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- Biochimie Métabolique -
Réponses affichées : 100
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2,3,7,8-tetrachlorodibenzo-p-dioxin counteracts the p53 response to a genotoxicant by upregulating expression of the metastasis marker agr2 in the hepatocarcinoma cell line HepG2
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AMBOLET-CAMOIT A, BUI LC, PIERRE S, CHEVALLIER A, MARCHAND A, COUMOUL X, GARLATTI M, ANDREAU K, BAROUKI R, AGGERBECK M
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2010 - Toxicol Sci 115(2):501-12 |
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant that binds the aryl hydrocarbon receptor (AhR), a transcription factor that triggers various biological responses. In this study, we show that TCDD treatment counteracts the p53 activation (phosphorylation and acetylation) elicited by a genotoxic compound, etoposide, in the human hepatocarcinoma cell line HepG2 and we delineated the mechanisms of this interaction. Using small interfering RNA knockdown experiments, we found that the newly described metastasis marker, anterior gradient-2 (AGR2), is involved in this effect. Both AGR2 messenger RNA (mRNA) and protein levels were increased (sixfold and fourfold, respectively) by TCDD treatment, and this effect was mediated by the AhR receptor. The half-life of AGR2 mRNA was unchanged by TCDD treatment. Analysis of the promoter of the AGR2 gene revealed three putative xenobiotic-responsive elements (XREs) in the proximal 3.5-kb promoter. Transient transfection of HepG2 cells by the Gaussia luciferase reporter gene driven by various deleted and mutated fragments of the promoter indicated that only the most proximal XRE was active. Binding of the AhR to the endogenous AGR2 promoter was also triggered by TCDD treatment. These results suggest that AhR ligands such as TCDD might contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants via the increased expression of the metastasis marker AGR2.
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Unité(s) :
Biochimie Métabolique
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Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis
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BARNERIAS C, SAUDUBRAY JM, TOUATI G, DE LONLAY P, DULAC O, PONSOT G, MARSAC C, BRIVET M, DESGUERRE I
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2010 - Dev Med Child Neurol 52(2):e1-e9 |
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Aim To describe the phenotype and genotype of pyruvate dehydrogenase complex (PDHc) deficiency. Method Twenty-two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15-year period. Results Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non-progressive infantile encephalopathy (three males, three females; age at diagnosis 2-9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1-13mo); and (4) those with relapsing ataxia (three males; 18-30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non-progressive encephalopathy and long-term survival in four cases. Interpretation Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non-progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.
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Unité(s) :
Biochimie Métabolique, Métabolisme, Neurologie, U663
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Cell migration and metastasis markers as targets of environmental pollutants and the Aryl hydrocarbon receptor
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BAROUKI R, COUMOUL X
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2010 - Cell Adh Migr 4(1):72-76 |
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During the last few years, several studies have pointed to a surprising link between environmental pollutants cellular signaling and important cell functions such as plasticity, adhesion and migration. This unexpected link could be related to endogenous functions of pollutants receptors that may be disrupted by environmental factors, which is supported by observations in invertebrate species. It could also reveal novel toxic end-points and mechanisms of those pollutants, such as teratogenesis and cancer metastasis that are highly relevant from a public health point of view. In the present short article, we will review our recent observations on the aryl hydrocarbon receptor and its new molecular and cellular targets. We identified HEF1/NEDD9/CAS-L, a multifunctional protein involved in integrin-based signaling as a transcriptional target of the receptor, and showed that its induction was critical for cell plasticity mediated by environmental pollutants. We will put our studies in perspective with other observations made by several groups.
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Unité(s) :
Biochimie Métabolique
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Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency
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BOLLEE G, DOLLINGER C, BOUTAUD L, GUILLEMOT D, BENSMAN A, HARAMBAT J, DETEIX P, DAUDON M, KNEBELMANN B, CEBALLOS-PICOT I
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2010 - J Am Soc Nephrol 21(4):679-88 |
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Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. Little is known regarding the clinical presentation of APRT deficiency, especially in the white population. We retrospectively reviewed all 53 cases of APRT deficiency (from 43 families) identified at a single institution between 1978 and 2009. The median age at diagnosis was 36.3 years (range 0.5 to 78.0 years). In many patients, a several-year delay separated the onset of symptoms and diagnosis. Of the 40 patients from 33 families with full clinical data available, 14 (35%) had decreased renal function at diagnosis. Diagnosis occurred in six (15%) patients after reaching ESRD, with five diagnoses made at the time of disease recurrence in a renal allograft. Eight (20%) patients reached ESRD during a median follow-up of 74 months. Thirty-one families underwent APRT sequencing, which identified 54 (87%) mutant alleles on the 62 chromosomes analyzed. We identified 18 distinct mutations. A single T insertion in a splice donor site in intron 4 (IVS4 + 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 + 2insT mutation in two (0.98%) of 204 chromosomes of healthy newborns. This report, which is the largest published series of APRT deficiency to date, highlights the underdiagnosis and potential severity of this disease. Early diagnosis is crucial for initiation of effective treatment with allopurinol and for prevention of renal complications.
