Fryer, Steven JM Jones and Jan M Friedman. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet Journal of Rare Diseases 2014, 9:15 doi:10.1186/1750-1172-9-15
van Karnebeek CD, Stockler S.Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012 Mar;105(3):368-81.
van Karnebeek C, Houben R, Lafek M, Giannasi W, Stockler S. The treatable intellectual disability APP www.treatable-id.org: a digital tool to enhance diagnosis and care for rare diseases.Orphanet Journal of Rare Diseases. 2012, 7:47.
van Karnebeek C, Hartmann H, Jaggumantri S, Bok L, Cheng B, Connolly M, Coughlin C, Das A, Gospe S, Jakobs C, van der Lee H, Mercimek-Mahmutoglu S, Meyer U, Struyst E, Sinclair G, Van Hove J, Collet JP, Plecko B, Stockler S. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence & future trials. Mol Genet Metab 2012 Nov;107(3):335-44.