Publications by authors named "Catherine Brunel-Guitton"

27 Publications

  • Page 1 of 1

Prenatal pleural effusions and chylothorax: An unusual presentation for CM-AVM syndrome due to RASA1.

Am J Med Genet A 2020 10 10;182(10):2454-2460. Epub 2020 Aug 10.

Service de Génétique Médicale, CHU Sainte-Justine, Montréal, Canada.

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http://dx.doi.org/10.1002/ajmg.a.61779DOI Listing
October 2020

Evaluation of the quality of clinical data collection for a pan-Canadian cohort of children affected by inherited metabolic diseases: lessons learned from the Canadian Inherited Metabolic Diseases Research Network.

Orphanet J Rare Dis 2020 04 10;15(1):89. Epub 2020 Apr 10.

Health Sciences Centre Winnipeg, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases.

Methods: At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN's clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data.

Results: As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method - 0% missing).

Discussion: Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.
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http://dx.doi.org/10.1186/s13023-020-01358-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149838PMC
April 2020

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians.

Can J Neurol Sci 2019 11;46(6):717-726

School of Epidemiology & Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care.

Methods: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities.

Results: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend "mitochondrial cocktails" for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority.

Conclusions: While Canadian physicians' views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.
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http://dx.doi.org/10.1017/cjn.2019.240DOI Listing
November 2019

Muscle problems in juvenile-onset acid maltase deficiency (Pompe disease).

Paediatr Child Health 2019 Jul 8;24(4):270-271. Epub 2019 May 8.

Department of Neurology Paediatrics, Children's Hospital London Health Science Centre, London, Ontario.

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http://dx.doi.org/10.1093/pch/pxy153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587424PMC
July 2019

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex 1 deficiency.

Mol Genet Metab Rep 2019 Jun 30;19:100472. Epub 2019 Apr 30.

Head Division of Biochemical Genetics, BC Children's Hospital, University of British Columbia, Room K3-205, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in Here, we report the fifth patient with related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495215PMC
June 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

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency.

Mol Genet Metab Rep 2019 Mar 18;18:32-38. Epub 2019 Jan 18.

University of British Columbia, Head Division of Biochemical Genetics, BC Children's Hospital, Room K3-205, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in Here, we report the fifth patient with related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.
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http://dx.doi.org/10.1016/j.ymgmr.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349952PMC
March 2019

Acute pediatric hyperammonemia: current diagnosis and management strategies.

Hepat Med 2018 12;10:105-115. Epub 2018 Sep 12.

Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada,

Acute hyperammonemia may induce a neurologic impairment leading to an acute life-threatening condition. Coma duration, ammonia peak level, and hyperammonemia duration are the main risk factors of hyperammonemia-related neurologic deficits and death. In children, hyperammonemia is mainly caused by severe liver failure and inborn errors of metabolism. In an acute setting, obtaining reliable plasma ammonia levels can be challenging because of the preanalytical difficulties that need to be addressed carefully. The management of hyperammonemia includes 1) identification of precipitating factors and cerebral edema presence, 2) a decrease in ammonia production by reducing protein intake and reversing catabolism, and 3) ammonia removal with pharmacologic treatment and, in the most severe cases, with extracorporeal therapies. In case of severe coma, transcranial Doppler ultrasound could be the method of choice to noninvasively monitor cerebral blood flow and titrate therapies.
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http://dx.doi.org/10.2147/HMER.S140711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140721PMC
September 2018

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment.

JIMD Rep 2018 2;39:89-96. Epub 2017 Aug 2.

Department of Medical Genetics, McGill University Health Centre (MUHC), Montreal, QC, Canada.

Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally considered a likely "non-disease," but this is based on limited supporting information, with only nine individuals with GA3 described in the literature. Clinicians encountering a patient with GA3 therefore still face a dilemma of whether or not this should be dismissed as irrelevant.We have identified three unrelated Canadian patients with GA3. Two came to clinical attention because of symptoms, while the third was identified by a population urine-based newborn screening programme and has so far remained asymptomatic. We describe the clinical histories, biochemical characterisation and genotypes of these individuals. Examination of allele frequencies underlines the fact that GA3 is underdiagnosed. While one probable factor is that some GA3 patients remain asymptomatic, we highlight other plausible reasons whereby this diagnosis might be overlooked.Gastrointestinal disturbances were previously reported in some GA3 patients. In one of our patients, severe episodes of cyclic vomiting were the major problem. A trial of antibiotic treatment, to minimise bacterial GA production, was followed by significant clinical improvement.At present, there is insufficient evidence to define any specific clinical phenotype as attributable to GA3. However, we consider that it would be premature to assume that this condition is completely benign in all individuals at all times.
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http://dx.doi.org/10.1007/8904_2017_49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953897PMC
August 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

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.

