G A Mitchell

Duke University Medical Center, Durham, North Carolina, United States

Are you G A Mitchell?

Claim your profile

Publications (152)918.5 Total impact

  • Source
    Dataset: mmc1
  • Source
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/glutamate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.
    Neuron 10/2013; 80(2):429-41. · 15.77 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/glutamate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.
    Neuron 10/2013; 80(2):429-449. · 15.77 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To describe the long-term ophthalmologic outcomes of patients with methylmalonic aciduria and homocystinuria, cobalamin C type (cblC). Retrospective case series. All patients with cblC referred to the Department of Ophthalmology of the Centre Hospitalier Universitaire Sainte-Justine from 1984 through 2012 were studied. Twelve such patients were identified. Clinical ophthalmic examinations, neuroimaging, electroretinography, and the results of MMACHC mutation analysis were reviewed retrospectively. We examined visual acuity, ocular alignment, presence of maculopathy and peripheral retinopathy, optic atrophy, and nystagmus. Photopic and scotopic electroretinograms were reviewed. We examined and compared mutations in the MMACHC gene. Neuroimaging abnormalities were compiled when available. Twelve cblC patients were followed up from 2 to 23 years (average, 10 years). Eleven of 12 patients were diagnosed before the age of 1 year (range, birth-2 years). An initial ophthalmic examination was performed within the first year of age in 9 of 12 patients. Visual acuity at the time of presentation was variable, ranging from light perception to 20/20. Visual acuity was worse than 20/100 in 75% (9/12) of patients at last follow-up. Eight patients (67%) had obvious maculopathy on fundus examination. Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]). Funduscopic deterioration was documented in 1 patient, whereas electrophysiologic changes occurred in 4 patients. Neuroimaging results were available in 7 of the patients, revealing corpus callosum atrophy (7/7 [100%]) and periventricular white matter loss (6/7 [85%]). Most children in our series had early-onset disease with neurologic manifestations and abnormal ophthalmologic examination results. Despite early treatment, many early-onset cblC patients have poor visual function. The author(s) have no proprietary or commercial interest in any materials discussed in this article.
    Ophthalmology 10/2013; · 5.56 Impact Factor
  • Canadian Journal of Diabetes 10/2013; 37S4:S58. · 0.46 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-1 and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insig1 and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor γ (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirt1-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-1α signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.-Rodrigue-Way, A., Caron, V., Bilodeau, S., Keil, S., Hassan, M., Lévy, E., Mitchell. G. A., Tremblay, A. Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARγ/PGC-1α pathway and Insig1/2 expression in hepatocytes.
    Canadian Journal of Diabetes 10/2013; 37S4:S65. · 0.46 Impact Factor
  • Movement Disorders 07/2013; · 4.56 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Neuraminidases (sialidases) catalyze the removal of sialic acid residues from sialylated glycoconjugates. We now report that mammalian neuraminidase 1 (Neu1), in addition to its catabolic function in lysosomes, is transported to the cell surface where it is involved in regulation of insulin signaling. Insulin binding to its receptor rapidly induces interaction of the receptor with Neu1, which hydrolyzes sialic acid residues in the glycan chains of the receptor and, consequently, induces its activation. Cells from sialidosis patients with a genetic deficiency of Neu1 show impairment of insulin-induced phosphorylation of downstream protein kinase AKT, while treatment of these cells with purified Neu1 restores signaling. Genetically-modified mice with ∼10% of the normal Neu1 activity exposed to a high-fat diet develop hyperglycemia and insulin resistance twice as fast as their wild type counterparts. Together, these studies identify Neu1 as a novel component of the signaling pathways of energy metabolism and glucose uptake.
    Diabetes 03/2013; · 7.90 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies.The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.
    Orphanet Journal of Rare Diseases 01/2013; 8(1):8. · 4.32 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Carboxylation of [2-(14)C] pyruvate diminished following incubation of HLLKO hepatocytes with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function, demonstrating an acyl-CoA-related mechanism for this complication.