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Unité(s) :
Biochimie Générale, Biochimie Métabolique, Néphrologie Adulte, U845 (FT)
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Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency
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BONNEFONT JP, BASTIN J, LAFORET P, AUBEY F, MOGENET A, ROMANO S, RICQUIER D, GOBIN-LIMBALLE S, VASSAULT A, BEHIN A, EYMARD B, BRESSON JL, DJOUADI F
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2010 - Clin Pharmacol Ther 88(1):101-8 |
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Carnitine palmitoyltransferase 2 (CPT2) deficiency is a rare mitochondrial fatty acid oxidation (FAO) disorder characterized by myalgia, exercise intolerance, and rhabdomyolysis. We evaluate the efficacy of bezafibrate (BZ), a hypolipidemic drug, as a treatment for this form of CPT2 deficiency. A pilot trial was conducted with BZ in six patients for 6 months. There was a follow-up period of 3 years. The oxidation rates of the long-chain fatty acid derivative palmitoyl-CoA, measured in the mitochondria of the patients' muscles, were markedly lower than normal before treatment and increased significantly (+39 to +206%; P = 0.028) in all patients after BZ treatment. The evaluation of the therapeutic effects by the patients themselves (using the Short Form Health Survey (SF-36)), as well as by the physicians, indicated an improvement in the condition of the patients; there was an increase in physical activity and a decline in muscular pain. The results suggest that BZ has a therapeutic effect in the muscular form of CPT2 deficiency.
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Unité(s) :
Biochimie Métabolique, CIC, Métabolisme, U781
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Management of West syndrome in a patient with methylmalonic aciduria
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CAMPEAU PM, VALAYANNOPOULOS V, TOUATI G, BAHI-BUISSON N, BODDAERT N, PLOUIN P, RABIER D, BENOIST JF, DULAC O, DE LONLAY P, DESGUERRE I
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2010 - J. Child Neurol. 25(1):94-97 |
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Infantile spasms (or West syndrome) occur occasionally in patients with branched-chain organic acidurias. We describe a patient diagnosed with methylmalonic aciduria at 4.5 months of age during an episode of metabolic decompensation. The child was developmentally delayed and hypotonic; his electroencephalography (EEG) showed hypsarrythmia and brain magnetic resonance imaging (MRI) demonstrated moderate abnormalities in the globi pallidi. Following the failure of vigabatrin and lamotrigine to control the spasms, hydrocortisone was introduced. Methylmalonic acid excretion increased at the onset of steroid therapy but was rapidly corrected with transient protein restriction and initiation of metronidazole therapy. Full control of spasms and hypsarrythmia permitted the discontinuation of hydrocortisone therapy a year following its initiation. Tone and development improved although the latter remained delayed. This case illustrates the importance of screening for inborn errors of metabolism in seizure disorders, and that, although challenging, the management of methylmalonic aciduria with concurrent steroid therapy is possible and beneficial.
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Unité(s) :
Biochimie Métabolique, Explorations Fonctionnelles, Métabolisme, Neurologie, Radiologie Pédiatrique
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Gestational age-related reference values for amniotic fluid organic acids
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OTTOLENGHI C, ABERMIL N, LESCOAT A, AUPETIT J, BEAUGENDRE O, MORICHON-DELVALLEZ N, RICQUIER D, CHADEFAUX-VEKEMANS B, RABIER D
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2010 - Prenat Diagn 30(1):43-48 |
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BACKGROUND: Normative data for amniotic fluid (AF) levels of organic acids at different gestational ages are lacking. They can provide a useful framework to investigate the accuracy of prenatal diagnosis for organic acidemias. METHODS: We report on the concentration of 21 organic acids in AF obtained by gas chromatography/mass spectrometry between the 12th and 34th weeks of gestation from 92 pregnancies that were not at risk for organic acidurias. RESULTS: We infer normal reference values that can be compared with 134 pregnancies at risk for several metabolic conditions, that is, propionic acidemia, methylmalonic acidemia (methylmalonyl-CoA mutase deficiency or defects in cobalamin metabolism), 4-hydroxybutyric acidemia, glutaric acidemia and pyroglutamic acidemia. CONCLUSION: Most of the metabolites tested did not show conspicuous variations across gestational ages in normal fetuses, with ranges that were consistently similar to available reference values from pooled samples in previous reports. With rare exceptions, knowledge of pathological versus normal values for relevant metabolites leads to clear-cut differentiation of affected versus unaffected fetuses. Nevertheless, it is strongly recommended that mutational analysis and/or additional biochemical approaches complement organic acid analysis for an adequate diagnostic workup. Copyright (c) 2009 John Wiley & Sons, Ltd.