Genet Med 2017 12 27;19(12). Epub 2017 Jul 27.

Division of Neurology, McMaster University, Hamilton, Ontario, Canada.

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.
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http://dx.doi.org/10.1038/gim.2017.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804217PMC
December 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

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

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

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

Mitochondrial Diseases and Cardiomyopathies.

Can J Cardiol 2015 Nov 28;31(11):1360-76. Epub 2015 Aug 28.

Medical Genetics Division, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada.

Mitochondrial cardiomyopathies are clinically and genetically heterogeneous. An integrative approach encompassing clinical, biochemical, and molecular investigations is required to reach a specific diagnosis. In this review we summarize the clinical and genetic aspects of mitochondrial disorders associated with cardiomyopathy, including disorders of oxidative phosphorylation. It also describes groups of disorders that, although not usually classified as mitochondrial disorders, stem from defects in mitochondrial function (eg, disorders of β-oxidation and the carnitine cycle), are associated with secondary mitochondrial impairment (eg, organic acidurias), and are important diagnostically because they are treatable. Current biochemical and molecular techniques for the diagnosis of mitochondrial cardiomyopathies are described, and a diagnostic algorithm is proposed, to help clinicians in their approach to cardiomyopathies in the context of mitochondrial diseases.
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http://dx.doi.org/10.1016/j.cjca.2015.08.017DOI Listing
November 2015

An N-terminal formyl methionine on COX 1 is required for the assembly of cytochrome c oxidase.

Hum Mol Genet 2015 Jul 24;24(14):4103-13. Epub 2015 Apr 24.

Department of Human Genetics and Montreal Neurological Institute, McGill University, Montreal, QC., Canada,

Protein synthesis in mitochondria is initiated by formylmethionyl-tRNA(Met) (fMet-tRNA(Met)), which requires the activity of the enzyme MTFMT to formylate the methionyl group. We investigated the molecular consequences of mutations in MTFMT in patients with Leigh syndrome or cardiomyopathy. All patients studied were compound heterozygotes. Levels of MTFMT in patient fibroblasts were almost undetectable by immunoblot analysis, and BN-PAGE analysis showed a combined oxidative phosphorylation (OXPHOS) assembly defect involving complexes I, IV and V. The synthesis of only a subset of mitochondrial polypeptides (ND5, ND4, ND1, COXII) was decreased, whereas all others were translated at normal or even increased rates. Expression of the wild-type cDNA rescued the biochemical phenotype when MTFMT was expressed near control levels, but overexpression produced a dominant-negative phenotype, completely abrogating assembly of the OXPHOS complexes, suggesting that MTFMT activity must be tightly regulated. fMet-tRNA(Met) was almost undetectable in control cells and absent in patient cells by high-resolution northern blot analysis, but accumulated in cells overexpressing MTFMT. Newly synthesized COXI was under-represented in complex IV immunoprecipitates from patient fibroblasts, and two-dimensional BN-PAGE analysis of newly synthesized mitochondrial translation products showed an accumulation of free COXI. Quantitative mass spectrophotometry of an N-terminal COXI peptide showed that the ratio of formylated to unmodified N-termini in the assembled complex IV was ∼350:1 in controls and 4:1 in patient cells. These results show that mitochondrial protein synthesis can occur with inefficient formylation of methionyl-tRNA(Met), but that assembly of complex IV is impaired if the COXI N-terminus is not formylated.
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http://dx.doi.org/10.1093/hmg/ddv149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476453PMC
July 2015

Normal Cerebrospinal Fluid Pyridoxal 5'-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy.

JIMD Rep 2015 12;22:67-75. Epub 2015 Mar 12.

Divisions of Medical Genetics (AL, AML, CBG, GM) and Neurology (PD, ER), Department of Paediatrics, Biochemical Genetics Laboratory (CBG, PA), CHU Sainte-Justine and Université de Montréal, 3175 Côte-Sainte-Catherine, Montreal, QC, Canada, H3T 1C5.