    PLoS ONE 01/2013; 8(7):e60581. · 3.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994. We recorded the clinical course of 78 Québec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1month of age (26 patients) and those treated before 1month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter. No hospitalizations for acute complications of HT1 occurred during 5731months of nitisinone treatment, versus 184 during 1312months without treatment (p<0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26months, versus 7 late-treated patients (26%, p<0.001), and no early-treated patient (p<0.001). No early-treated patient has developed detectable liver disease after more than 5years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p<0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia. Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1month had no detectable liver disease after more than 5years.
    Molecular Genetics and Metabolism 07/2012; 107(1-2):49-54. · 2.83 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) participates in hepatic very-low density lipoprotein (VLDL) assembly and in adipose tissue basal lipolysis. Global ablation of Ces3/Tgh expression decreases serum triacylglycerol and nonesterified fatty acid levels and improves insulin sensitivity. To understand the tissue-specific role of Ces3/TGH in lipid and glucose homeostasis, we have generated mice with a liver-specific deletion of Ces3/Tgh expression (L-TGH KO). Elimination of hepatic Ces3/Tgh expression dramatically decreased plasma VLDL-triacylglycerol and VLDL-cholesterol concentrations but only moderately increased liver triacylglycerol levels in mice fed standard chow diet. Significantly reduced plasma triacylglycerol and cholesterol without hepatic steatosis were also observed in L-TGH KO mice challenged with Western diet. L-TGH KO mice presented with increased plasma ketone bodies and hepatic fatty acid oxidation. Intrahepatic triacylglycerol in L-TGH KO mice was stored in significantly smaller lipid droplets. Augmented hepatic triacylglycerol levels in chow-fed L-TGH KO mice did not affect glucose tolerance or glucose production from hepatocytes, but impaired insulin tolerance was observed in female mice. CONCLUSION: Our data suggest that ablation of hepatic Ces3/Tgh expression decreases plasma lipid levels without causing severe hepatic steatosis. (HEPATOLOGY 2012.).
    Hepatology 06/2012; · 12.00 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Adipose triglyceride lipase (ATGL) catalyzes the first step of lipolysis of cytoplasmic triacylglycerols in white adipose tissue (WAT) and several other organs. We created adipose-specific ATGL-deficient (ATGLAKO) mice. In these mice, in vivo lipolysis, measured as the increase of plasma nonesterified fatty acid and glycerol levels after injection of a β3-adrenergic agonist, was undetectable. In isolated ATGLAKO adipocytes, β3-adrenergic-stimulated glycerol release was 10-fold less than in controls. Under fed conditions, ATGLAKO mice had normal viability, mild obesity, low plasma nonesterified fatty acid levels, increased insulin sensitivity, and increased daytime food intake. After 5 h of fasting, ATGLAKO WAT showed phosphorylation of the major protein kinase A-mediated targets hormone-sensitive lipase and perilipin A and ATGLAKO liver showed low glycogen and triacylglycerol contents. During a 48-h fast, ATGLAKO mice developed striking and complex differences from controls: progressive reduction of oxygen consumption, high respiratory exchange ratio, consistent with reduced fatty acid availability for energy production, lethargy, hypothermia, and undiminished fat mass, but greater loss of lean mass than controls. Plasma of 48 h-fasted ATGLAKO mice had a unique pattern: low 3-hydroxybutyrate, insulin, adiponectin, and fibroblast growth factor 21 with elevated leptin and corticosterone. ATGLAKO WAT, liver, skeletal muscle, and heart showed increased levels of mRNA related to autophagy and proteolysis. In murine ATGL deficiency, adipose lipolysis is critical for fasting energy homeostasis, and fasting imposes proteolytic stress on many organs, including heart and skeletal muscle.
    Endocrinology 02/2012; 153(5):2198-207. · 4.72 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To describe and validate a new protocol for molecular diagnosis of spinal muscular atrophy (SMA), a frequent neuromuscular disease of childhood. SMA is caused in most cases by homozygous deletion of the SMN1 gene. We describe a triplex quantitative real-time PCR method in which fragments of SMN1, SMN2 (a nearly-identical neighboring gene with markedly reduced function) and of a control gene, CFTR, are amplified in the same tube. We validated this method in three ways. First, testing the same samples ten times yielded CV values <4.6%. Second, in 104 previously-genotyped individuals, SMN copy numbers identical to those of the previously-determined genotype was unambiguously obtained in all cases. Finally, results using the technique in practice are described and analyzed for reproducibility of amplification efficiency and for inter-run variability. In over 1200 samples, this technique has proven accurate, fast, economical and reproducible.