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Unité(s) :
Biochimie Métabolique, Centre de Génétique Médicale Jean Frézal
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New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria
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VALAYANNOPOULOS V, HAUDRY C, SERRE V, BARTH M, BODDAERT N, ARNOUX JB, CORMIER-DAIRE V, RIO M, RABIER D, VASSAULT A, MUNNICH A, BONNEFONT JP, DE LONLAY P, ROTIG A, LEBRE AS
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2010 - Mitochondrion 10(4):335-41 |
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Deficiencies in two subunits of the succinyl-coenzyme A synthetase (SCS) have been involved in patients with encephalomyopathy and mild methylmalonic aciduria (MMA). In this study, we described three new SUCLG1 patients and performed a meta-analysis of the literature. Our report enlarges the phenotypic spectrum of SUCLG1 mutations and confirms that a characteristic metabolic profile (presence of MMA and C4-DC carnitine in urines) and basal ganglia MRI lesions are the hallmarks of SCS defects. As mitochondrial DNA depletion in muscle is not a constant finding in SUCLG1 patients, this may suggest that diagnosis should not be based on it, but also that alternative physiopathological mechanisms may be considered to explain the combined respiratory chain deficiency observed in SCS patients.
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Unité(s) :
Biochimie Métabolique, Centre de Génétique Médicale Jean Frézal, Métabolisme, Radiologie Pédiatrique, U781
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Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity
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BUI LC, TOMKIEWICZ C, CHEVALLIER A, PIERRE S, BATS AS, MOTA S, RAINGEAUD J, PIERRE J, DIRY M, TRANSY C, GARLATTI M, BAROUKI R, COUMOUL X
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2009 - Oncogene 28(41):3642-51 |
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Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.
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Unité(s) :
Biochimie Métabolique
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Hypoxanthine-guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis
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CEBALLOS-PICOT I, MOCKEL L, POTIER MC, DAUPHINOT L, SHIRLEY TL, TORERO-IBAD R, FUCHS J, JINNAH HA
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2009 - Hum Mol Genet 18(13):2317-27 |
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Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency results in Lesch-Nyhan disease (LND), where affected individuals exhibit a characteristic neurobehavioral disorder that has been linked with dysfunction of dopaminergic pathways of the basal ganglia. Since the functions of HPRT, a housekeeping enzyme responsible for recycling purines, have no direct relationships with the dopaminergic pathways, the mechanisms whereby HPRT deficiency affect them remain unknown. The current studies demonstrate that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype, using several different cell models for HPRT deficiency. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient (HPRT(-)) sublines derived from the MN9D cell line. Despite the variation inherent in such mutant sublines, several consistent abnormalities were evident. Most notable were increases in the mRNAs for engrailed 1 and 2, transcription factors known to play a key role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels, demonstrating a functional relationship between HPRT and engrailed. The functional relevance of the abnormal developmental molecular signature of the HPRT(-) MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. To verify that these abnormalities were not idiosyncratic to the MN9D line, HPRT(-) sublines from the SK-N-BE(2) M17 human neuroblastoma line were evaluated and an increased expression of engrailed mRNAs was also seen. Over-expression of engrailed occurred even in primary fibroblasts from patients with LND in a manner that suggested a correlation with disease severity. These results provide novel evidence that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms.
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Unité(s) :
Biochimie Métabolique
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Characterisation of a human liver cystathionine beta synthase mRNA sequence corresponding to the c.[833T>C;844_845ins68] mutation in CBS gene
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CHASSE JF, BAROUKI R
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2009 - Mol Cell Biochem 332(1-2):183-7 |
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Cystathionine beta synthase (CBS) is the only reaction that removes homocysteine from methionine cycle and redirects it to the transsulfuration pathway. The c.[833T>C;844_845ins68] mutation in the CBS gene has been reported initially as corresponding to classic homocystinuria. Studies showing that the insertion is associated with very smalls amounts of the transcript in the nucleus; others suggest that the heterozygous and homozygous subjects are protected against hyperhomocysteinemia and that the insertion tends to rescue the protein function. The liver is the major organ which metabolizes the circulating homocysteine to cystathionine. We have determined the sequence of the liver mRNA corresponding to the CBS c.[833T>C;844_845ins68] gene. We have shown that a novel splicing event could account for the modification in protein and possibly in enzyme activity.
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Unité(s) :
Biochimie Métabolique
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Long-term outcome in methylmalonic aciduria: A series of 30 French patients
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COSSON MA, BENOIST JF, TOUATI G, DECHAUX M, ROYER N, GRANDIN L, JAIS JP, BODDAERT N, BARBIER V, DESGUERRE I, CAMPEAU PM, RABIER D, VALAYANNOPOULOS V, NIAUDET P, DE LONLAY P
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2009 - Mol Genet Metab 97(3):172-8 |
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OBJECTIVE: To better delineate the natural history of patients with methylmalonic aciduria (MMA). STUDY DESIGN: Thirty patients with vitamin-B(12)-unresponsive MMA (25 aged 1.5 to 22.0years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3y (range: 1.4-19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies. RESULTS: Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5y (range 1.5-18.6). Renal function further deteriorated in 4 patients within a median period of 5.8y (range 2-7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut degrees , 3 mut- and 5 cblA. Mortality, number of acute decompensations (p=0.031), median MMA urinary excretion (p=0.006) and neurological impairment (p<0.0001) were higher in mut degrees patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut degrees patients and was more severe. CONCLUSIONS: Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut degrees phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.
