Carnitine Palmitoyltransferase I (CPT Ia) is an enzyme that regulates entry of long chain fatty acids into the mitochondria for oxidation. Classic CPT I deficiency is a very rare disorder that presents with hypoketotic hypoglyemia with a risk of sudden unexpected death.

Our research group identified a variant in the CPT Ia gene that is common in BC First Nations. Individuals who are homozygous for the CPT I P479L variant have reduced, but not deficient, CPT I enzyme activity. This CPT I variant, is most prevalent along coastal regions of BC and on Vancouver Island. Approximately 20% of First Nations are homozygous for the CPTI variant along the BC coast compared to 4% in the Interior regions of the province. Every year in BC, ~ 200 babies are born with the CPT I P479L variant. The vast majority of babies with the CPT I variant are healthy and do not develop health problems. However, it is possible the CPT I variant may lead to low blood sugar in some children during long periods of fasting especially when fasting occurs during inter-current illness (fever, vomiting or diarrhea). By investigation of sudden unexpected death (SUD) cases in BC, our research group found an association between the CPT I variant and SUD.


Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B12 status compared with pregnant women of European ethnicity
British Journal of Nutrition
Theresa H. Schroder, Graham Sinclair, Andre Mattman, Benjamin Jung, Susan I. Barr, Hilary D. Vallance, Yvonne Lamers
DOI: 10.1017/s0007114517002331

Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation
Molecular Case Studies
Stephanie C. Bourne and Katelin N. Townsend and Casper Shyr and Allison Matthews and Scott A. Lear and Raj Attariwala and Anna Lehman and Wyeth W. Wasserman and Clara van Karnebeek and Graham Sinclair and Hilary Vallance and William T. Gibson
DOI: 10.1101/mcs.a001156

Reference interval of methylmalonic acid concentrations in dried blood spots of healthy, term newborns to facilitate neonatal screening of vitamin B12 deficiency
Clinical Biochemistry
Theresa H. Schroder, Andre Mattman, Graham Sinclair, Hilary D. Vallance, Yvonne Lamers
DOI: 10.1016/j.clinbiochem.2016.03.007

Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families.
Molecular genetics and metabolism
Sass JO, Gemperle-Britschgi C, Tarailo-Graovac M, Patel N, Walter M, Jordanova A, Alfadhel M, Baric I, Çoker M, Damli-Huber A, Faqeih EA, van Karnebeek CD
DOI: 10.1016/j.ymgme.2016.07.008
PubMed: 27477828

A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening
Molecular Genetics and Metabolism
Graham B. Sinclair, Clara D.M. van Karnebeek, Manuel Ester, Frances Boyd, Tanya Nelson, Sylvia Stockler-Ipsiroglu, Hilary Vallance
DOI: 10.1016/j.ymgme.2016.05.002

Integrated Multianalyte Second-Tier Testing for Newborn Screening for MSUD, IVA, and GAMT Deficiencies
Journal of Inborn Errors of Metabolism and Screening
Graham B. Sinclair, Manuel Ester, Gabriella Horvath, Clara D. van Karnebeek, Sylvia Stockler-Ipsirogu, Hilary Vallance
DOI: 10.1177/2326409816666296

Exome Sequencing and the Management of Neurometabolic Disorders.
The New England journal of medicine
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, van Karnebeek CD
DOI: 10.1056/nejmoa1515792
PubMed: 27276562

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.
Brain : a journal of neurology
Zaharieva IT, Thor MG, Oates EC, van Karnebeek C, Hendson G, Blom E, Witting N, Rasmussen M, Gabbett MT, Ravenscroft G, Sframeli M, Suetterlin K, Muntoni F
DOI: 10.1093/brain/awv352
PubMed: 26700687

RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness and multiorgan involvement
European Journal of Human Genetics
Alexandre Janer, Clara DM van Karnebeek, Florin Sasarman, Hana Antonicka, Malak Al Ghamdi, Casper Shyr, Mary Dunbar, Sylvia Stockler-Ispiroglu, Colin J Ross, Hilary Vallance, Janis Dionne, Wyeth W Wasserman, Eric A Shoubridge
DOI: 10.1038/ejhg.2014.293

Methylmalonic aciduria: A common incidental finding in infants undergoing metabolic investigation
Clinical Biochemistry
Bojana Rakic, Graham Sinclair, Ramona Salvarinova, Hilary Vallance
DOI: 10.1016/j.clinbiochem.2014.07.063

