Publications by authors named "Grant A Mitchell"

88 Publications

Retinopathy of transcobalamin II deficiency: long-term stability with treatment.

Ophthalmology 2021 Jan 18. Epub 2021 Jan 18.

Department of Ophthalmology, Hôpital Maisonneuve-Rosemont and Université de Montréal, Montreal, Canada.

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http://dx.doi.org/10.1016/j.ophtha.2021.01.015DOI Listing
January 2021

Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting.

J Inherit Metab Dis 2020 09 23;43(5):960-968. Epub 2020 Apr 23.

Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu City, Japan.

d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver.
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http://dx.doi.org/10.1002/jimd.12243DOI Listing
September 2020

Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice.

PLoS Biol 2020 03 27;18(3):e3000688. Epub 2020 Mar 27.

Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.
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http://dx.doi.org/10.1371/journal.pbio.3000688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141696PMC
March 2020

Fulminant Necrotizing Enterocolitis and Multiple Organ Dysfunction in a Toddler with Mitochondrial DNA Depletion Syndrome-13.

J Pediatr Intensive Care 2020 Mar 10;9(1):54-59. Epub 2019 Oct 10.

Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Canada.

Necrotizing enterocolitis (NEC) is exceptional after the neonatal period. A toddler with encephalopathy, mitochondrial myopathy, and hypertrophic cardiomyopathy developed fatal NEC and multiple organ dysfunction within 48 hours of the introduction of enteral feeding. She was subsequently found to have pathogenic mutations in , a cause of mitochondrial DNA depletion syndrome-13. Intestinal dysmotility in the context of deficient mitochondrial respiration may have contributed to the development of NEC. Current paradigms call for early introduction of enteral nutrition to reinstate energy homeostasis. Enteral feeding should be administered with caution during metabolic crises of patients with mitochondrial DNA depletion syndromes.
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http://dx.doi.org/10.1055/s-0039-1697620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978174PMC
March 2020

A variant of neonatal progeroid syndrome, or Wiedemann-Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL.

Eur J Hum Genet 2020 04 6;28(4):461-468. Epub 2019 Nov 6.

Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada.

Neonatal progeroid syndrome, also known as Wiedemann-Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.
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http://dx.doi.org/10.1038/s41431-019-0539-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080780PMC
April 2020

Inborn errors of mitochondrial acyl-coenzyme a metabolism: acyl-CoA biology meets the clinic.

Mol Genet Metab 2019 Sep - Oct;128(1-2):30-44. Epub 2019 May 9.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada. Electronic address:

The last decade saw major advances in understanding the metabolism of Coenzyme A (CoA) thioesters (acyl-CoAs) and related inborn errors (CoA metabolic diseases, CAMDs). For diagnosis, acylcarnitines and organic acids, both derived from acyl-CoAs, are excellent markers of most CAMDs. Clinically, each CAMD is unique but strikingly, three main patterns emerge: first, systemic decompensations with combinations of acidosis, ketosis, hypoglycemia, hyperammonemia and fatty liver; second, neurological episodes, particularly acute "stroke-like" episodes, often involving the basal ganglia but sometimes cerebral cortex, brainstem or optic nerves and third, especially in CAMDs of long chain fatty acyl-CoA metabolism, lipid myopathy, cardiomyopathy and arrhythmia. Some patients develop signs from more than one category. The pathophysiology of CAMDs is not precisely understood. Available data suggest that signs may result from CoA sequestration, toxicity and redistribution (CASTOR) in the mitochondrial matrix has been suggested to play a role. This predicts that most CAMDs cause deficiency of CoA, limiting mitochondrial energy production, and that toxic effects from the abnormal accumulation of acyl-CoAs and from extramitochondrial functions of acetyl-CoA may also contribute. Recent progress includes the following. (1) Direct measurements of tissue acyl-CoAs in mammalian models of CAMDs have been related to clinical features. (2) Inborn errors of CoA biosynthesis were shown to cause clinical changes similar to those of inborn errors of acyl-CoA degradation. (3) CoA levels in cells can be influenced pharmacologically. (4) Roles for acetyl-CoA are increasingly identified in all cell compartments. (5) Nonenzymatic acyl-CoA-mediated acylation of intracellular proteins occurs in mammalian tissues and is increased in CAMDs.
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http://dx.doi.org/10.1016/j.ymgme.2019.05.002DOI Listing
April 2020

An Epistatic Interaction between and Reveals New Pathways of Adipose Tissue Lipolysis.