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Unité(s) :
Biochimie Métabolique, Métabolisme, Néphrologie Pédiatrique, Biostatistique, Radiologie Pédiatrique, U781
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Multiple OXPHOS deficiency in the liver, kidney, heart and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria
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DE KEYZER Y, VALAYANNOPOULOS V, BENOIST JF, BATTEUX F, LACAILLE F, HUBERT L, CHRETIEN D, CHADEFEAUX-VEKEMANS B, NIAUDET P, TOUATI G, MUNNICH A, DE LONLAY P
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2009 - Pediatr Res 66(1):91-95 |
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We investigated respiratory chain (RC), tricarboxylic acid cycle (TCA) enzyme activities and oxidative stress in the tissues of 6 patients with organic acidemias (OA) presenting various severe complications to further document the role of mitochondrial OXPHOS dysfunction in the development of complications. Two children with propionic acidemia (PA) presenting a severe cardiomyopathy, and four with methylmalonic aciduria (MMA), who developed a neurological disease (3/4) and renal failure (2/4) were followed. We measured RC and TCA cycle enzyme activity in patient tissues and assessed oxidative metabolism in fibroblasts in vitro. Various RC deficiencies were found in tissues of PA and MMA patients. TCA cycle enzyme activities were normal when investigated, reactive oxygen species were decreased as well as detoxifying systems activities in the two patients tested. In conclusion, mitochondrial dysfunction was found in all investigated tissues of 6 patients with organic acidemia presenting with severe complications. Reactive oxygen species production and detoxification were decreased in fibroblast primary cultures. Our results bring further support for a role of secondary respiratory deficiency in the development of late multiorgan complications of these diseases.
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Unité(s) :
Biochimie Métabolique, Métabolisme, Pédiatrie Générale, Néphrologie Pédiatrique, U781
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[Recommendations for metrological control of measuring equipments in the clinical laboratories.]
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DUMONTET M, GIROUD C, VASSAULT A, GUITEL F, PERRIN A, BRACONNIER F, FERARD G, BEAUDEUX JL
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2009 - Ann Biol Clin (Paris) 67(4):465-476 |
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The control of the measuring equipments (balances, mass standards, micropipettes, dilutors, volumetric glassware, thermometers...) is essential to obtain reliable analytical results. This control requires knowledge and use of the main standards, instructions for use, metrological verifications and confirmations as well as creation of checking and standardizing certificates ensuring metrological traceability. These items should help to control the quality of the analytical performances (fidelity and trueness in particular).
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Unité(s) :
Biochimie Métabolique
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Misleading behavioural phenotype with adenylosuccinate lyase deficiency
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GITIAUX C, CEBALLOS-PICOT I, MARIE S, VALAYANNOPOULOS V, RIO M, VERRIERES S, BENOIST JF, VINCENT MF, DESGUERRE I, BAHI-BUISSON N
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2009 - Eur. J. Human Genet. 17(1):133-136 |
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Adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features and are usually discovered during screens for unexplained encephalopathy using the Bratton-Marshall assay that reveals the excretion of the succinylaminoimidazolecarboxamide riboside (SAICAr). Here, we report on two sisters aged 11 and 12 years presented with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combined excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that gave a behavioural profile mimicking Angelman syndrome. Both patients had an increased succinyladenosine/SAICAr ratio of 1.6, and exhibited a novel homozygous missense mutation (c.674T>C; p.Met225Thr) in the exon 6 of the ADSL gene. We suggest that these clinical features might be a new presentation of adenylosuccinate lyase deficiency. On the basis of this observation, although adenylosuccinate lyase deficiency is a rare disorder, this diagnosis should be considered in patients with mental retardation and a behavioural profile suggestive of Angelman syndrome.European Journal of Human Genetics advance online publication, 1 October 2008; doi:10.1038/ejhg.2008.174.
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Unité(s) :
Biochimie Métabolique, Génétique Médicale Pédiatrique, Métabolisme, Neurologie
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Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations
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KAPOOR RR, FLANAGAN SE, FULTON P, CHAKRAPANI A, CHADEFAUX B, BEN-OMRAN T, BANERJEE I, SHIELD JP, ELLARD S, HUSSAIN K
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2009 - Eur J Endocrinol 161(5):731-5 |
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BACKGROUND: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism-hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. OBJECTIVES: To study the genotype-phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. RESULTS: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 micromol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. CONCLUSION: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.
