BC Children's Hospital Research Institute is pleased to congratulate the recipients of the 2018 Outstanding Achievement Awards and the 2018 BCCHR Studentships and Fellowships.
Newborn screening is designed to identify infants with treatable rare disorders at birth in order to start therapies before the infants get sick. These disorders can lead to developmental disability, growth failure, liver disease, seizures, and even death if untreated. The investigation of potential new candidate disorders for screening, evaluation of new screening tests or improvement of existing methods, and the measurement of the long-term effectiveness of screening to improve health are all active aspects of my research.
We have a focus on disorders affecting the use of fats as an energy source and a variant of one of these disorders that is common to coastal BC First Nations. This variant is associated with an increased risk of infant death, but may also have benefits related to traditional diets.. Investigation of this variant will lead to a better understanding of its clinical impact and help to identify effective interventions.
The p.P479L variant in CPT1A is associated with infectious disease in a BC First Nation
Paediatrics & Child Health
Graham Sinclair and Sorcha Collins and Laura Arbour and Hilary Vallance
Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B12 status compared with pregnant women of European ethnicity.
The British journal of nutrition
Schroder TH, Sinclair G, Mattman A, Jung B, Barr SI, Vallance HD, Lamers Y
De Novo Mutations in YWHAG Cause Early-Onset Epilepsy.
American journal of human genetics
Guella I, McKenzie MB, Evans DM, Buerki SE, Toyota EB, Van Allen MI, Epilepsy Genomics Study, Suri M, Elmslie F, Farrer MJ
Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy.
American journal of human genetics
Lehman A, Thouta S, Mancini GMS, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R, CAUSES Study, EPGEN Study, Guella I, Claydon T
A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy-Expanding NDST1 syndrome.
American journal of medical genetics. Part A
Armstrong L, Tarailo-Graovac M, Sinclair G, Seath KI, Wasserman WW, Ross CJ, van Karnebeek CD
Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation.
Cold Spring Harbor molecular case studies
Bourne SC, Townsend KN, Shyr C, Matthews A, Lear SA, Attariwala R, Lehman A, Wasserman WW, van Karnebeek C, Sinclair G, Vallance H, Gibson WT
A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening.
Sinclair GB, van Karnebeek CD, Ester M, Boyd F, Nelson T, Stockler-Ipsiroglu S, Vallance H
Exome Sequencing and the Management of Neurometabolic Disorders.
Tarailo-Graovac M, Shyr C, Ross CJ, Horvath GA, Salvarinova R, Ye XC, Zhang LH, Bhavsar AP, Lee JJ, Drögemöller BI, Abdelsayed M, Alfadhel M, Armstrong L, Baumgartner MR, Burda P, Connolly MB, Cameron J, Demos M, Dewan T, Dionne J
Reference interval of methylmalonic acid concentrations in dried blood spots of healthy, term newborns to facilitate neonatal screening of vitamin B12 deficiency.
Schroder TH, Mattman A, Sinclair G, Vallance HD, Lamers Y
Health economic evaluation of plasma oxysterol screening in the diagnosis of Niemann-Pick Type C disease among intellectually disabled using discrete event simulation.
van Karnebeek CD, Mohammadi T, Tsao N, Sinclair G, Sirrs S, Stockler S, Marra C
Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.
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
The genotypic and phenotypic spectrum of PIGA deficiency.
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
AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset.
Armstrong L, Biancheri R, Shyr C, Rossi A, Sinclair G, Ross CJ, Tarailo-Graovac M, Wasserman WW, van Karnebeek CD
Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.
van Karnebeek CD, Sly WS, Ross CJ, Salvarinova R, Yaplito-Lee J, Santra S, Shyr C, Horvath GA, Eydoux P, Lehman AM, Bernard V, Newlove T, Ukpeh H, Chakrapani A, Preece MA, Ball S, Pitt J, Vallance HD, Coulter-Mackie M, Nguyen H
Performance of serum and dried blood spot acylcarnitine profiles for detection of fatty acid ß-oxidation disorders in adult patients with rhabdomyolysis.
Al-Thihli K, Sinclair G, Sirrs S, Mezei M, Nelson J, Vallance H
Detection of a novel intragenic rearrangement in the creatine transporter gene by next generation sequencing.
Yu H, van Karnebeek C, Sinclair G, Hill A, Cui H, Zhang VW, Wong LJ
Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations.
Sinclair GB, Collins S, Popescu O, McFadden D, Arbour L, Vallance HD
Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials.
van Karnebeek CD, Hartmann H, Jaggumantri S, Bok LA, Cheng B, Connolly M, Coughlin CR 2nd, Das AM, Gospe SM Jr, Jakobs C, van der Lee JH, Mercimek-Mahmutoglu S, Meyer U, Struys E, Sinclair G, Van Hove J, Collet JP, Plecko BR, Stockler S
Guanidinoacetate methyltransferase deficiency: first steps to newborn screening for a treatable neurometabolic disease.
Mercimek-Mahmutoglu S, Sinclair G, van Dooren SJ, Kanhai W, Ashcraft P, Michel OJ, Nelson J, Betsalel OT, Sweetman L, Jakobs C, Salomons GS
Enhanced interpretation of newborn screening results without analyte cutoff values.
Marquardt G, Currier R, McHugh DM, Gavrilov D, Magera MJ, Matern D, Oglesbee D, Raymond K, Rinaldo P, Smith EH, Tortorelli S, Turgeon CT, Lorey F, Wilcken B, Wiley V, Greed LC, Lewis B, Boemer F, Schoos R, Marie S
The use of parenteral nutrition for the management of PKU patient undergoing chemotherapy for lymphoma: a case report.
