Pranesh Chakraborty

Government of Ontario, Canada, XIA, Ontario, Canada

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Publications (45)129.13 Total impact

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    ABSTRACT: Introduction: Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. Methods: Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. Results: We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. Conclusions: The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.
    JIMD reports. 02/2015;
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    ABSTRACT: Background: Improvements in health care for children with chronic diseases must be informed by research that emphasizes outcomes of importance to patients and families. To support a program of research in the field of rare inborn errors of metabolism (IEM), we conducted a broad scoping review of primary studies that: (i) focused on chronic pediatric diseases similar to IEM in etiology or manifestations and in complexity of management; (ii) reported patient- and/or family-oriented outcomes; and (iii) measured these outcomes using self-administered tools. Methods: We developed a comprehensive review protocol and implemented an electronic search strategy to identify relevant citations in Medline, EMBASE, DARE and Cochrane. Two reviewers applied pre-specified criteria to titles/abstracts using a liberal accelerated approach. Articles eligible for full-text review were screened by two independent reviewers with discrepancies resolved by consensus. One researcher abstracted data on study characteristics, patient- and family-oriented outcomes, and self-administered measures. Data were validated by a second researcher. Results: 4,118 citations were screened with 304 articles included. Across all included reports, the most-represented diseases were diabetes (35%), cerebral palsy (23%) and epilepsy (18%). We identified 43 unique patient- and family-oriented outcomes from among five emergent domains, with mental health outcomes appearing most frequently. The studies reported the use of 405 independent self-administered measures of these outcomes. Conclusions: Patient- and family-oriented research investigating chronic pediatric diseases emphasizes mental health and appears to be relatively well-developed in the diabetes literature. Future research can build on this foundation while identifying additional outcomes that are priorities for patients and families.
    BMC Pediatrics 02/2015; 15(7). · 1.92 Impact Factor
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    ABSTRACT: Aminoacyl-transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes required for the first step of protein translation. Each aminoacyl-transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases. Lysyl-transfer RNA synthetase (KARS) links the amino acid lysine to its cognate transfer RNA. We report 2 siblings with severe infantile visual loss, progressive microcephaly, developmental delay, seizures, and abnormal subcortical white matter. Exome sequencing identified mutations within the KARS gene (NM_005548.2):c.1312C>T; p.Arg438Trp and c.1573G>A; p.Glu525Lys occurring within a highly conserved region of the catalytic domain. Our patients' phenotype is remarkably similar to a phenotype recently reported in glutaminyl-transfer RNA synthetase (QARS), another bifunctional ARS gene. This finding expands the phenotypic spectrum associated with mutations in KARS and draws attention to aminoacyl-transfer RNA synthetase as a group of enzymes that are increasingly being implicated in human disease.
    Journal of child neurology. 10/2014;
  • Clinical Biochemistry 10/2014; 47(15):134–135. · 2.23 Impact Factor
  • Clinical Biochemistry 10/2014; 47(15):135. · 2.23 Impact Factor
  • Clinical Biochemistry 10/2014; 47(15):132–133. · 2.23 Impact Factor
  • Clinical Biochemistry 10/2014; 47(15):133. · 2.23 Impact Factor
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    ABSTRACT: Introduction: NBS involves testing a small sample of blood taken from the heel of the newborn for a number of serious and life-limiting conditions. In Canada, newborn screening programs fall under provincial and territorial jurisdiction with no federal coordination. To date, we know very little about the underlying beliefs around different consent practices or how terminology is interpreted by different individuals. Differences in attitudes may have important healthcare consequences. This study will empirical data comparing stakeholder opinions on their understanding of consent-related terminology, the perceived applicability of different consent approaches to newborn screening, and the requirements of these different approaches. Methods and Analysis: Parents, healthcare professionals and policy makers will be recruited in the provinces of Ontario and Newfoundland and Labrador. Parents will be identified through records held by each provincial screening program. Healthcare professionals will be purposively sampled on the basis of engagement with newborn screening. Within each province we will identify policy makers who have policy analysis or advisory responsibilities relating to newborn bloodspot screening. Data collection will be by qualitative interviews. We will conduct 20 interviews with parents of young children, 10 interviews with key healthcare professionals across the range of appropriate specialties and 10 with policy-makers at each site (40 per site, total, N=80). The examination of the transcripts will follow a thematic analysis approach. Recruitment started in June 2014 and is expected to be complete by June 2015. Ethics and Dissemination: This study received ethics approval from the Ottawa Health Science Network Research Ethics Board, the Children’s Hospital of Eastern Ontario Research Ethics Board (both Ontario), and the Health Research Ethics Authority (Newfoundland and Labrador). Results will be reported in peer-reviewed publications and conference presentations. The results will have specific application to the development of parent education materials for newborn screening.
