• Stockler, Sylvia (Sylvia Stoeckler-Ipsiroglu, Sylvia Stöckler-Ipsiroglu)

    Titles
    Investigator, BC Children's Hospital
    Professor and Head, Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia
    Program Director, Biochemical Diseases, BC Children's Hospital
    Degrees / Designations
    MD
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    Phone
    604-875-2628
    Fax
    604-875-2349
    Lab Phone
    Mailing Address
    BC Children's Hospital
    Room K3-205, 4480 Oak Street
    Vancouver, BC V6H 3V4
    Affiliate Websites
    Research Areas
    • Pathophysiology and treatment of neurometabolic disorders
    • Cerebral creatine deficiency syndromes (GAMT, AGAT Creatine transporter (SLC6A8) deficiency)
    • Cerebral glucose deficiency syndromes (GLUT 1 Deficiency, PHHI, Fatty acid oxidation defects)
    • Epilepsy
    • Mental retardation
    Summary
    My research concentrates on the pathobiochemistry of genetic neurometabolic diseases. We are using an integrated approach based on clinical, biochemical, molecular genetic, magnetic resonance spectroscopy (MRS), and imaging analyses to study two disease groups as a model for this. First, creatine deficiency syndromes: three novel genetic disorders of creatine synthesis and transport in the brain. Clinical features include mental retardation, expressive speech delay, and epilepsy. We study the three diseases on all levels, from an epidemiological description of molecular defects to an evaluation of treatment. The second group are disorders of energy substrate depletion in the developing brain (fatty acid oxidation defects, persistent hyperinsulinemic hypoglycemia). We are interested in the potential of ketone bodies and anaplerotic substrates to prevent brain injury caused by this. Our paramount aim is to develop improved treatment strategies in both disease groups and extend them to other metabolic diseases of the brain.
    Current Projects

    Tackling mental retardation: Development of screening and diagnostic methods for the recognition of X-linked creatine transporter (CRTR) deficiency, a newly described mental retardation syndrome
    Mental retardation affects 2-3% of the general population. The majority of cases are genetic in origin but otherwise unexplained. About 70% of patients with unexplained mental retardation are males, suggesting a high contribution of X-linked disorders. Recent studies have shown that X-linked creatine transporter (CRTR) deficiency accounts for 2% of X-linked mental retardation. This equals the incidence of Fragile-X syndrome, which currently is considered the most frequent cause of X-linked mental retardation.

    Recently it has also been shown that patients with X-linked CRTR deficiency have a low ratio of urinary creatine to creatinine excretion. The BC Children's Hospital (BCCH) Biochemical Genetics Laboratory has now established a liquid chromatography/tandem mass spectrometry method for the measurement of both. This opens the exciting possibility of establishing a reliable, high throughput screening method for X-linked CRTR deficiency. Diagnosis will be confirmed by molecular genetic and functional creatine uptake studies in skin fibroblasts.

    Oral creatine substitution is effective in the treatment of some creatine deficiency syndromes (GAMT and AGAT deficiency), however, current protocols of oral creatine substitution for CRTR deficiency have not proven effective. So far, the limited number of known patients has made the search for better treatment difficult. This screening program will also help to overcome this obstacle.

    The final goal is to develop BCCH and CFRI as the North American diagnostic and research center for cerebral creatine deficiency syndromes.

    Metabolic neuroprotection by ketone bodies and anaplerotic substrates in a rat model of insulin-induced infantile hypoglycemia
    Severe recurrent hypoglycemia in infancy is a recognised pediatric condition with potential neurological sequeleae. Determinants of the severity of brain injury are incompletely understood. The developing vs. adult brain has a higher potential for the utilisation of alternative energy substrates and it has been suggested that an intact ketogenic response to low circulating glucose levels is a protective factor. Most conditions causing severe recurrent hypoglycemia in infancy (persistent hyperinsulinemic hypoglycemia of infancy, fatty acid oxidation defects) also disrupt this ketogenic response. We hypothesise that the supplementation of ketone bodies in these conditions may improve the neurological outcome.

    To investigate this neuroprotective effect and its limitations we will develop a model of hyperinsulinemic hypoglycemia in infant rats and study the effects of D-3-hydroxybutyrate administration. Based on recent analyses of the interconnections between pathways of energy metabolism and glutamate synthesis in the brain, we anticipate that ketone bodies may show biochemical limitations to sustaining glutamergic brain function and possibly neuronal survival. Current understanding suggests this could be patched by additional provision of anaplerotic substrates.

    Clinically, the aim of this project is to establish an experimental basis for a trial of ketones and anaplerotic substrates in conditions of recurrent severe hypoglycemia of infancy or related conditions. Experimentally, the model will lend itself to studies of the pathobiochemical significance of alternative energy substrate metabolism and anaplerotic pathways in the developing brain.

    Selected Publications

    Stockler-Ipsiroglu S, van Karnebeek C, Longo N, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes of 48 individuals and recommendations for diagnosis, treatment and monitoring. 2014 Jan;111(1):16-25.

    Randall DR, Colobong KE, Hemmelgarn H, Sinclair GB, Hetty E, Thomas A, Bodamer OA, Volkmar B, Fernhoff PM, Casey R, Chan AK, Mitchell G, Stockler S, Melancon S, Rupar T, Clarke LA.: Heparin cofactor II-thrombin complex: a biomarker of MPS disease. Mol Genet Metab. 2008 August;94(4):456-61.