Rapid second-tier testing for newborn screening and therapeutic monitoring of maple syrup urine disease
Clinical Biochemistry
Graham Sinclair, Clara van Karnebeek, Ramona Salvarinova, Gloria Ho, Keiko Ueda, Barbara Cheng, Alette Giezen, Sylvia Stockler, Hilary Vallance
DOI: 10.1016/j.clinbiochem.2014.07.075

Is it time to consider LC–MS/MS measurement of mucopolysaccharides as the first line screening test for Sanfilippo disease?
Clinical Biochemistry
Hilary Vallance, Graham Sinclair, Ramona Salvarinova, Michelle Demos, Tim Wood, Pamela Lavoie, Christiane Auray-Blais
DOI: 10.1016/j.clinbiochem.2014.07.051

Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking
Orphanet Journal of Rare Diseases
Sylvia Stockler, Silvia Corvera, David Lambright, Kevin Fogarty, Ekaterina Nosova, Deborah Leonard, Robert Steinfeld, Cameron Ackerley, Casper Shyr, Nicolas Au, Kathrin Selby, Margot van Allen, Hilary Vallance, Ron Wevers, David Watkins, David Rosenblatt, Colin J Ross, Elizabeth Conibear, Wyeth Wasserman, Clara van Karnebeek
DOI: 10.1186/s13023-014-0141-5

Limitation of TREC-based newborn screening for ZAP70 Severe Combined Immunodeficiency
Clinical Immunology
Serge Grazioli, Mary Bennett, Kyla J. Hildebrand, Hilary Vallance, Stuart E. Turvey, Anne K. Junker
DOI: 10.1016/j.clim.2014.04.015

Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood
The American Journal of Human Genetics
Clara D. van Karnebeek, William S. Sly, Colin J. Ross, Ramona Salvarinova, Joy Yaplito-Lee, Saikat Santra, Casper Shyr, Gabriella A. Horvath, Patrice Eydoux, Anna M. Lehman, Virginie Bernard, Theresa Newlove, Henry Ukpeh, Anupam Chakrapani, Mary Anne Preece, Sarah Ball, James Pitt, Hilary D. Vallance, Marion Coulter-Mackie, Hien Nguyen, Lin-Hua Zhang, Amit P. Bhavsar, Graham Sinclair, Abdul Waheed, Wyeth W. Wasserman, Sylvia Stockler-Ipsiroglu
DOI: 10.1016/j.ajhg.2014.01.006

Prediction of obstetrical risk using maternal serum markers and clinical risk factors.
Prenatal diagnosis
Metcalfe A, Langlois S, Macfarlane J, Vallance H, Joseph KS
DOI: 10.1002/pd.4281
PubMed: 24226970

Long-term outcomes of blood phenylalanine concentrations in children with classical phenylketonuria
Molecular Genetics and Metabolism
Carol Hartnett, Ramona Salvarinova-Zivkovic, Eva Yap-Todos, Barbara Cheng, Alette Giezen, Gabriella Horvath, Yolanda Lillquist, Hilary Vallance, Sylvia Stockler-Ipsiroglu
DOI: 10.1016/j.ymgme.2013.01.007

Performance of serum and dried blood spot acylcarnitine profiles for detection of fatty acid ß-oxidation disorders in adult patients with rhabdomyolysis
Journal of Inherited Metabolic Disease
Khalid Al-Thihli, Graham Sinclair, Sandra Sirrs, Michelle Mezei, Judie Nelson, Hilary Vallance
DOI: 10.1007/s10545-012-9578-7

Three years experience with dried blood spot a-glucosidase screening for Pompe disease in British Columbia, Canada
BMC Musculoskeletal Disorders
Gabriella Horvath, Sandra Sirrs, Sylvia Stockler, Ramona Salvarinova-Zivkovic, Hilary Vallance, Paula Waters
DOI: 10.1186/1471-2474-14-s2-p2

Carnitine Palmitoyltransferase I and Sudden Unexpected Infant Death in British Columbia First Nations
G. B. Sinclair, S. Collins, O. Popescu, D. McFadden, L. Arbour, H. D. Vallance
DOI: 10.1542/peds.2011-2924