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Unité(s) :
Biochimie Métabolique
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Causes, consequences, detection, and prevention of identification errors in laboratory diagnostics
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LIPPI G, BLANCKAERT N, BONINI P, GREEN S, KITCHEN S, PALICKA V, VASSAULT AJ, MATTIUZZI C, PLEBANI M
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2009 - Clin Chem Lab Med 47(2):143-53 |
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Abstract Laboratory diagnostics, a pivotal part of clinical decision making, is no safer than other areas of healthcare, with most errors occurring in the manually intensive preanalytical process. Patient misidentification errors are potentially associated with the worst clinical outcome due to the potential for misdiagnosis and inappropriate therapy. While it is misleadingly assumed that identification errors occur at a low frequency in clinical laboratories, misidentification of general laboratory specimens is around 1% and can produce serious harm to patients, when not promptly detected. This article focuses on this challenging issue, providing an overview on the prevalence and leading causes of identification errors, analyzing the potential adverse consequences, and providing tentative guidelines for detection and prevention based on direct-positive identification, the use of information technology for data entry, automated systems for patient identification and specimen labeling, two or more identifiers during sample collection and delta check technology to identify significant variance of results from historical values. Once misidentification is detected, rejection and recollection is the most suitable approach to manage the specimen. Clin Chem Lab Med 2009;47:143-53.
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Unité(s) :
Biochimie Métabolique
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Multicenter evaluation of the hemolysis index in automated clinical chemistry systems
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LIPPI G, LUCA-SALVAGNO G, BLANCKAERT N, GIAVARINA D, GREEN S, KITCHEN S, PALICKA V, VASSAULT AJ, PLEBANI M
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2009 - Clin Chem Lab Med 47(8):934-9 |
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Abstract Background: In vitro hemolysis, the prevailing cause of preanalytical error in routine laboratory diagnostics, might influence the reliability of several tests, affect the quality of the total testing process and jeopardize patient safety. Although laboratory instrumentation is now routinely equipped with systems capable of automatically testing and eventually correcting for hemolysis interference, to our knowledge there are no reports that have compared the efficiency of different analytical platforms for identifying and classifying specimens with hemolysis. Methods: Serum from a healthy volunteer was spiked with varying amounts of hemolyzed blood from the same volunteer, providing a serum free hemoglobin concentration ranging from 0.0 g/L to 2.0 g/L as measured by the reference cyanmethemoglobin assay. The spiked serum samples were shipped to seven separate laboratories and the hemolysis index (HI) was tested in triplicate on the following analytical platforms: Roche Modular System P (n=4) and Integra 400 Plus (n=1), Siemens Dimension RxL (n=3), ADVIA 2400 (n=1) and ADVIA 1800 (n=1), Olympus AU 680 (n=1) and Coulter DXC 800 (n=1). Results: Satisfactory agreement of HI results was observed among the various analytical platforms, despite a trend toward overestimation by the ADVIA 2400 and 1800. After normalizing results according to the instrument-specific alert value, discrepancies were considerably reduced. All instruments except for the Dimension RxL gave values normalized to the instrument-specific alert value, <1.0 for the sample with 0.048 g/L free hemoglobin, and >1.0 for the sample with 0.075 g/L free hemoglobin. The results of the four Modular System P tests were also highly reproducible among the different facilities. When evaluating instruments that provided quantitative HI results, the mean intra-assay coefficient of variation (CV) calculated for the triplicate determinations was always between 0.1% and 2.7%. Conclusions: The results of this multicenter evaluation confirm that efficiency of different analytical platforms to correctly identify and classify unsuitable samples is satisfactory. However, more effort should be placed on the standardization of reporting HI. All the instruments that we tested provide either quantitative or qualitative results that are essentially comparable, but which should always be compared with the instrument-specific alert values to harmonize their efficiency. Clin Chem Lab Med 2009;47:934-9.
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Unité(s) :
Biochimie Métabolique
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A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome
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LOPES PEREIRA P, MAGNOL L, SAHUN I, BRAULT V, DUCHON A, PRANDINI P, GRUART A, BIZOT JC, CHADEFAUX-VEKEMANS B, DEUTSCH S, TROVERO F, DELGADO-GARCIA JM, ANTONARAKIS SE, DIERSSEN M, HERAULT Y
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2009 - Hum Mol Genet 18(24):4756-69 |
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Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.