    Clinical biochemistry 11/2011; 45(1-2):88-91. · 2.02 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Hyperammonemia results from reduction of hepatocyte function or enzyme of urea cycle deficiency. Hyperammonemia contributes to cerebral edema that may lead to cerebral herniation. The threshold of toxicity of ammonemia is unknown. We conducted a retrospective observational study in our pediatric intensive care unit. All children who developed hyperammonemia from January 2000 to April 2009 were included. Clinical and laboratory data at admission, specific treatments implemented, and ammonemias the first 7 days after inclusion were collected. The outcome assessed was 28 day mortality. Risk of mortality was estimated by a logistic regression model. Ninety patients with liver failure (63.3%) and primary or secondary urea cycle defect (23.3%) were included. Patients with urea cycle defects were more likely to receive ammonia scavengers than patients with liver failure (47.6% versus 3.5%). The 28 day mortality rate was 31.1%. Risk of mortality increased according to the ammonemia within 48 h: odds ratio 1.5, 1.9, 3.3, 2.4 for ammonemia above 100, 150, 200, and 300 μmol/L, respectively. Peak ammonemia ≥200 μmol/L within the first 48 h was an independent risk factor for mortality, with greater risk found in liver failure than in urea cycle defect. Our study identifies a threshold of exposure to ammonia (≥200 μmol/L) above which mortality increases significantly, especially in liver failure. Specific treatments of hyperammonemia are rarely used in liver failure when compared with urea cycle defect even though use of ammonia scavengers may help to decrease ammonemia.
    Journal of Hepatology 05/2011; 56(1):123-8. · 9.86 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Accumulation of cytoplasmic triacylglycerol (TG) underlies hepatic steatosis, a major cause of cirrhosis. The pathways of cytoplasmic TG metabolism are not well known in hepatocytes, but evidence suggests an important role in lipolysis for adipose triglyceride lipase (ATGL). We created mice with liver-specific inactivation of Pnpla2, the ATGL gene. These ATGLLKO mice had severe progressive periportal macrovesicular and pericentral microvesicular hepatic steatosis (73, 150, and 226 μmol TG/g liver at 4, 8, and 12 months, respectively). However, plasma levels of glucose, TG, and cholesterol were similar to those of controls. Fasting 3-hydroxybutyrate level was normal, but in thin sections of liver, beta oxidation of palmitate was decreased by one-third in ATGLLKO mice compared with controls. Tests of very low-density lipoprotein production, glucose, and insulin tolerance and gluconeogenesis from pyruvate were normal. Plasma alanine aminotransferase levels were elevated in ATGLLKO mice, but histological estimates of inflammation and fibrosis and messenger RNA (mRNA) levels of tumor necrosis factor-α and interleukin-6 were similar to or lower than those in controls. ATGLLKO cholangiocytes also showed cytoplasmic lipid droplets, demonstrating that ATGL is also a major lipase in cholangiocytes. There was a 50-fold reduction of hepatic diacylglycerol acyltransferase 2 mRNA level and a 2.7-fold increase of lipolysosomes in hepatocytes (P < 0.001), suggesting reduced TG synthesis and increased lysosomal degradation of TG as potential compensatory mechanisms. CONCLUSION: Compared with the hepatic steatosis of obesity and diabetes, steatosis in ATGL deficiency is well tolerated metabolically. ATGLLKO mice will be useful for studying the pathophysiology of hepatic steatosis.
    Hepatology 04/2011; 54(1):122-32. · 12.00 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.
    The American Journal of Human Genetics 03/2011; 88(3):306-16. · 11.20 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied. 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001). SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.
    Journal of Medical Genetics 03/2011; 48(3):183-9. · 5.70 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: OBJECTIVE: To report the successful pregnancy of a woman with methylmalonic acidemia and hyperhomocysteinemia, cblC type [cobalamin C (cblC) deficiency] (MIM 277400). METHOD: Retrospective chart review. RESULTS: A 24-year-old woman presented at 14 weeks gestation with nausea, self-restricted protein diet, and weight loss. She had a past history of asymptomatic methylmalonic acidemia but had been lost to follow-up since the age of 15 years. Biochemical evaluation revealed combined methylmalonic acidemia and hyperhomocysteinemia. Complementation analysis confirmed cblC deficiency. One copy of the most common mutations in the MMACHC gene, c.271dupA, was identified. The women was treated from 15 weeks of gestation with a low protein diet (64 g/day) (1.1 g /kg of weight/day), L-carnitine (1 g per os 3 times daily to 3 g per os 3 times daily in the third trimester), aspirin (salicylic acid) 80 mg per day, folic acid 5 mg per day, and hydroxocobalamin 1 mg intramuscular every week to two times per week in the third trimester. The pregnancy was uneventful and the delivery at term. The newborn was healthy at delivery and at follow-up. CONCLUSION: We report on the successful outcome of pregnancy in a treated woman with cblC disease. The pregnancy was uneventful for both fetus and mother with the delivery of a term healthy boy. There is a need for an international registry on the management and outcomes of pregnancy in women with inborn errors of metabolism.
    Journal of Inherited Metabolic Disease 09/2010; · 4.07 Impact Factor