    Horvath GA, Davidson AG, Stockler-Ipsiroglu SG, Lillquist YP, Waters PJ, Olpin S, Andresen BS, Palaty J, Nelson J, Vallance H.: Newborn screening for MCAD deficiency: experience of the first three years in British Columbia, Canada. Can J Public Health. 2008 Jul-Aug;99(4):276-80.

    Mercimek-Mahmutoglu S, Rami B, Feucht M, Herle M, Rittinger O, Stoeckler-Ipsiroglu S, Schober E.: Long-term follow up of the patients with congenital hyperinsulinism in Austria. J Pediatr Endocrinol Metab. 2008 June;21(6): 523-32.

    Huemer M, Födinger M, Bodamer OA, Mühl A, Herle M, Weigmann C, Ulmer H, Stöckler-Ipsiroglu S, Möslinger D.: Total homocysteine, B-vitamins and genetic polymorphisms in patients with classical phenylketonuria. Mol Genet Metab. 2008 May;94(1):46-51.

    Horvath GA, Stockler-Ipsiroglu SG, Salvarinova-Zivkovic R, Lillquist YP, Connolly M, Hyland K, Blau N, Rupar T, Waters PJ.: Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. Mol Genet Metab. 2008 May;94(1):127-31.

    Cerebral Creatine Deficiency Syndromes
    Original (Peer Reviewed) Articles
    Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S et al. GAMT deficiency. Features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 2006, Epub www.neurology.org and Neurology 2006; 67: in press. (Corresp Author)

    Item CB, Stockler-Ipsiroglu S, Willheim C, Muhl A, Bodamer OA. Use of denaturing HPLC to provide efficient detection of mutations causing guanidinoacetate methyltransferase deficiency. Mol Genet Metab. 2005 Sep-Oct; 86(1-2):328-34. Epub 2005 Jul 28. (Corresp Author)

    Item CB, Mercimek-Mahmutoglu S, Battini R, Edlinger-Horvat C, Stromberger C, Bodamer O, Mühl A, Vilaseca MA, Korall H, Stöckler-Ipsiroglu S. Characterisation of 7 novel mutations in seven patients with GAMT deficiency. Hum Mutat 2004; 23:524. (Corresp Author)

    Stromberger C, Bodamer O, Stöckler-Ipsiroglu S. Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inher Metab Dis 2003; 26:299-308. (Corresp Author)

    Book Articles
    Schütz PW and Stöckler-Ipsiroglu S. Creatine deficiency syndromes. In: Neurobiology of Disease. Gilman S ed; Elsevier Inc 2006, 41-49.

    Stöckler-Ipsiroglu S and Salomons GS. Creatine Deficiency Syndromes. In: Inborn Metabolic Diseases. Diagnosis and Treatment. Fernandes J, Saudubray JM, van den Berghe G (eds). Springer 4th ed 2006, 212-217.

    Stöckler-Ipsiroglu S, Battini R, de Grauw T, Schulze A. Disorders of creatine metabolism. In: Physician´s guide to the treatment and follow up of metabolic diseases. Blau N, Hoffmann GF, Leonard J, Clarke JTR. Springer Verlag, Heidelberg, Germany. 2006, 255-266.

    Cerebral Glucose Deficiency and Metabolic Epilepsies
    Original (Peer Reviewed) Articles
    Plecko B, Hikel C, Korenke GC, Schmitt B, Baumgartner M, Baumeister F, Jakobs C, Struys E, Erwa W, Stockler-Ipsiroglu S. Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics. 2005 Jun; 36(3):2005.

    Plecko B, Hoeger H, Jakobs C, Struys E, Stromberger C, Leschnik M, Muehl A, Stoeckler-Ipsiroglu S. Pipecolic acid concentrations in brain tissue of nutritional pyridoxine deficient rats. J Inher Metab Dis 2005; 28(5):689-93.

    Plecko B, Stöckler-Ipsiroglu S, Schober E, Harrer G, Mlynarik V, Gruber S, Moser E, Möslinger D, Silgoner H, Ipsiroglu O. Oral -hydroxybutyrate supplementation in two patients with persistent hyperinsulinemic hypoglycemia: Monitoring of b-hydroxybutyrate levels in blood, CSF and in the brain by in vivo proton magnetic resonance spectroscopy. Pediatric Research 2002; 52:301-306. (Corresp Author)

    Grants
    Honours & Awards

    Science Award, Best clinical work in 1996 (Lancet 348: 798-90, 1996), Austrian Pediatric Society - 1997
    Habilitation Award of the Georg August University of Göttingen for the best habilitation (PhD) thesis - 1996
    International Horst Bickel Award for Progress in Treatment of Inborn Errors of Metabolism: Creatine replacement therapy in the first patient with guanidinoacetate methyltransferase deficiency - 1995
    Science Award, Excellent Clinical Publication (J Pediatr 124: 601-604, 1994), Austrian Pediatric Society - 1995
    Language scholarship of the Società Dante Alighieri, Rome -1981

    Research Group Members

    Peter Schutz, MD - Postdoctoral fellow and graduate student (PhD)
    Saadet Mahmutoglu, MD - Biochemical diseases subspecialty fellow
    Graham Sinclair, PhD - Biochemical genetics fellow
    Marion Coulter-Mackie, PhD - Collaborator
    Hilary Vallance, MD, PhD - Collaborator
    Brett Casey, MD - Collaborator