Cells 2019 04 29;8(5). Epub 2019 Apr 29.

Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.

White adipose tissue (WAT) lipolysis contributes to energy balance during fasting. Lipolysis can proceed by the sequential hydrolysis of triglycerides (TGs) by adipose triglyceride lipase (ATGL), then of diacylglycerols (DGs) by hormone-sensitive lipase (HSL). We showed that the combined genetic deficiency of ATGL and HSL in mouse adipose tissue produces a striking different phenotype from that of isolated ATGL deficiency, inconsistent with the linear model of lipolysis. We hypothesized that the mechanism might be functional redundancy between ATGL and HSL. To test this, the TG hydrolase activity of HSL was measured in WAT. HSL showed TG hydrolase activity. Then, to test ATGL for activity towards DGs, radiolabeled DGs were incubated with HSL-deficient lipid droplet fractions. The content of TG increased, suggesting DG-to-TG synthesis rather than DG hydrolysis. TG synthesis was abolished by a specific ATGL inhibitor, suggesting that ATGL functions as a transacylase when HSL is deficient, transferring an acyl group from one DG to another, forming a TG plus a monoglyceride (MG) that could be hydrolyzed by monoglyceride lipase. These results reveal a previously unknown physiological redundancy between ATGL and HSL, a mechanism for the epistatic interaction between and . It provides an alternative lipolytic pathway, potentially important in patients with deficient lipolysis.
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http://dx.doi.org/10.3390/cells8050395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563012PMC
April 2019

Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort.

J Inherit Metab Dis 2019 01;42(1):107-116

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

Background: The clinical significance of combined malonic and methylmalonic aciduria due to ACSF3 deficiency (CMAMMA) is controversial. In most publications, affected patients were identified during the investigation of various complaints.

Methods: Using a cross-sectional multicenter retrospective natural history study, we describe the course of all known CMAMMA individuals in the province of Quebec.

Results: We identified 25 CMAMMA patients (6 months to 30 years old) with a favorable outcome regardless of treatment. All but one came to clinical attention through the Provincial Neonatal Urine Screening Program (screening on day 21 of life). Median methylmalonic acid (MMA) levels ranged from 107 to 857 mmol/mol creatinine in urine (<10) and from 8 to 42 μmol/L in plasma (<0.4); median urine malonic acid (MA) levels ranged from 9 to 280 mmol/mol creatinine (<5). MMA was consistently higher than MA. These findings are comparable to those previously reported in CMAMMA. Causal ACSF3 mutations were identified in all patients for whom genotyping was performed (76% of cases). The most common ACSF3 mutations in our cohort were c.1075G > A (p.E359K) and c.1672C > T (p.R558W), representing 38.2 and 20.6% of alleles in genotyped families, respectively; we also report several novel mutations.

Conclusion: Because our province still performs urine newborn screening, our patient cohort is the only one free of selection bias. Therefore, the favorable clinical course observed suggests that CMAMMA is probably a benign condition, although we cannot exclude the possibility that a small minority of patients may present symptoms attributable to CMAMMA, perhaps as a result of interactions with other genetic or environmental factors.
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http://dx.doi.org/10.1002/jimd.12032DOI Listing
January 2019

Hereditary diseases of coenzyme A thioester metabolism.

Biochem Soc Trans 2019 02 9;47(1):149-155. Epub 2019 Jan 9.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, QC, Canada

Coenzyme A (CoA) thioesters (acyl-CoAs) are essential intermediates of metabolism. Inborn errors of acyl-CoA metabolism include a large fraction of the classical organic acidemias. These conditions can involve liver, muscle, heart and brain, and can be fatal. These conditions are increasingly detected by newborn screening. There is a renewed interest in CoA metabolism and in developing effective new treatments. Here, we review theories of the pathophysiology in relation to mitochondrial CoA sequestration, toxicity and redistribution (CASTOR).
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http://dx.doi.org/10.1042/BST20180423DOI Listing
February 2019

Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient alleles.

Mol Genet Metab Rep 2018 Mar 27;14:55-58. Epub 2017 Dec 27.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

Background: A high level of succinylacetone (SA) in blood is a sensitive, specific marker for the screening and diagnosis of hepatorenal tyrosinemia (HT1, MIM 276700). HT1 is caused by mutations in the gene, resulting in deficiency of fumarylacetoacetate hydrolase. HT1 newborns are usually clinically asymptomatic, but have coagulation abnormalities revealing liver dysfunction. Treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of HT1.