Levator palpebrae biopsy and diagnosis of progressive external ophthalmoplegia.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
Pfeffer G, Waters PJ, Maguire J, Vallance HD, Wong VA, Mezei MM
PubMed: 22728862

A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy.
Al-Thihli K, Ebrahim H, Hughes DA, Patel M, Tipple M, Salvarinova R, Gardiner J, Vallance H, Waters PJ
DOI: 10.1016/j.gene.2012.01.056
PubMed: 22336178

Late-onset nonketotic hyperglycinemia caused by a novel homozygous missense mutation in the GLDC gene
Molecular Genetics and Metabolism
Catherine Brunel-Guitton, Brett Casey, Marion Coulter-Mackie, Hilary Vallance, Deborah Hewes, Sylvia Stockler-Ipsiroglu, Saadet Mercimek-Mahmutoglu
DOI: 10.1016/j.ymgme.2011.02.009

Diagnosis and Management of patients with mitochondrial disease
BC Medical Journal

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.
Genetics in medicine : official journal of the American College of Medical Genetics
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, Zakowicz WM
DOI: 10.1097/gim.0b013e31820d5e67
PubMed: 21325949

Infantile cardioencephalopathy due to a COX15 gene defect: Report and review
American Journal of Medical Genetics Part A
Majid Alfadhel, Yolanda P. Lillquist, Paula J. Waters, Graham Sinclair, Eduard Struys, Deborah McFadden, Glenda Hendson, Lauren Hyams, John Shoffner, Hilary D. Vallance
DOI: 10.1002/ajmg.a.33881

IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.
Science (New York, N.Y.)
Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, Amiel J, Buist NR, Das AM, de Klerk JB, Feigenbaum AS, Grange DK, Salomons GS
DOI: 10.1126/science.1192632
PubMed: 20847235

Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut
Molecular Genetics and Metabolism
Sorcha A. Collins, Graham Sinclair, Sarah McIntosh, Fiona Bamforth, Robert Thompson, Isaac Sobol, Geraldine Osborne, Andre Corriveau, Maria Santos, Brendan Hanley, Cheryl R. Greenberg, Hilary Vallance, Laura Arbour
DOI: 10.1016/j.ymgme.2010.07.013

The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations
Molecular Genetics and Metabolism
Cheryl R. Greenberg, Louise A. Dilling, G. Robert Thompson, Lorne E. Seargeant, James C. Haworth, Susan Phillips, Alicia Chan, Hilary D. Vallance, Paula J. Waters, Graham Sinclair, Yolanda Lillquist, Ronald J.A. Wanders, Simon E. Olpin
DOI: 10.1016/j.ymgme.2008.12.018

In response to ‘Newborn screening in North America’ (Therrell and Adams (2007) J Inherit Metab Dis 30:447–465)
Journal of Inherited Metabolic Disease
H. Vallance, S. Sirrs, F. Bamforth, S. Stockler-Ipsiroglu
DOI: 10.1007/s10545-008-0846-5

Delays in diagnosing cystic fibrosis: can we find ways to diagnose it earlier?
Canadian family physician Medecin de famille canadien
Steinraths M, Vallance HD, Davidson AG
PubMed: 18556497

Mutation-based diagnostic testing for primary hyperoxaluria type 1: Survey of results
Clinical Biochemistry
Marion B. Coulter-Mackie, Qun Lian, Derek A. Applegarth, Jennifer Toone, Paula J. Waters, Hilary Vallance
DOI: 10.1016/j.clinbiochem.2008.01.018

Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase.
Human mutation
Dimmock DP, Zhang Q, Dionisi-Vici C, Carrozzo R, Shieh J, Tang LY, Truong C, Schmitt E, Sifry-Platt M, Lucioli S, Santorelli FM, Ficicioglu CH, Wong LJ
DOI: 10.1002/humu.9519
PubMed: 18205204

Screening for Fabry disease in patients with chronic kidney disease: limitations of plasma alpha-galactosidase assay as a screening test.
Clinical journal of the American Society of Nephrology : CJASN
Andrade J, Waters PJ, Singh RS, Levin A, Toh BC, Vallance HD, Sirrs S
DOI: 10.2215/cjn.02490607
PubMed: 18003767

Newborn screening for MCAD deficiency: experience of the first three years in British Columbia, Canada.
Canadian journal of public health = Revue canadienne de sante publique
Horvath GA, Davidson AG, Stockler-Ipsiroglu SG, Lillquist YP, Waters PJ, Olpin S, Andresen BS, Palaty J, Nelson J, Vallance H
PubMed: 18767270