Salvarinova-Zivkovic R, Hartnett C, Sinclair G, Dix D, Horvath G, Lillquist Y, Stockler-Ipsiroglu S
Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency.
Mercimek-Mahmutoglu S, Dunbar M, Friesen A, Garret S, Hartnett C, Huh L, Sinclair G, Stockler S, Wellington S, Pouwels PJ, Salomons GS, Jakobs C
Protective effects of d-3-hydroxybutyrate and propionate during hypoglycemic coma: clinical and biochemical insights from infant rats.
Schutz PW, Struys EA, Sinclair G, Stockler S
Glycine cleavage enzyme complex: molecular cloning and expression of the H-protein cDNA from cultured human skin fibroblasts.
Zay A, Choy FY, Patrick C, Sinclair G
Infantile cardioencephalopathy due to a COX15 gene defect: report and review.
Alfadhel M, Lillquist YP, Waters PJ, Sinclair G, Struys E, McFadden D, Hendson G, Hyams L, Shoffner J, Vallance HD
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.
McHugh D, Cameron CA, Abdenur JE, Abdulrahman M, Adair O, Al Nuaimi SA, Åhlman H, Allen JJ, Antonozzi I, Archer S, Au S, Auray-Blais C, Baker M, Bamforth F, Beckmann K, Pino GB, Berberich SL, Binard R, Boemer F, Bonham J
Treatment of intractable epilepsy in a female with SLC6A8 deficiency.
Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ, Horvath GA, Lowry N, Salomons GS, Casey B, Sinclair G, Davis C, Jakobs C, Stockler-Ipsiroglu S
Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut.
Collins SA, Sinclair G, McIntosh S, Bamforth F, Thompson R, Sobol I, Osborne G, Corriveau A, Santos M, Hanley B, Greenberg CR, Vallance H, Arbour L
The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations.
Greenberg CR, Dilling LA, Thompson GR, Seargeant LE, Haworth JC, Phillips S, Chan A, Vallance HD, Waters PJ, Sinclair G, Lillquist Y, Wanders RJ, Olpin SE
Heparin cofactor II-thrombin complex: a biomarker of MPS disease.
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
Generation of a conditional knockout of murine glucocerebrosidase: utility for the study of Gaucher disease.
Sinclair GB, Jevon G, Colobong KE, Randall DR, Choy FY, Clarke LA
Heterologous expression and characterization of a rare Gaucher disease mutation (c.481C > T) from a Canadian aboriginal population using archival tissue samples.
Sinclair G, Choy FY, Ferreira P
Second-Tier Testing for Newborn Screening
The performance of newborn screening programs can be defined by the positive predictive value (PPV) of the screening tests, a major component of which is the false positive rate. Traditional approaches to screening for some disorders have an unacceptable false positive rate, but attempts to minimize this rate by raising screening cutoffs can lead to increased false negative rates and the associated devastating outcomes of a missed case. We have developed a number of second-tier screening tests, sampled from the same original newborn screening bloodspot, as an approach to reduce false positive rates without negatively affecting the sensitivity of testing. Our work involves the development of a number of mass spectrometry-based testing approaches and evaluation of the performance impacts of these tests in routine use. To date, we have implemented second-tier testing for congenital adrenal hyperplasia (CAH) and Maple Syrup Urine Disease (MSUD) and have methods in development for Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), and Homocystinuria (HCY).
GAMT Deficiency Screening
Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited disorder of creatine biosynthesis that leads to severe neurological complications in affected children. Treatment with supplemental creatine and other dietary restrictions has been shown to be effective when initiated early. This makes GAMT deficiency a potential candidate for newborn screening. We are investigating the carrier frequency for GAMT deficiency in BC to determine a theoretical disease incidence and evaluating the measurement of guanidinoacetate (GAA) in bloodspots as a potential approach to population-wide newborn screening for this treatable disorder.
CPT1a P479L Variant
The carnitine palmitoyltransferase 1A (CPT1a) p.P479L variant has recently been found to be common in coastal First Nations communities in BC and also in aboriginal populations in Alaska, NWT, Nunavut, and Greenland. CPT1a is a central enzyme in fatty acid oxidation and is required for import of fatty acids into the mitochondrion to be utilized as an energy source. This variant (p.P479L) was first identified in individuals with symptoms suggestive of a fatty acid oxidation disorder and has been shown to decrease CPT1a activity in vitro. We have performed a population based retrospective study in BC to confirm that the variant is common to coastal communities and is associated with a small increased risk in sudden unexpected death in infancy. Similar results have been found in Nunavut and Alaska. There is evidence, however, that this variant is also associated with improved plasma lipid profiles and obesity markers in adults suggesting a selective advantage, possibly related to alterations in the regulation of enzyme activity. We are continuing to investigate both the potential harms and benefits of this variant through prospective studies with community participants and basic biochemical investigations using in vitro methods to better understand the biochemical and clinical implications of this common variant.Grants
BC Children's Hospital Telethon Competition; Determination of the incidence and natural history of carnitine palmitoyltransferase I deficiency in BC First Nations; COMP; $22,000CDN; Principal Investigator: Hilary Vallance; Coinvestigators: Graham Sinclair, Laura Arbour.
BC Children's Hospital Telethon Competition: Development of methods for screening X-linked creatine transporter deficiency (X-CRTRD) in mental retardation.; COMP; $9,910 CDN; Principal Investigator: Sylvia Stockler; Coinvestigators: Hilary Vallance, Graham Sinclair.Honours & Awards
2004 Garrod Association Biochemical Genetics Fellowship; $25,000CDN
2004 Bluma Tischler Postdoctoral Fellowship; $22,500CDNResearch Group Members
Michelle Dittrick, Clinical Research Program Manager