Observations: Two newborns screened positive for SA but had normal coagulation testing. Plasma and urine SA levels were 3-5 fold above the reference range but were markedly lower than in typical HT1. Neither individual received nitisinone or dietary therapy. They remain clinically normal, currently aged 9 and 15 years. Each was a compound heterozygote, having a splicing variant in with a prevalent "pseudodeficient" allele, c.1021C > T (p.Arg341Trp), which confers partial FAH activity. All newborns identified with mild hypersuccinylacetonemia in Québec have had genetic deficiencies of tyrosine degradation: either deficiency of the enzyme preceding FAH, maleylacetoacetate isomerase, or partial deficiency of FAH itself.

Conclusion: Compound heterozygotes for c.1021C > T (p.Arg341Trp) and a severely deficient FAH allele have mild hypersuccinylacetonemia and to date they have remained asymptomatic without treatment. It is important to determine the long term outcome of such individuals.
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http://dx.doi.org/10.1016/j.ymgmr.2017.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758842PMC
March 2018

Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

PLoS Genet 2017 12 12;13(12):e1007110. Epub 2017 Dec 12.

College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.
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http://dx.doi.org/10.1371/journal.pgen.1007110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741266PMC
December 2017

Remaining Challenges in the Treatment of Tyrosinemia from the Clinician's Viewpoint.

Adv Exp Med Biol 2017 ;959:205-213

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, QC, Canada.

This chapter provides a clinical perspective on the challenges that stand between current clinical practice and a cure for hepatorenal tyrosinemia (HT1). HT1 has been transformed in the last 50 years from an aggressive often undiagnosed childhood disease causing liver failure or liver cancer, with infant death in most patients, to a condition that is detectable at birth, and for which treatment with nitisinone (NTBC) and diet can prevent detectable liver or kidney abnormalities. What challenges remain? The properties of the affected metabolic pathway and the broad spectrum of severity seen in untreated patients are incompletely understood but potentially important for patients. Available treatments have potential complications, including liver transplantation (risks of surgery and of immunosuppression to prevent rejection), nitisinone and diet therapy (hypertyrosinemia, corneal opacities, nutritional imbalances and possibly developmental delay). The detection of liver cancer is imperfect and laborious. The effects of tyrosinemia during pregnancy are little-known. Although animal models of HT1 are becoming standard research tools in cell replacement and gene modification therapy, these techniques are not currently applicable to HT1 itself. Treatment adherence is variable, causing concern about long term outcome for some patients. Around the world, there are great disparities in the diagnosis and treatment of HT1. Most affected individuals are born in places where newborn screening for HT1 is not performed and where appropriate treatment is not available. We hope that this list will help to focus on some of these remaining obstacles to a cure for HT1.
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http://dx.doi.org/10.1007/978-3-319-55780-9_19DOI Listing
December 2017

The Québec NTBC Study.

Adv Exp Med Biol 2017 ;959:187-195

Divisions of Medical Genetics (RL), Gastroenterology (LP) and General Pediatrics (JFT), Department of Pediatrics, Université Laval, Québec, Canada.

In this chapter we describe the current Quebec NTBC Study protocol. Quebec's unique characteristics have influenced the development of the protocol, including a high prevalence of hepatorenal tyrosinemia (HT1), universal newborn screening for HT1, availability of treatment with nitisinone (NTBC) and special diet, a large territory, where HT1 treatment is coordinated by a small number of centers. Screened newborns are seen within 3 weeks of birth. Patients with liver dysfunction (prolonged prothrombin time and/or international normalized ratio (INR) provide sensitive, rapidly available indicators) are treated by NTBC and special diet. The specific diagnosis is confirmed by diagnostic testing for succinylacetone (SA) in plasma and urine samples obtained before treatment. After an initial period of frequent surveillance, stable patients are followed every 3 months by assay of plasma amino acids and NTBC and plasma and urine SA. Abdominal ultrasound is done every 6 months. Patients have an annual visit to the coordinating center that includes multidisciplinary evaluations in metabolic genetics, hepatology, imaging (for abdominal ultrasound and magnetic resonance imaging) and other specialties as necessary. If hepatocellular carcinoma is suspected by imaging and/or because of progressive elevation of alphafetoprotein, liver transplantation is discussed. To date, no patient in whom treatment was started before 1 month of age has developed hepatocellular carcinoma, after surveillance for up to 20 years in some. This patient group is the largest in the world that has been treated rapidly following newborn screening. The protocol continues to evolve to adapt to the challenges of long term surveillance.
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http://dx.doi.org/10.1007/978-3-319-55780-9_17DOI Listing
December 2017

The Liver in Tyrosinemia Type I: Clinical Management and Course in Quebec.