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Unité(s) :
Biochimie Métabolique
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Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency
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MONNOT S, SERRE V, CHADEFAUX-VEKEMANS B, AUPETIT J, ROMANO S, DE LONLAY P, RIVAL JM, MUNNICH A, STEFFANN J, BONNEFONT JP
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2009 - Hum Mutat 30(5):734-740 |
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Pyruvate carboxylase (PC), a key enzyme for gluconeogenesis and anaplerotic pathways, consists of four domains, namely, biotin carboxylase (BC), carboxyltransferase (CT), pyruvate carboxylase tetramerization (PT), and biotin carboxyl carrier protein (BCCP). PC deficiency is a rare metabolic disorder inherited in an autosomal recessive way. The most severe form (form B) is characterized by neonatal lethal lactic acidosis, whereas patients with form A suffer chronic lactic acidosis with psychomotor retardation. Diagnosis of PC deficiency relies on enzymatic assay and identification of the PC gene mutations. To date, six mutations of the PC gene have been identified. We report nine novel mutations of the PC gene, in five unrelated patients: three being affected with form B, and the others with form A. Three of them were frameshift mutations predicted to introduce a premature termination codon, the remaining ones being five nucleotide substitutions and one in frame deletion. Impact of these mutations on mRNA was assessed by RT-PCR. Evidence for a deleterious effect of the missense mutations was achieved using protein alignments and three-dimensional structural prediction, thanks to our modeling of the human PC structure. Altogether, our data and those previously reported indicate that form B is consistently associated with at least one truncating mutation, mostly lying in CT (C-terminal part) or BCCP domains, whereas form A always results from association of two missense mutations located in BC or CT (N-terminal part) domains. Finally, although most PC mutations are suggested to interfere with biotin metabolism, none of the PC-deficient patients was biotin-responsive. Hum Mutat 0:1-7, 2009. (c) 2009 Wiley-Liss, Inc.
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Unité(s) :
Biochimie Métabolique, Métabolisme, U781
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Secondary creatine deficiency in ornithine delta-aminotransferase deficiency
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VALAYANNOPOULOS V, BODDAERT N, MENTION K, TOUATI G, BARBIER V, CHABLI A, SEDEL F, KAPLAN J, DUFIER JL, SEIDENWURM D, RABIER D, SAUDUBRAY JM, DE LONLAY P
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2009 - Mol Genet Metab 97(2):109-13 |
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AIMS: Ornithine delta-aminotransferase (OAT) deficiency causes gyrate atrophy (GA) of the retina, as a consequence of high plasma ornithine concentrations. Because creatine synthesis requires the conversion of arginine and glycine into ornithine and guanidinoacetate, high ornithine concentration inhibits this reaction thus causing secondary creatine deficiency. The aim of this study was to evaluate the neuropsychological features and creatine metabolism in patients with GA. METHODS: The study involved 7 GA patients, aged from 11 to 27 years who underwent neuropsychological evaluation and cerebral proton magnetic resonance spectroscopy (MRS). RESULTS: Neurocognitive impairment was found in 5/7 patients, including mental retardation (3/7), school failure (1/7), major visuospatial dyspraxia (1/7), aggressive behavior (3/7) and epilepsy (2/7). Two patients had normal neuropsychological evaluation. Cerebral proton magnetic resonance spectroscopy revealed a profound creatine deficiency in all patients. MRS data were confirmed by decreased levels of creatine and/or guanidinoacetate in plasma and urine in all patients. CONCLUSIONS: In our group of patients with GA, we found a high prevalence of neurological impairment, not reported so far, and possibly related to secondary creatine deficiency and hyperornithinemia. We propose to treat mentally retarded GA patients with high doses of creatine, as it may normalize brain creatine levels and help to reduce ornithine levels.
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Unité(s) :
Biochimie Métabolique, Métabolisme, Radiologie Pédiatrique, U781, Ophtalmologie, Centre de Génétique Médicale Jean Frézal
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Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria sensitive to vitamin B(12)
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VALAYANNOPOULOS V, HUBERT L, BENOIST JF, ROMANO S, ARNOUX JB, CHRETIEN D, KAPLAN J, FAKHOURI F, RABIER D, ROTIG A, LEBRE AS, MUNNICH A, DE KEYZER Y, DE LONLAY P
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2009 - J Inherit Metab Dis 32(2):159-62 |
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An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the patient's liver. We suggest that patients with B(12)-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications.
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Unité(s) :
Centre de Génétique Médicale Jean Frézal, U781, Biochimie Métabolique
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Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria
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COSSON MA, TOUATI G, LACAILLE F, VALAYANNNOPOULOS V, GUYOT C, GUEST G, VERKARRE V, CHRETIEN D, RABIER D, MUNNICH A, BENOIST JF, DE KEYZER Y, NIAUDET P, DE LONLAY P
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2008 - Mol. Genet. Metab. 95(1-2):107-109 |
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A boy who was diagnosed with methylmalonic aciduria (MMA) at the age of 10 days developed persistent hepatomegaly and raised transaminases from the age of 4 years. He was subsequently diagnosed with Leigh syndrome and required a kidney transplantation for end-stage renal failure. A massive hepatoblastoma led to his death by the age of 11 years. Methylmalonyl-CoA mutase activity was undetectable on both cultured skin fibroblasts and kidney biopsy and multiple respiratory chain deficiency was demonstrated in the kidney. Mitochondrial dysfunction and/or post-transplant immunosuppressive therapy should be considered as a possible cause of liver cancer in this patient.