Unlabelled: Deficiency of pyridox(am)ine 5'-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5'-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known.

Case Presentation: A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5'-phosphate, 52 nmol/L (normal, 23-64); homovanillic acid, 392 nmol/L (normal, 450-1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179-711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5'-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5'-phosphate does not rule out PNPO deficiency.
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http://dx.doi.org/10.1007/8904_2015_413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486275PMC
July 2015

The 3' addition of CCA to mitochondrial tRNASer(AGY) is specifically impaired in patients with mutations in the tRNA nucleotidyl transferase TRNT1.

Hum Mol Genet 2015 May 4;24(10):2841-7. Epub 2015 Feb 4.

Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, QC, Canada,

Addition of the trinucleotide cytosine/cytosine/adenine (CCA) to the 3' end of transfer RNAs (tRNAs) is essential for translation and is catalyzed by the enzyme TRNT1 (tRNA nucleotidyl transferase), which functions in both the cytoplasm and mitochondria. Exome sequencing revealed TRNT1 mutations in two unrelated subjects with different clinical features. The first presented with acute lactic acidosis at 3 weeks of age and developed severe developmental delay, hypotonia, microcephaly, seizures, progressive cortical atrophy, neurosensorial deafness, sideroblastic anemia and renal Fanconi syndrome, dying at 21 months. The second presented at 3.5 years with gait ataxia, dysarthria, gross motor regression, hypotonia, ptosis and ophthalmoplegia and had abnormal signals in brainstem and dentate nucleus. In subject 1, muscle biopsy showed combined oxidative phosphorylation (OXPHOS) defects, but there was no OXPHOS deficiency in fibroblasts from either subject, despite a 10-fold-reduction in TRNT1 protein levels in fibroblasts of the first subject. Furthermore, in normal controls, TRNT1 protein levels are 10-fold lower in muscle than in fibroblasts. High resolution northern blots of subject fibroblast RNA suggested incomplete CCA addition to the non-canonical mitochondrial tRNA(Ser(AGY)), but no obvious qualitative differences in other mitochondrial or cytoplasmic tRNAs. Complete knockdown of TRNT1 in patient fibroblasts rendered mitochondrial tRNA(Ser(AGY)) undetectable, and markedly reduced mitochondrial translation, except polypeptides lacking Ser(AGY) codons. These data suggest that the clinical phenotypes associated with TRNT1 mutations are largely due to impaired mitochondrial translation, resulting from defective CCA addition to mitochondrial tRNA(Ser(AGY)), and that the severity of this biochemical phenotype determines the severity and tissue distribution of clinical features.
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http://dx.doi.org/10.1093/hmg/ddv044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406295PMC
May 2015

Inborn errors of cytoplasmic triglyceride metabolism.

J Inherit Metab Dis 2015 Jan 10;38(1):85-98. Epub 2014 Oct 10.

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

Triglyceride (TG) synthesis, storage, and degradation together constitute cytoplasmic TG metabolism (CTGM). CTGM is mostly studied in adipocytes, where starting from glycerol-3-phosphate and fatty acyl (FA)-coenzyme A (CoA), TGs are synthesized then stored in cytoplasmic lipid droplets. TG hydrolysis proceeds sequentially, producing FAs and glycerol. Several reactions of CTGM can be catalyzed by more than one enzyme, creating great potential for complex tissue-specific physiology. In adipose tissue, CTGM provides FA as a systemic energy source during fasting and is related to obesity. Inborn errors and mouse models have demonstrated the importance of CTGM for non-adipose tissues, including skeletal muscle, myocardium and liver, because steatosis and dysfunction can occur. We discuss known inborn errors of CTGM, including deficiencies of: AGPAT2 (a form of generalized lipodystrophy), LPIN1 (childhood rhabdomyolysis), LPIN2 (an inflammatory condition, Majeed syndrome, described elsewhere in this issue), DGAT1 (protein loosing enteropathy), perilipin 1 (partial lipodystrophy), CGI-58 (gene ABHD5, neutral lipid storage disease (NLSD) with ichthyosis and "Jordan's anomaly" of vacuolated polymorphonuclear leukocytes), adipose triglyceride lipase (ATGL, gene PNPLA2, NLSD with myopathy, cardiomyopathy and Jordan's anomaly), hormone-sensitive lipase (HSL, gene LIPE, hypertriglyceridemia, and insulin resistance). Two inborn errors of glycerol metabolism are known: glycerol kinase (GK, causing pseudohypertriglyceridemia) and glycerol-3-phosphate dehydrogenase (GPD1, childhood hepatic steatosis). Mouse models often resemble human phenotypes but may diverge markedly. Inborn errors have been described for less than one-third of CTGM enzymes, and new phenotypes may yet be identified.
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http://dx.doi.org/10.1007/s10545-014-9767-7DOI Listing
January 2015

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.