Adv Exp Med Biol 2017 ;959:75-83

Departments of Nutrition (MB) and Radiology (JD), Divisions of Gastroenterology, Hepatology and Nutrition (FA, UH), Medical Genetics (CBG, MG, GAM) and Nephrology (AM, VP), Department of Pediatrics and Department of Pharmacy (SA, JFB), CHU Sainte-Justine and Université de Montréal, Montreal, Canada.

HT1 is a severe autosomal recessive disorder due to the deficiency of fumarylacetoacetate hydrolase (FAH), the final enzyme in the degradation of tyrosine. Before the era of treatment with 2-(2-N-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), even with newborn screening and optimal diet therapy, HT1 patients often developed liver failure. Death was common in patients who did not undergo liver transplantation. For the last two decades, NTBC has revolutionized the management of HT1 patients. In screened newborns treated within the first month of life, we have not observed hepatocarcinoma. If patients are not detected at birth by neonatal screening, the diagnosis and treatment must be performed on an emergency basis, and patients are at risk for complications. Long term adhesion to treatment and reliable early detection of hepatocellular carcinoma (HCC) are two important challenges. In this chapter, we describe the clinical, biological, histo-pathological and imaging findings of HT1 in Québec before the era of NTBC. We also describe the hepatic status of nontransplanted tyrosinemic patients in Quebec and current management practices in the Quebec NTBC Study.
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http://dx.doi.org/10.1007/978-3-319-55780-9_6DOI Listing
December 2017

Tyrosinemia and Liver Transplantation: Experience at CHU Sainte-Justine.

Adv Exp Med Biol 2017 ;959:67-73

Departments of Nutrition (MB) and Radiology (JD), Divisions of Gastroenterology, Hepatology and Nutrition (FA, UH), Medical Genetics (CBG, MG, GAM) and Nephrology (AM, VP), Department of Pediatrics and Department of Pharmacy (SA, JFB), CHU Sainte-Justine and Université de Montréal, Montreal, Canada.

Tyrosinemia is a disease of the tyrosine metabolism, affecting mainly liver, kidney and peripheral nerves. Two forms of liver disease caused by a deficiency of FAH are recognised: (1) acute liver failure; (2) chronic liver disease. Since the introduction of NTBC [2-(2-nitro-4-trifluoromethyl benzoyl)-1-3-cyclohexanedione] (nitisinone) in the treatment of tyrosinemia, no liver disease has been observed when started in the first weeks of life. Liver transplantation is a good option for the treatment of tyrosinemic patients developing liver nodules, with high suspicion of hepatocarcinoma. In the long-term outcome of the liver transplant, survival was of 90% in tyrosinemic patients.
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http://dx.doi.org/10.1007/978-3-319-55780-9_5DOI Listing
December 2017

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients.

Mol Genet Metab 2017 07 22;121(3):206-215. Epub 2017 May 22.

Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; Division of Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland; Bioanalytics & Biochemistry, Department of Natural Sciences, University of Applied Sciences, Rheinbach, Germany. Electronic address:

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.
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http://dx.doi.org/10.1016/j.ymgme.2017.05.014DOI Listing
July 2017

Reply.

J Pediatr 2017 08 24;187:334-335. Epub 2017 May 24.

Division of Endocrinology and Research Center CHU Sainte-Justine; Department of Pediatrics Université de Montréal Montreal, Quebec, Canada.

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http://dx.doi.org/10.1016/j.jpeds.2017.04.067DOI Listing
August 2017

Epistatic interaction between the lipase-encoding genes Pnpla2 and Lipe causes liposarcoma in mice.