Newborn screening by tandem mass spectrometry: ethical and social issues.
Canadian journal of public health = Revue canadienne de sante publique
Avard D, Vallance H, Greenberg C, Potter B
PubMed: 17896737

Variability in the storage and use of newborn dried bloodspots in Canada: is it time for national standards?
Genomics, society, and policy
Avard D, Vallance H, Greenberg C, Laberge C, Kharaboyan L, Plant M

Common HEXB polymorphisms reduce serum HexA and HexB enzymatic activities, potentially masking Tay-Sachs disease carrier identification.
Molecular genetics and metabolism
Vallance H, Morris TJ, Coulter-Mackie M, Lim-Steele J, Kaback M
DOI: 10.1016/j.ymgme.2005.10.012
PubMed: 16352452

A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy.
Molecular genetics and metabolism
Leary SC, Mattman A, Wai T, Koehn DC, Clarke LA, Chan S, Lomax B, Eydoux P, Vallance HD, Shoubridge EA
DOI: 10.1016/j.ymgme.2006.04.016
PubMed: 16765077

Neonatal hyperphenylalaninemia, perinatal hemochromatosis, and renal tubulopathy: a unique patient or a novel metabolic disorder?
Molecular genetics and metabolism
Waters PJ, Khashu M, Lillquist Y, Senger C, Mattman A, Demos M, Setchell K, Rupar A, Scott P, Blau N, Vallance HD
DOI: 10.1016/j.ymgme.2005.07.032
PubMed: 16182582

6-Pyruvoyl-tetrahydropterin synthase deficiency with mild hyperphenylalaninemia
Annals of Neurology
Michelle K. Demos, Paula J. Waters, Hilary D. Vallance, Yolanda Lillquist, Nawal Makhseed, Keith Hyland, Nenad Blau, Mary B. Connolly
DOI: 10.1002/ana.20532

The Brugada ECG pattern in a neonate.
Journal of cardiovascular electrophysiology
Sanatani S, Mahkseed N, Vallance H, Brugada R
DOI: 10.1046/j.1540-8167.2005.40607.x
PubMed: 15817096

Biochemical Approach to the Investigation of Pediatric Mitochondrial Disease
Pediatric and Developmental Pathology
Hilary Vallance
DOI: 10.1007/s10024-004-5053-2

Expansion of the 22q13 deletion phenotype in four patients with autism spectrum disorder125
Journal of Investigative Medicine
E. Lopez-Rangel and H. Vallance and J. Palaty and E. Mickelson and M. Hrynchak and E. Separovic and P. M. MacLeod and L. Arbour and L. Clarke and M. E.S. Lewis
DOI: 10.1097/00042871-200401001-00125

A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344G (MERRF) mitochondrial DNA mutation.
Pediatric cardiology
Vallance HD, Jeven G, Wallace DC, Brown MD
DOI: 10.1007/s00246-003-0446-y
PubMed: 15164143

Carnitine transporter defect due to a novel mutation in the SLC22A5 gene presenting with peripheral neuropathy.
Journal of inherited metabolic disease
Makhseed N, Vallance HD, Potter M, Waters PJ, Wong LT, Lillquist Y, Pasquali M, Amat di San Filippo C, Longo N
DOI: 10.1023/b:boli.0000045837.23328.f4
PubMed: 15617188

A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency
Clinical Biochemistry
Nelson L.S. Tang, Joannie Hui, Collin K.K. Yong, Lawrence T.K. Wong, Derek A. Applegarth, Hilary D. Vallance, L.K. Law, Simon L.M. Fung, Tony W.L. Mak, Y.M. Sung, K.L. Cheung, T.F. Fok
DOI: 10.1016/s0009-9120(02)00432-0

Carrier Testing for Autosomal- Recessive Disorders
Critical Reviews in Clinical Laboratory Sciences
Hilary Vallance, Jason Ford
DOI: 10.1080/10408360390247832

Mucopolysaccharidosis Type VII (Sly Syndrome) Presenting as Neonatal Cholestasis With Hepatosplenomegaly
Journal of Pediatric Gastroenterology and Nutrition
Peter M. Gillett, Richard A. Schreiber, Gareth P. Jevon, David M. Israel, Tom Warshawski, Hilary Vallance, Lorne A. Clarke
DOI: 10.1097/00005176-200108000-00025