    BMJ Open 10/2014; ACEEPTED. · 2.06 Impact Factor
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    ABSTRACT: [LINK TO FULL PAPER:] In this article we review the literature regarding the public understanding of the potential benefits and burdens of expanded newborn bloodspot screening. We draw attention to broadened notions of benefit that go beyond early identification of asymptomatic individuals and resultant intervention to reduce morbidity or mortality, and include benefits gained by families through knowledge that may facilitate life choices, as well as gains generated by avoiding diagnostic delays. We also reflect on burdens such as increasing false-positive results and parental anxiety, together with risks of overdiagnosis when the natural history of a condition is poorly understood. We conclude that these expanded notions of benefit and burden bring with them implications for parental consent and confidentiality in the context of secondary use of residual bloodspots. Balancing benefits and burdens will be even more pertinent given technological advances that may permit whole exome or genome sequencing within newborn screening programs.
    Personalized Medicine 08/2014; 11(6):593-607. · 1.13 Impact Factor
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    ABSTRACT: Accumulation of propionylcarnitine (C3) in neonatal dried blood spots (DBS) is indicative of inborn errors of propionate metabolism including propionic acidemia (PA), methylmalonic aciduria (MMA), and cobalamin (Cbl) metabolic defects. Concentrations of C3 in affected newborns overlap with healthy individuals rendering this marker neither specific nor sensitive. While a conservative C3 cutoff together with relevant acylcarnitines ratios improve screening sensitivity, existing mass spectrometric methods in newborn screening laboratories are inadequate at improving testing specificity. Therefore, using the original screening DBS, we sought to measure 2-methylcitric acid (MCA), a pathognomonic hallmark of C3 disorders to decrease the false positive rate and improve the positive predictive value of C3 disorders. MCA was derivatized with 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE). No separate extraction step was required and derivatization was performed directly using a 3.2-mm disc of DBS as a sample (65°C for 45 min). The reaction mixture was analyzed by liquid chromatography tandem mass spectrometry. MCA was well separated and eluted at 2.3 min with a total run time of 7 min. The median and (range) of MCA of 0.06 μmol/L (0-0.63) were in excellent agreement with the literature. The method was applied retrospectively on DBS samples from established patients with PA, MMA, Cbl C, Cbl F, maternal vitamin B12 deficiency (n = 20) and controls (n = 337). Comparison with results obtained by another method was satisfactory (n = 252). This method will be applied as a second tier test for samples which trigger positive PA or MMA results by the primary newborn screening method.
    JIMD reports. 07/2014;
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    ABSTRACT: Introduction: Newborn bloodspot screening is routinely offered to all newborn babies in Canada. As with many procedures for children, this requires proxy decision-making on the part of the parents. In addition, technical advances have led to a situation where the information generated by screening can exceed providers’ capacity to intervene therapeutically. Studies have indicated support for mandated screening in the case of treatable conditions, and a need for consent for those that are not treatable. However, these studies assume that parents have a shared understanding of terms such as informed or implied consent, but also the requirements that the different approaches create. To date, there has been little exploration of the perceived benefits or drawbacks from alternative consent approaches. Objective: To explore the attitudes of parents towards different consent approaches for newborn bloodspot screening. Methods: Qualitative interviews with parents in Ontario and Newfoundland & Labrador, Canada. Results & Conclusion: We will present the results of semi-structured interviews with parents regarding consent practices for newborn bloodspot screening. Specifically, we present results of thematic analyses focussing on parent interpretations of key terms such as informed consent and implied consent, together with evaluations of necessary requirements for different approaches within the newborn screening context. In particular we report perceived differences between these approaches, and practicalities required by the differing approaches to consent.
    2014 Joint Garrod and Canadian Newborn & Child Screening Symposium,, Ottawa, Ontario; 05/2014
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    ABSTRACT: Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy. We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain. Our findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.