PLoS Genet 2017 May 1;13(5):e1006716. Epub 2017 May 1.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

Liposarcoma is an often fatal cancer of fat cells. Mechanisms of liposarcoma development are incompletely understood. The cleavage of fatty acids from acylglycerols (lipolysis) has been implicated in cancer. We generated mice with adipose tissue deficiency of two major enzymes of lipolysis, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), encoded respectively by Pnpla2 and Lipe. Adipocytes from double adipose knockout (DAKO) mice, deficient in both ATGL and HSL, showed near-complete deficiency of lipolysis. All DAKO mice developed liposarcoma between 11 and 14 months of age. No tumors occurred in single knockout or control mice. The transcriptome of DAKO adipose tissue showed marked differences from single knockout and normal controls as early as 3 months. Gpnmb and G0s2 were among the most highly dysregulated genes in premalignant and malignant DAKO adipose tissue, suggesting a potential utility as early markers of the disease. Similar changes of GPNMB and G0S2 expression were present in a human liposarcoma database. These results show that a previously-unknown, fully penetrant epistatic interaction between Pnpla2 and Lipe can cause liposarcoma in mice. DAKO mice provide a promising model for studying early premalignant changes that lead to late-onset malignant disease.
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http://dx.doi.org/10.1371/journal.pgen.1006716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432192PMC
May 2017

Atypical juvenile presentation of G gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the gene.

Mol Genet Metab Rep 2017 Jun 7;11:24-29. Epub 2017 Apr 7.

CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.

G-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the gene that encodes G ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of G ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of G ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of G-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for G gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in : a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of G ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled G ganglioside and by immunohistochemistry with anti-G and anti-G antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to G-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.
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http://dx.doi.org/10.1016/j.ymgmr.2017.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388932PMC
June 2017

A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.

Cell Metab 2017 Apr;25(4):823-837.e8

Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive intermediates that non-enzymatically modify proteins. Based on this mechanism, we predicted, validated, and characterized a protein modification: 3-hydroxy-3-methylglutaryl(HMG)-lysine. In a model of altered HMG-CoA metabolism, we found evidence of two additional protein modifications: 3-methylglutaconyl(MGc)-lysine and 3-methylglutaryl(MG)-lysine. Using quantitative proteomics, we compared the "acylomes" of two reactive acyl-CoA species, namely HMG-CoA and glutaryl-CoA, which are generated in different pathways. We found proteins that are uniquely modified by each reactive metabolite, as well as common proteins and pathways. We identified the tricarboxylic acid cycle as a pathway commonly regulated by acylation and validated malate dehydrogenase as a key target. These data uncover a fundamental relationship between reactive acyl-CoA species and proteins and define a new regulatory paradigm in metabolism.
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http://dx.doi.org/10.1016/j.cmet.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399522PMC
April 2017

Premature Ovarian Failure in French Canadian Leigh Syndrome.

J Pediatr 2017 05 8;184:227-229.e1. Epub 2017 Mar 8.

Division of Endocrinology and Research Center, CHU Sainte-Justine, Montréal, Québec, Canada; Centre de Santé et de Services Sociaux de Chicoutimi, Chicoutimi, Québec, Canada. Electronic address:

In all surviving girls with Leigh syndrome, French Canadian variety, a mitochondrial disease, we detected premature ovarian failure, manifested as absent or arrested breast development, lack of menarche, high follicle-stimulating hormone, a prepubertal uterus, and small ovaries. Pubertal onset and progression should be evaluated in girls with mitochondrial diseases.
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http://dx.doi.org/10.1016/j.jpeds.2017.02.008DOI Listing
May 2017

Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency.

J Med Genet 2017 04 22;54(4):241-247. Epub 2016 Nov 22.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Québec, Canada.

Background: A high level of succinylacetone (SA) in blood is a sensitive, specific newborn screening marker for hepatorenal tyrosinemia type 1 (HT1, MIM 276700) caused by deficiency of fumarylacetoacetate hydrolase (FAH). Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio). Early treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of severe liver disease and neurological crises.

Methods And Results: Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation. Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15). Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant. In one, a single heterozygous sequence variant was identified, c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity. The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years.

Conclusions: MHSA can be caused by sequence variants in . Such individuals have thus far remained asymptomatic despite receiving no specific treatment.
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http://dx.doi.org/10.1136/jmedgenet-2016-104289DOI Listing
April 2017

A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice.

Diabetologia 2016 12 27;59(12):2654-2663. Epub 2016 Sep 27.

Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.