Publication Stats

4k Citations
918.50 Total Impact Points

Institutions

  • 2013
    • Duke University Medical Center
      • Center for Human Genome Variation
      Durham, North Carolina, United States
    • McGill University Health Centre
      Montréal, Quebec, Canada
  • 1992–2013
    • Université de Montréal
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 2011
    • University of Liège
      Luik, Walloon Region, Belgium
    • Université de Sherbrooke
      • Division of Genetics
      Sherbrooke, Quebec, Canada
    • Northwest A & F University
      • College of Animal Science and Technology
      Yangling, Shaanxi Sheng, China
  • 2010
    • Centre Hospitalier Universitaire de Liège
      Luik, Walloon Region, Belgium
  • 1994–2009
    • CHU Sainte-Justine
      • Department of Medical Genetics
      Montréal, Quebec, Canada
  • 2008
    • McGill University
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 2000–2008
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
    • Oregon Health and Science University
      • Department of Molecular & Medical Genetics
      Portland, OR, United States
  • 1990–2008
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2007
    • Gifu University
      • Department of Pediatrics
      Gihu, Gifu, Japan
  • 2006
    • State University of New York
      New York City, New York, United States
  • 1996–2004
    • Gifu University Hospital
      Gihu, Gifu, Japan
  • 1999
    • University of Québec in Chicoutimi
      Saguenay, Quebec, Canada
  • 1988–1999
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, Maryland, United States
  • 1998
    • University of Toronto
      • Department of Biochemistry
      Toronto, Ontario, Canada
  • 1994–1996
    • Medical College of Wisconsin
      • Department of Biochemistry
      Milwaukee, WI, United States
  • 1993
    • SickKids
      Toronto, Ontario, Canada
  • 1988–1992
    • Howard Hughes Medical Institute
      Maryland, United States

Disciplines