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Unité(s) :
Anatomie Pathologique, Biochimie Métabolique, Gastro-Hépatologie et Nutrition Pédiatriques, Métabolisme, Néphrologie Pédiatrique, U781
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Evidence of cataplerosis in a patient with neonatal classical galactosemia presenting as citrin deficiency
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FEILLET F, MERTEN M, BATTAGLIA-HSU SF, RABIER D, KOBAYASHI K, STRACZEK J, BRIVET M, FAVRE E, GUÉANT JL
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2008 - J. Hepatol. 48(3):517-522 |
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Classical galactosemia is an autosomal recessive disorder caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase. Undoubtedly, some of the short term complications are linked to the toxic effects of the accumulated abnormal metabolites (galactose-1-phosphate and galactitol). However, the physiopathology of neonatal liver failure remains unclear. We report the case of a 7-week-old girl who was first diagnosed with liver failure, hypoprotidaemia, ascites and generalized edemas. High citrulline (293mumol/L), on initial plasma amino acid, suggested the diagnosis of citrin deficiency. As the citric acid cycle intermediates were non-detectable (oxoglutarate, succinate and citrate), a cataplerotic state was suspected. As a result, citrate (as an anaplerotic treatment) induced a clear improvement in her liver function. Four weeks later, this patient was switched to a galactose-free formula (as recommended in citrin deficiency with galactosemia) and her pathological status returned to normal. Citrin deficiency was later ruled out by molecular biology studies; then we reintroduced a galactose-containing formula which re-evoked rapidly vomiting, galactose aversion and hepatic cytolysis and the diagnosis of classical galactosemia was established. Our case clearly shows that cataplerosis could play a role in the pathophysiology of the neonatal liver disease observed in classical galactosemia.
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Unité(s) :
Biochimie Métabolique
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L-arginine metabolism in dog kidney and isolated nephron segments
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LEVILLAIN O, RABIER D, DUCLOS B, GAUDREAU P, VINAY P
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2008 - Metabolism 57(1):9-23 |
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The renal basic amino acid metabolism often differs in rodents, strict carnivores, and omnivore species. Given the pivotal role of L-arginine and L-ornithine in several metabolic pathways and the fact that the dog is closely related to humans, being also an omnivore, we tested whether L-arginine metabolism and L-ornithine catabolism take place in the dog kidney. We examined the metabolism of L-arginine in dog cortical tubules to integrate local L-arginine metabolism into a general physiological and metabolic framework. To achieve these goals, we first ascertained the protein expression of relevant enzymes by Western blot. L-Arginine catabolism was studied in suspensions of canine cortical proximal tubules, medullary thick ascending limbs, and papillary collecting ducts either incubated without exogenous L-arginine being added (small endogenous quantities) or incubated with L-arginine being added in supraphysiological amounts (2 mmol/L with or without the presence of alternative metabolic substrates, 2 mmol/L L-glutamine, or lactate). The results revealed that dog kidneys consumed L-citrulline and released L-arginine and L-ornithine. Argininosuccinate synthetase and lyase, arginase II, and ornithine aminotransferase were detected in the renal cortex. Arginase II activity was found in a suspension of proximal tubules by measuring the amounts of urea and L-ornithine produced. A fraction of this L-ornithine was further partially metabolized through the intramitochondrial ornithine aminotransferase pathway, leading to changes in L-glutamate, glucose, L-alanine, and ammonia metabolism without L-proline accumulation. Medullary thick ascending limbs expressed a very low arginase activity, whereas papillary collecting ducts did not. In conclusion, the dog kidney produces L-arginine. Part of this L-arginine is further catabolized by arginase II, suggesting that its physiological role was to produce L-ornithine for the body.
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Unité(s) :
Biochimie Métabolique
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Consequences of impaired purine recycling in dopaminergic neurons
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LEWERS JC, CEBALLOS-PICOT I, SHIRLEY TL, MOCKEL L, EGAMI K, JINNAH HA
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2008 - Neuroscience 152(3):761-772 |
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A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.
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Unité(s) :
Biochimie Métabolique
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Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories
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LIPPI G, BLANCKAERT N, BONINI P, GREEN S, KITCHEN S, PALICKA V, VASSAULT AJ, PLEBANI M
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2008 - Clin. Chem. Lab. Med. 46(6):764-772 |
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Prevention of medical errors is a major goal of healthcare, though healthcare workers themselves have not yet fully accepted or implemented reliable models of system error, and neither has the public. While there is widespread perception that most medical errors arise from an inappropriate or delayed clinical management, the issue of laboratory errors is receiving a great deal of attention due to their impact on the quality and efficiency of laboratory performances and patient safety. Haemolytic specimens are a frequent occurrence in clinical laboratories, and prevalence can be as high as 3.3% of all of the routine samples, accounting for up to 40%-70% of all unsuitable specimens identified, nearly five times higher than other causes, such as insufficient, incorrect and clotted samples. This article focuses on this challenging issue, providing an overview on prevalence and leading causes of in vivo and in vitro haemolysis, and tentative guidelines on identification and management of haemolytic samples in clinical laboratories. This strategy includes continuous education of healthcare personnel, systematic detection/quantification of haemolysis in any sample, immediate clinicians warning on the probability of in vivo haemolysis, registration of non-conformity, completing of tests unaffected by haemolysis and request of a second specimen for those potentially affected.