Aims/hypothesis: To directly assess the role of beta cell lipolysis in insulin secretion and whole-body energy homeostasis, inducible beta cell-specific adipose triglyceride lipase (ATGL)-deficient (B-Atgl-KO) mice were studied under normal diet (ND) and high-fat diet (HFD) conditions.

Methods: Atgl mice were cross-bred with Mip-Cre-ERT mice to generate Mip-Cre-ERT;Atgl mice. At 8 weeks of age, these mice were injected with tamoxifen to induce deletion of beta cell-specific Atgl (also known as Pnpla2), and the mice were fed an ND or HFD.

Results: ND-fed male B-Atgl-KO mice showed decreased insulinaemia and glucose-induced insulin secretion (GSIS) in vivo. Changes in GSIS correlated with the islet content of long-chain saturated monoacylglycerol (MAG) species that have been proposed to be metabolic coupling factors for insulin secretion. Exogenous MAGs restored GSIS in B-Atgl-KO islets. B-Atgl-KO male mice fed an HFD showed reduced insulinaemia, glycaemia in the fasted and fed states and after glucose challenge, as well as enhanced insulin sensitivity. Moreover, decreased insulinaemia in B-Atgl-KO mice was associated with increased energy expenditure, and lipid metabolism in brown (BAT) and white (WAT) adipose tissues, leading to reduced fat mass and body weight.

Conclusions/interpretation: ATGL in beta cells regulates insulin secretion via the production of signalling MAGs. Decreased insulinaemia due to lowered GSIS protects B-Atgl-KO mice from diet-induced obesity, improves insulin sensitivity, increases lipid mobilisation from WAT and causes BAT activation. The results support the concept that fuel excess can drive obesity and diabetes via hyperinsulinaemia, and that an islet beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion.
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http://dx.doi.org/10.1007/s00125-016-4105-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518076PMC
December 2016

Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis, and Insulin Resistance.

Diabetes 2016 Nov 23;65(11):3396-3409. Epub 2016 Aug 23.

Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada

Obesity and type 2 diabetes are associated with impaired mitochondrial function in adipose tissue. To study the effects of primary deficiency of mitochondrial energy metabolism in fat, we generated mice with adipose-specific deficiency of fumarate hydratase (FH), an integral Krebs cycle enzyme (AFHKO mice). AFHKO mice have severe ultrastructural abnormalities of mitochondria, ATP depletion in white adipose tissue (WAT) and brown adipose tissue, low WAT mass with small adipocytes, and impaired thermogenesis with large unilocular brown adipocytes. AFHKO mice are strongly protected against obesity, insulin resistance, and fatty liver despite aging and high-fat feeding. AFHKO white adipocytes showed normal lipolysis but low triglyceride synthesis. ATP depletion in normal white adipocytes by mitochondrial toxins also decreased triglyceride synthesis, proportionally to ATP depletion, suggesting that reduced triglyceride synthesis may result nonspecifically from adipocyte energy deficiency. At thermoneutrality, protection from insulin resistance and hepatic steatosis was diminished. Taken together, the results show that under the cold stress of regular animal room conditions, adipocyte-specific FH deficiency in mice causes mitochondrial energy depletion in adipose tissues and protects from obesity, hepatic steatosis, and insulin resistance, suggesting that in cold-stressed animals, mitochondrial function in adipose tissue is a determinant of fat mass and insulin sensitivity.
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http://dx.doi.org/10.2337/db16-0136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860441PMC
November 2016

Clinical course of sly syndrome (mucopolysaccharidosis type VII).

J Med Genet 2016 06 23;53(6):403-18. Epub 2016 Feb 23.

Edward A. Doisy Department of Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, St. Louis, Missouri, USA.

Background: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.

Methods: We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.

Results: We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.

Conclusions: MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.
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http://dx.doi.org/10.1136/jmedgenet-2015-103322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893087PMC
June 2016

Biosynthesis of glycosaminoglycans: associated disorders and biochemical tests.

J Inherit Metab Dis 2016 Mar 21;39(2):173-88. Epub 2015 Dec 21.

Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.

