• van Karnebeek, Clara


    Investigator, BC Children's Hospital
    Principal Investigator, Centre for Molecular Medicine and Therapeutics
    Affiliate Associate Professor, Division of Biochemical Diseases, Department of Pediatrics, Faculty of Medicine, University of British Columbia

    Degrees / Designations
    MD, PhD, FCCMG
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    604-875-2345 ext. 5500
    Lab Phone
    604-875-2345 ext. 5500
    Mailing Address
    BC Children’s Hospital

    Biochemical Diseases Clinic
    Rm K3-201 
    4480 Oak Street
    Vancouver, BC  V6H 3V4

    Affiliate Websites
    Research Areas
    • Discovery of novel gene defects via integrated genomics and metabolomics
    • Treatable inborn errors of metabolism causing intellectual disability and epilepsy
    • Clinical and digital tools for the prevention, enhanced diagnosis and treatment of intellectual disability

    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 Omics2TreatID (omics2treatid.org), 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 2 years, 400 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.

    Current Projects

    Treatable Intellectual Disability Endeavor in British Columbia: (TIDE-BC, www.tidebc.org). Role: co-founder & lead clinician scientist. With the funding obtained via the highly competitive Collaborative Area of Innovation grant (BC Children’s Hospital Foundation, Vancouver CA) of $2.25 million dollars, we currently are implementing the diagnostic TIDE protocol in the province of British Columbia to enhance early diagnosis of treatable inborn errors of metabolism. In the first year 5% of ID patients were found to suffer a disease we can treat to prevent brain damage and help them achieve optimal function. Our goal is to produce leading edge knowledge in the field of rare diseases and measurable improvements in child health through personalized medicine. Dr Stockler-Ipsiroglu and I coordinate the roles and input of a collaborative team of more than 30 scientists and clinicians. One of our most exciting projects within TIDE is the collaborative whole exome sequencing to discover new treatable intellectual disabilities; so far we have been successful in more than 4 families … with more to come.

    Collaborative Research in Pyridoxine Dependent Epilepsy, a rare metabolic epilepsy. Role: clinical researcher & organizer of the 2010 Vancouver Workshop and the 2011 / 2012 International Workshop to set up an international trial for ‘Lysine restriction in Pyridoxine Dependent Epilepsy’ with implementation of novel trial methodologies (project leader: Sylvia Stockler-Ipsiroglu, MD PhD). We have published the 1st study on the results of a new treatment for PDE, the lysine restricted diet and are now developing a worldwide study to produce more solid evidence for the effectiveness of this approach (www.pde-online.org)

    Creation and design of the website www.TreatableID.org with Apps for handheld devices, based on our Systematic review on Treatable Metabolic Disorders causing Intellectual Disability.  Performed in BC Children’s Hospital, University of British Columbia (Vancouver, CA) during the period 2009-2011 in collaboration with Sylvia Stockler-Ipsiroglu, MD PhD (neurometabolic specialist, principal applicant on this grant). Our evidence-based approach to rare diseases, i.e. the identification of treatable inborn errors of metabolism presenting with intellectual disability and grading the levels of evidence for therapeutic effect, is an innovation in this field. This Knowledge Translation & Transfer activity via modern-day digital tools with rigorous evaluation, has the potential to reach the all clinicians confronted with the challenging task to identify / rule out a treatable case in their ID patients. This App was published recently in the Orphanet Journal of Rare Diseases and has won numerous prizes. This activity lies at the basis of TIDE-BC.

    Selected Publications

    Salvarinova R, Ye CX, Rossi A, Biancheri R, Roland EH, Pavlidis P, Ross CJ, Tarailo-Graovac M, Wasserman WW, van Karnebeek CD. 2015. Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities. Neurogenetics 16(2):145-9. PMID: 25432320. DOI: 10.1007/s10048-014-0432-y.

    van Karnebeek C, Häberle J. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. Carbonic Anhydrase VA Deficiency. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. 2015 Apr 2. PMID: 25834911.

    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. [Epub ahead of print]. PMID: 25885783.

    Sayson B, Popurs MA, Lafek M, Berkow R, Stockler-Ipsiroglu S, van Karnebeek CD. 2015. Retrospective analysis supports algorithm as efficient diagnostic approach to treatable intellectual developmental disabilities. Mol Genet Metab . PMID: 25801009. DOI: 10.1016/j.ymgme.2015.03.001.

    Tarailo-Graovac M, Sinclair G, Stockler-Ipsiroglu S, Van Allen M, Rozmus J, Shyr C, Biancheri R, Oh T, Sayson B, Lafek M, Ross CJ, Robinson WP, Wasserman WW, Rossi A, van Karnebeek CD. The genotypic and phenotypic spectrum of PIGA deficiency. Orphanet J Rare Dis. 2015 Feb 27;10(1):23. doi: 10.1186/s13023-015-0243-8. PMID: 25885527.

    van Karnebeek CD and Jaggumantri S. 2015. Current treatment and management of pyridoxine-dependent epilepsy. Curr Treat Options Neurol 17(2):335,014-0335-0. PMID: 25639976. DOI: 10.1007/s11940-014-0335-0.

    van Karnebeek CD, Mohammadi T, Tsao N, Sinclair G, Sirrs S, Stockler S, Marra C. 2015. Health economic evaluation of plasma oxysterol screening in the diagnosis of niemann-pick type C disease among intellectually disabled using discrete event simulation. Mol Genet Metab 114(2):226-32. PMID: 25095726. DOI: 10.1016/j.ymgme.2014.07.004.

    Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, et al (van Karnebeek CD). 2015. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet 96(2):245-57. PMID: 25597510. PMCID: PMC4320260. DOI: 10.1016/j.ajhg.2014.12.013.

    Janer A, van Karnebeek CD, Sasarman F, Antonicka H, Al Ghamdi M, Shyr C, Dunbar M, Stockler-Ispiroglu S, Ross CJ, Vallance H, et al. 2015. RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness, and multiorgan involvement. Eur J Hum Genet . PMID: 25604853. DOI: 10.1038/ejhg.2014.293.

    Shyr C, Tarailo-Graovac M, Gottlieb M, Lee J, van Karnebeek C, Wasserman WW. 2014. FLAGS, frequently mutated genes in public exomes. BMC Med Genomics 7(1):64. PMID: 25466818. PMCID: PMC4267152. DOI: 10.1186/s12920-014-0064-y.

    Leach EL, Shevell M, Bowden K, Stockler-Ipsiroglu S, van Karnebeek C. 2014. Treatable inborn errors of metabolism presenting as cerebral palsy mimics: Systematic literature review. Orphanet J Rare Dis 9:197,014-0197-2. PMID: 25433678. PMCID: PMC4273454. DOI: 10.1186/s13023-014-0197-2.

    Stockler S, Corvera S, Lambright D, Fogarty K, Nosova E, Leonard D, Steinfeld R, Ackerley C, Shyr C, Au N, et al (van Karnebeek CD). 2014. Single point mutation in rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking. Orphanet J Rare Dis 9:141,014-0141-5. PMID: 25233840. PMCID: PMC4177245. DOI: 10.1186/s13023-014-0141-5.

    Armstrong L, Biancheri R, Shyr C, Rossi A, Sinclair G, Ross CJ, Tarailo-Graovac M, Wasserman WW, van Karnebeek CD. 2014. AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset. Neurogenetics 15(3):157-9. PMID: 24958424. DOI: 10.1007/s10048-014-0411-3.

    Dunbar M, Jaggumantri S, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. 2014. Treatment of X-linked creatine transporter (SLC6A8) deficiency: Systematic review of the literature and three new cases. Mol Genet Metab 112(4):259-74. PMID: 24953403. DOI: 10.1016/j.ymgme.2014.05.011.

    Stockler-Ipsiroglu S and van Karnebeek CD. 2014. Cerebral creatine deficiencies: A group of treatable intellectual developmental disorders. Semin Neurol 34(3):350-6. PMID: 25192512. DOI: 10.1055/s-0034-1386772.

    van Karnebeek C, Murphy T, Giannasi W, Thomas M, Connolly M, Stockler-Ipsiroglu S. 2014. Diagnostic value of a multidisciplinary clinic for intellectual disability. Can J Neurol Sci 41(3):333-45. PMID: 24718818.

    van Karnebeek CD, Shevell M, Zschocke J, Moeschler JB, Stockler S. 2014. 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 111(4):428-38. PMID: 24518794. DOI: 10.1016/j.ymgme.2014.01.011.

    van Karnebeek CD, Stockler-Ipsiroglu S, Jaggumantri S, Assmann B, Baxter P, Buhas D, Bok LA, Cheng B, Coughlin CR,2nd, Das AM, et al. 2014. Lysine-restricted diet as adjunct therapy for pyridoxine-dependent epilepsy: The PDE consortium consensus recommendations. JIMD Rep 15:1-11. PMID: 24748525. PMCID: PMC4270869. DOI: 10.1007/8904_2014_296.


    2015-2017: CAUSES Clinic,"Mining for Miracles," CoPI Jan Friedman, $2,500,000.

    2013-2018: CIHR Operating Grant - "Expanding the number of treatable intellectual disabilities through an integrated "-omics" approach," $772,999.

    2013-2015: Genome BC: Synergizing -omics to discover treatable intellectual disabilities.

    2012: The Canadian Society for MPS & Related Diseases “Morquio Better Project”, $50,000. 

    2011-2012: Bluma Tischler Postgraduate Fellowship Award, UBC. Detecting pyridoxine dependent epilepsies in neonates and infants: a treatable cause of medically refractory epilepsy and intellectual impairment, $20,400.

    2011-2016: Collaborative Area of Innovation, B.C.’s Children’s Hospital. “Treatable Intellectual Disability Endeavor in B.C. (TIDE-BC)." $2.25 million.

    2010-2011: Collaborative Area of Innovation BC Children’s Hospital Project (www.tidebc.org)“: Treatable Intellectual Disability Endeavor in BC. Project Development Grant, $25,000.

    2010-2011: Foundation Metakids, Netherlands, Development of evidence-based diagnostic protocol & digital tools for treatable intellectual disability, $35,000.

    2010-2011: BC Clinical Genomics Network: High throughput sequencing for treatable inborn errors of metabolism causing intellectual disability and epilepsy. A pilot study, $25,000.

    Honours & Awards
    • 2014 MSFHR 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
    Research Group Members

    Maja Tarailo-Graovac, PhD
    Casper Shyr, PhD candidate
    Bryan Sayson, BSc
    Sravan Jaggumantri, PhD
    Michelle Higginson, MSc
    Xiaohua Han
    Linhua Zhang, PhD
    Jessica Lee, PhD candidate
    Hilal Al-Shekaili, PhD candidate
    Dallas Generaux, MSc