    BMC Medical Genetics 03/2014; 15(1):36. · 2.45 Impact Factor
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    ABSTRACT: Growing discussion on the use of whole-genome or exome sequencing (WG/ES) in newborn screening (NBS) has raised concerns regarding the generation of incidental information on millions of infants annually. It is unknown whether integrating WG/ES would alter public expectations regarding participation in universal NBS. We assessed public willingness to participate in NBS using WG/ES compared with current NBS. Our secondary objective was to assess the public's beliefs regarding a parental responsibility to participate in WG/ES-based NBS compared with current NBS. We examined self-reported attitudes regarding willingness to participate in NBS using a cross-sectional national survey of Canadian residents recruited through an internet panel, reflective of the Canadian population by age, gender and region. Our results showed that fewer respondents would be willing to participate in NBS using WG/ES compared with NBS using current technologies (80 vs 94%, P<0.001), or perceived a parental responsibility to participate in WG/ES-based NBS vs current NBS (30 vs 48%, P<0.001). Our findings suggest that integrating WG/ES into NBS might reduce participation, and challenge the moral authority that NBS programmes rely upon to ensure population benefits. These findings point to the need for caution in the untargeted use of WG/ES in public health contexts.European Journal of Human Genetics advance online publication, 19 February 2014; doi:10.1038/ejhg.2014.22.
    European journal of human genetics: EJHG 02/2014; · 3.56 Impact Factor
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    ABSTRACT: Background:Prematurity may influence amino acids, enzymes and endocrine markers levels obtained through newborn screening. Identifying which analytes are the most affected by degree of prematurity could provide insight into how prematurity impacts metabolism.Methods:We examined the associations between degree of prematurity and levels of amino acids, enzymes and endocrine markers in all newborns with and without adjustment for birth weight, feeding status, sample timing, transfusion and sex.Results:Our analysis included 373,819 children born at term (> 36 weeks gestation), 26,483 near-term children (33-36 weeks gestation), 4354 very premature children (28-32 weeks gestation) and 1146 extremely premature children (<28 weeks gestation). Of the amino acids showing consistent trends across categories of prematurity, the levels of 3 amino acids (arginine, leucine and valine) were at least 50% different between extremely premature and term children. Levels of 17-hydroxyprogesterone (17-OHP) increased with increasing prematurity while thyrotropin stimulating hormone (TSH) values consistently decreased with increasing prematurity. None of the three enzyme markers we examined showed a trend in levels across categories of prematurity.Conclusion:This study demonstrates that children at different stages of prematurity are metabolically distinct. Future research should focus on the mechanism by which prematurity impacts upon the specific analytes influenced by prematurity.Pediatric Research (2013); doi:10.1038/pr.2013.212.
    Pediatric Research 11/2013; · 2.84 Impact Factor
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    ABSTRACT: To examine the role of primary care providers in informing and supporting families who receive positive screening results. Cross-sectional survey. Ontario. Family physicians, pediatricians, and midwives involved in newborn care. Beliefs, practices, and barriers related to providing information to families who receive positive screening results for their newborns. A total of 819 providers participated (adjusted response rate of 60.9%). Of the respondents, 67.4% to 81.0% agreed that it was their responsibility to provide care to families of newborns who received positive screening results, and 64.2% to 84.8% agreed they should provide brochures or engage in general discussions about the identified conditions. Of the pediatricians, 67.3% endorsed having detailed discussions with families, but only 24.1% of family physicians and 27.6% of midwives endorsed this practice. All provider groups reported less involvement in information provision than they believed they should have. This discrepancy was most evident for family physicians: most stated that they should provide brochures (64.2%) or engage in general discussions (73.5%), but only a minority did so (15.3% and 27.7%, respectively). Family physicians reported insufficient time (42.2%), compensation (52.2%), and training (72.3%) to play this role, and only a minority agreed they were up to date (18.5%) or confident (16.5%) regarding newborn screening. Providers of primary newborn care see an information-provision role for themselves in caring for families who receive positive newborn screening results. Efforts to further define the scope of this role combined with efforts to mitigate existing barriers are warranted.
    Canadian family physician Medecin de famille canadien 08/2013; 59(8):861-8. · 1.19 Impact Factor
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    ABSTRACT: Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as beta-alanine. Existing reports describe a highly variable clinical and biochemical phenotype, which can make diagnosis a challenge. To date, only three reported cases have been confirmed at the molecular level, through identification of homozygous mutations in ALDH6A1, the gene encoding MMSDH. Confirmation by enzyme assay has until now not been possible, due to the extreme instability of the enzyme substrate.Methods and results: We report a child with severe developmental delays, abnormal myelination on brain MRI, and transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p. Arg535Cys) of ALDH6A1. The resulting amino acid changes, both occurring in residues conserved among mammals, are predicted to be damaging at the protein level. Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean. We present the fourth reported case of MMSDH deficiency with confirmation at the molecular level, and expand on what is already an extremely variable clinical and biochemical phenotype. Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity. This report illustrates the emerging utilization of whole exome sequencing and variant data filtering using clinical data as an early tool in the diagnosis of rare and variable conditions.