Glycosaminoglycans (GAG) are long, unbranched heteropolymers with repeating disaccharide units that make up the carbohydrate moiety of proteoglycans. Six distinct classes of GAGs are recognized. Their synthesis follows one of three biosynthetic pathways, depending on the type of oligosaccharide linker they contain. Chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin sulfate contain a common tetrasaccharide linker that is O-linked to specific serine residues in core proteins. Keratan sulfate can contain three different linkers, either N-linked to asparagine or O-linked to serine/threonine residues in core proteins. Finally, hyaluronic acid does not contain a linker and is not covalently attached to a core protein. Most inborn errors of GAG biosynthesis are reported in small numbers of patients. To date, in 20 diseases, convincing evidence for pathogenicity has been presented for mutations in a total of 16 genes encoding glycosyltransferases, sulfotransferases, epimerases or transporters. GAG synthesis defects should be suspected in patients with a combination of characteristic clinical features in more than one connective tissue compartment: bone and cartilage (short long bones with or without scoliosis), ligaments (joint laxity/dislocations), and subepithelial (skin, sclerae). Some produce distinct clinical syndromes. The commonest laboratory tests used for this group of diseases are analysis of GAGs, enzyme assays, and molecular testing. In principle, GAG analysis has potential as a general first-line diagnostic test for GAG biosynthesis disorders.
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http://dx.doi.org/10.1007/s10545-015-9903-zDOI Listing
March 2016

A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect.

JIMD Rep 2016 26;29:19-32. Epub 2015 Nov 26.

Department of Psychology, University of Montreal, Montreal, QC, Canada.

Cobalamin C is a rare inborn disorder of metabolism that results in multisystemic abnormalities, including progressive visual deficits. Although the cellular pathophysiology of cblC is a field of active study, little attention has been dedicated to documenting the cognitive consequences of the defect. The neuropsychological assessment of nine individuals aged between 23 months and 24 years was conducted to establish cognitive profiles. Results reveal a marked heterogeneity, with intellectual functioning ranging from extremely low to average, and cognitive difficulties (e.g., attention) evidenced even in those who are not intellectually disabled. Central nervous system abnormalities and multisystem disease are likely to be major contributing factors to the observed cognitive impairments, with the presence of visual deficits constituting an additional impediment to normal cognitive development. This study underscores the importance of conducting in-depth neuropsychological assessments in individuals with cblC, the results of which may be particularly helpful for clinical management, guidance toward rehabilitation services, and educational/vocational planning.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059201PMC
http://dx.doi.org/10.1007/8904_2015_517DOI Listing
November 2015

Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome.

Can J Cardiol 2016 Jan 13;32(1):135.e1-7. Epub 2015 Apr 13.

Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada. Electronic address:

Background: We report a 13-year-old female patient followed since birth for multiple rare congenital defects, including hypotrichosis, telangiectasia, and severe dilatation of the ascending aorta.

Methods: Comprehensive phenotype assessment throughout childhood included repeated echocardiographic measurements, evaluation of renal function, and immunohistochemical analysis of skin biopsy samples. Whole-exome sequencing was performed for the patient and both unaffected parents.

Results: We identified a novel de novo mutation in the transcription factor SOX18 (c.481C>T:p.Gln161*) in the patient, which was absent in all unaffected family members. Echocardiography revealed early onset and progressive dilatation of the ascending aorta. Skin biopsy results confirmed the defects of the blood vasculature in the presence of intact lymphatic vessels. Assessment of renal function did not show any signs of renal problems or renal failure in the patient.

Conclusions: The genetic finding of a pathogenic SOX18 mutation enabled the diagnosis of the rare hypotrichosis-lymphedema-telangiectasia syndrome in our patient. The identification of a novel stop gain mutation in the SOX18 gene in association with dilatation of the aorta highlights the importance of this gene during the development of the circulatory system. Our study highlights the importance of whole-exome sequencing in the rapid identification of genes and gene mutations involved in rare conditions and thus expanding the knowledge and spectrum of clinical manifestations associated with them.
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http://dx.doi.org/10.1016/j.cjca.2015.04.004DOI Listing
January 2016

Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome.

Hum Genet 2015 Sep 23;134(9):981-91. Epub 2015 Jun 23.

Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada,

Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS.
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http://dx.doi.org/10.1007/s00439-015-1577-yDOI Listing
September 2015

Potential mechanism underlying the PNPLA3(I) (148) (M) -Hepatic steatosis connection.

Hepatology 2016 Feb 30;63(2):676-7. Epub 2015 Jul 30.

Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada.

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http://dx.doi.org/10.1002/hep.27943DOI Listing
February 2016