Hum Mutat 2015 Jan 27;36(1):69-78. Epub 2014 Nov 27.

Biomedical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
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http://dx.doi.org/10.1002/humu.22709DOI Listing
January 2015

Late-onset nonketotic hyperglycinemia caused by a novel homozygous missense mutation in the GLDC gene.

Mol Genet Metab 2011 Jun 22;103(2):193-6. Epub 2011 Feb 22.

Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Canada.

Nonketotic hyperglycinemia (NKH) is an inborn error of the glycine metabolism. A 9-year-old boy with learning disability and intermittent choreoathetosis during febrile illnesses had elevated plasma glycine level and CSF/plasma glycine ratio (0.044) and a novel homozygous missense mutation (c.605C>T; p.Ala202Val) in the GLDC gene, confirming the diagnosis of NKH. This is the first report of late-onset NKH with a confirmed underlying genetic defect. NKH should be in the differential diagnosis of intermittent choreoathetosis.
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http://dx.doi.org/10.1016/j.ymgme.2011.02.009DOI Listing
June 2011

Treatment of cobalamin C (cblC) deficiency during pregnancy.

J Inherit Metab Dis 2010 Dec 10;33 Suppl 3:S409-12. Epub 2010 Sep 10.

Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5.

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.
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http://dx.doi.org/10.1007/s10545-010-9202-7DOI Listing
December 2010

LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.

Mol Biol Cell 2010 Apr 3;21(8):1315-23. Epub 2010 Mar 3.

Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada.

Mutations in LRPPRC are responsible for the French Canadian variant of Leigh syndrome (LSFC), a neurodegenerative disorder caused by a tissue-specific deficiency in cytochrome c oxidase (COX). To investigate the pathogenic mechanism of disease, we studied LRPPRC function in LSFC and control fibroblasts. The level of mutated LRPPRC is reduced in LSFC cells, and this results in decreased steady-state levels of most mitochondrial mRNAs, but not rRNAs or tRNAs, a phenotype that can be reproduced by siRNA-mediated knockdown of LRPPRC in control cells. Processing of the primary transcripts appears normal. The resultant defect in mitochondrial protein synthesis in LSFC cells disproportionately affects the COX subunits, leading to an isolated COX assembly defect. Further knockdown of LRPPRC produces a generalized assembly defect in all oxidative phosphorylation complexes containing mtDNA-encoded subunits, due to a severe decrease in all mitochondrial mRNAs. LRPPRC exists in a high-molecular-weight complex, and it coimmunoprecipitates with SLIRP, a stem-loop RNA-binding protein. Although this interaction does not depend on mitochondrial mRNA, both proteins show reduced stability in its absence. These results implicate LRPPRC in posttranscriptional mitochondrial gene expression as part of a ribonucleoprotein complex that regulates the stability and handling of mature mRNAs.
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http://dx.doi.org/10.1091/mbc.e10-01-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854090PMC
April 2010

Enzyme replacement therapy in pediatric patients with Gaucher disease: what should we use as maintenance dosage?

Mol Genet Metab 2009 Feb 10;96(2):73-6. Epub 2008 Dec 10.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Que. H3T1C5, Canada.

Introduction: No consensus exists on the minimal dose of enzyme replacement therapy (ERT) effective to maintain therapeutic goals in pediatric Gaucher patients.

Objective: Evaluate the efficacy of low dosage ERT to maintain treatment goals.

Results: Six patients had a maintenance dose of 30-35U/kg/month. All patients, with the exception of one L444P/L444P homozygote, maintained therapeutic goals.

Discussion: A low maintenance dose may be adequate in most pediatric patients. L444P homozygotes may require a higher maintenance dosage.
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http://dx.doi.org/10.1016/j.ymgme.2008.11.158DOI Listing
February 2009
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