Novel point mutation (W184R) in neonatal type 2 Gaucher disease.
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society
Choy FY, Wong K, Vallance HD, Baldwin V
DOI: 10.1007/s100240050023
PubMed: 10679038

The Liver Biopsy and the Jaundiced Infant
Pathology Case Reviews
Avrum J. Ostry, Hilary D. Vallance, James E. Dimmick, Garcth P. levon
DOI: 10.1097/00132583-199905000-00005

Diagnosis of inborn errors of metabolism using 1H NMR spectroscopic analysis of urine.
Journal of Inherited Metabolic Disease
Bamforth FJ, Dorian V, Vallance H, Wishart DS
DOI: 10.1023/a:1005531432766
PubMed: 10384391

D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity?
Annals of neurology
van der Knaap MS, Jakobs C, Hoffmann GF, Nyhan WL, Renier WO, Smeitink JA, Catsman-Berrevoets CE, Hjalmarson O, Vallance H, Sugita K, Bowe CM, Chalmers RA
DOI: 10.1002/1531-8249(199901)45:13.0.co;2-n
PubMed: 9894884

Identification of 6 new mutations in the iduronate sulfatase gene
Human Mutation
Hilary D. Vallance, Lynn Bernard, Michael Rashed, Doris Chiu, Grace Le, Jenny Toone, Derek A. Applegarth, Marion Coulter-Mackie
DOI: 10.1002/(sici)1098-1004(1999)13:43.0.co;2-3

Early amniocentesis for biochemical genetic prenatal diagnosis
The Lancet
JR Toone, DA Applegarth, HD Vallance, RD Wilson
DOI: 10.1016/s0140-6736(05)79157-1

DNA-based diagnosis of arylsulfatase A deficiencies as a supplement to enzyme assay: A case in point
Clinical Biochemistry
Marion B. Coulter-Mackie, Derek A. Applegarth, Jennifer Toone, Hilary Vallance
DOI: 10.1016/s0009-9120(96)00124-5

Are patients with homocystinuria being missed?
European Journal of Pediatrics
Derek A. Applegarth, Hilary D. Vallance, David Seccombe
DOI: 10.1007/bf02074844

An improved method for quantification of very long chain fatty acids in plasma
Clinical Biochemistry
Hilary Vallance, Applegarth Derek
DOI: 10.1016/0009-9120(94)90053-1

Measurement of pyruvate dehydrogenase complex (PDHC) in interleukin-2 (IL-2) stimulated lymphocytes.
Journal of inherited metabolic disease
Vallance HD, Toone JR, Applegarth DA
DOI: 10.1007/bf00711604
PubMed: 7837773

Oral zinc therapy in the treatment of a-mannosidosis
American Journal of Medical Genetics
Lawrence T. K. Wong, Hilary Vallance, Angela Savage, A. G. F. Davidson, Derek Applegarth
DOI: 10.1002/ajmg.1320460413


Current Project
Treatable Intellectual Disability Endeavour (TIDE-BC)
Development of an LC/MS/MS method for amino acid profiling.

Current Project
CPTI variant communications
Development of public health messaging and information for health care providers.

Current Project
Natural history of the CPT I variant in BC First Nations
An anonymized study to evaluate health parameters available in public health databases (PopBC) to expand our knowledge of the natural history the CPT I variant.


Collaborative Area of Innovation Title: TIDE BC Treatable Intellectual Disability Endeavour in B.C. (TIDE-BC) ~ $2.25M. PI: Stockler S Co-Investigators: Dr. Jean-Paul Collet, Dr. Clara van Karnebeek, Dr. Carlo Marra, Dr. Hilary Vallance and Dr. Wyeth Wasserman. (2011-2014).

Children's and Women's Health Center: Telethon fund Title: Defining the clinical risks associated with CPT1a p.P479L homozygosity in children from BC First Nations ~ $22,000. Coinvestigators: Arbour L. (2011-2013)

CIHR Emerging Team Grant Title: Emerging team in rare diseases: Achieving the 'triple aim' for inborn errors of metabolism ~ $1,490,492. (2012-2017).

Honours & Awards

Dr. Parminder Singh Award, British Columbia Pediatric Society — 2011