    Orphanet Journal of Rare Diseases 07/2013; 8(1):98. · 3.96 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Key points A novel clinical syndrome of congenital sideroblastic anemia, B cell immunodeficiency, periodic fevers and developmental delay is describedBone marrow transplant resulted in complete and durable resolution of the hematologic and immunologic manifestations.
    Blood 04/2013; · 9.78 Impact Factor
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    ABSTRACT: Context:Recent studies in critically ill populations have suggested both adrenal insufficiency (AI) and vitamin D deficiency to be associated with worse clinical outcome. There are multiple mechanisms through which these pleiotropic hormones might synergistically influence critical illness.Objective:The aim of the study was to investigate potential relationships between vitamin D status, adrenal status, and cardiovascular dysfunction in critically ill children.Design:We conducted a secondary analysis of data from a prospective cohort study.Setting and Patients:The study was conducted on 319 children admitted to 6 Canadian tertiary-care pediatric intensive care units.Main Outcome Measures:Vitamin D status was determined through total 25-hydroxyvitamin D (25OHD) levels. AI was defined as a cortisol increment under 9 μg/dL after low-dose cosyntropin. Clinically significant cardiovascular dysfunction was defined as catecholamine requirement during pediatric intensive care unit admission.Results:Using 3 different thresholds to define vitamin D deficiency, no association was found between vitamin D status and AI. Furthermore, linear regression failed to identify a relationship between 25OHD and baseline or post-cosyntropin cortisol. However, the association between AI and cardiovascular dysfunction was influenced by vitamin D status; compared to children with 25OHD above 30 nmol/L, AI in the vitamin D-deficient group was associated with significantly higher odds of catecholamine use (odds ratio, 5.29 vs 1.63; P = .046).Conclusions:We did not find evidence of a direct association between vitamin D status and critical illness-related AI. However, our results do suggest that vitamin D deficiency exacerbates the effect of AI on cardiovascular stability in critically ill children.
    The Journal of Clinical Endocrinology and Metabolism 04/2013; · 6.31 Impact Factor
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    ABSTRACT: Available from:
    American College of Genetics and Genomics Annual Meeting; 03/2013
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    ABSTRACT: BACKGROUND:: Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population. The objective of this study was to describe the impact of CHD surgery on vitamin D status and relationship between postoperative levels and clinical course. METHODS:: A prospective cohort study was conducted from 2009 to 2011 at a single tertiary care pediatric hospital. A total of 58 children with CHD were enrolled and blood collected preoperatively, intraoperatively, and postoperatively. Serum 25-hydroxyvitamin D (25OHD) was measured using liquid chromatography-mass spectrometry. RESULTS:: The mean preoperative 25OHD was 58.0 nM (SD, 22.4), with 42% being deficient (<50 nM). Postoperatively, we identified a 40% decline in 25OHD to 34.2 nM (SD, 14.5) with 86% being deficient. Intraoperative measurements determined that initiation of cardiopulmonary bypass coincided with abrupt decline. CHD patients requiring catecholamines had lower postoperative 25OHD (38.2 vs. 26.5 nM, P = 0.007), findings confirmed through multivariate logistic regression. Lower postoperative 25OHD was associated with increased fluid requirements and intubation duration. CONCLUSIONS:: Most CHD patients are vitamin-D deficient postoperatively due to low preoperative levels and a significant intraoperative decline. Interventional studies will be required to determine whether prevention of postoperative vitamin D deficiency improves outcome.
    Anesthesiology 03/2013; · 6.17 Impact Factor

Publication Stats

209 Citations
129.13 Total Impact Points


  • 2014
    • Government of Ontario, Canada
      XIA, Ontario, Canada
  • 2008–2014
    • Children's Hospital of Eastern Ontario
      Ottawa, Ontario, Canada
    • University of Ottawa
      • Department of Epidemiology and Community Medicine
      Ottawa, Ontario, Canada
  • 2012–2013
    • University of Toronto
      • Institute of Health Policy, Management and Evaluation
      Toronto, Ontario, Canada
  • 2009–2013
    • The Children’s Hospital of Eastern Ontario
      Ottawa, Ontario, Canada