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Unité(s) :
Biochimie Métabolique
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Modified glutamine catabolism in macrophages of Ucp2 knock-out mice
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NUBEL T, EMRE Y, RABIER D, CHADEFAUX B, RICQUIER D, BOUILLAUD F
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2008 - Biochim. Biophys. Acta - Bioenergetics 1777(1):48-54 |
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Uncoupling protein 2 (UCP2) belongs to a family of transporters of the mitochondrial inner membrane and is reported to uncouple respiration from ATP synthesis. Our observation that the amino acid glutamine specifically induces UCP2 protein expression prompted us to investigate metabolic consequences of a UCP2 knockdown (Ucp2-KO) when glutamine is offered as a substrate. We found that Ucp2-KO macrophages incubated in the presence of glutamine exhibit a lower ammonium release, a decreased respiratory rate, and an intracellular accumulation of aspartate. Therefore, we conclude that UCP2 expression is required for efficient oxidation of glutamine in macrophages. This role of UCP2 in glutamine metabolism appears independent from the uncoupling activity of UCP2.
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Unité(s) :
Biochimie Métabolique, UPR 9078
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Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping
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SERVAIS A, MORINIERE V, GRŸNFELD JP, NO‘L LH, GOUJON JM, CHADEFAUX-VEKEMANS B, ANTIGNAC C
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2008 - Clin. J. Amer. Soc. Nephrol. 3(1):27-35 |
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BACKGROUND AND OBJECTIVES: Cystinosis is an autosomal recessive disease characterized by the intralysosomal accumulation of cystine, as a result of a defect in cystine transport across the lysosomal membrane. Three clinical forms have been described on the basis of severity of symptoms and age of onset: infantile cystinosis, characterized by renal proximal tubulopathy and progression to end-stage renal disease before 12 yr of age; juvenile form, with a markedly slower rate of progression; and adult form, with only ocular abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fourteen patients in nine unrelated families with noninfantile cystinosis were studied. Information about clinical outcome, biochemical data, renal histopathologic data, and genotyping was collected. RESULTS: Eight patients had Fanconi syndrome. Proteinuria was present in all patients. Serum creatinine at last follow-up, without specific treatment, ranged between 69 and 450 mumol/L, at an age of 12 to 56 yr. Four patients reached end-stage renal disease by 12 to 28 yr. Renal biopsies, available in four cases, disclosed focal segmental glomerulosclerosis in three and crystals in three. Genetic screening showed that patients were compound heterozygous for mutations in the CTNS gene in four families and homozygous in two families. Patients had at least one "mild" mutation. A single heterozygous mutation was identified in one family and none in two families (only 72% mutations found). CONCLUSION: Renal involvement is heterogeneous in patients with noninfantile cystinosis even within families, and renal disease should be assessed even in families of patients with seemingly isolated ocular forms.
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Unité(s) :
Néphrologie Adulte, Néphrologie Pédiatrique, Anatomie Pathologique, Génétique Médicale Pédiatrique, Biochimie Métabolique, U574
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What's new in metabolic and genetic hypoglycaemias: diagnosis and management
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VALAYANNOPOULOS V, ROMANO S, MENTION K, VASSAULT A, RABIER D, POLAK M, ROBERT JJ, KEYZER Y, DE LONLAY P
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2008 - Eur. J. Pediat. 167(3):257-265 |
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Hypoglycaemia in children can be a life-threatening situation that needs to be assessed rigorously in order to treat efficiently and avoid relapse that can be responsible for cerebral damage. The diagnosis of impairment in glucose homeostasis requires the knowledge of the mechanisms regulating blood glucose concentration. The clinical history and presentation, when available, especially the timing of hypoglycaemia with respect to the last meal and some simple clinical and biological tests may allow diagnosing the vast majority of patients presenting with hypoglycaemia. Recently, new metabolic and endocrinologic genetic causes of hypoglycaemia have been identified that may give new insight to the complex mechanisms of glucose regulation and thus contribute to the discovery of new genes regulating glucose homeostasis. New diagnostic tests such as the 18-fluoro-Dopa PET-scan have also been recently developed.
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Unité(s) :
U781, Biochimie Métabolique, Métabolisme, Endocrinologie Pédiatrique et Gynécologie, Diabétologie Pédiatrique
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Early neurological phenotype in 4 children with biallelic PRODH mutations
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AFENJAR A, MOUTARD ML, DOUMMAR D, GUET A, RABIER D, VERMERSCH AI, MIGNOT C, BURGLEN L, HERON D, THIOULOUSE E, DE VILLEMEUR TB, CAMPION D, RODRIGUEZ D
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2007 - Brain Dev. 29(9):547-552 |
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Hyperprolinemia type I (HPI) results from a deficiency of proline oxidase (POX), involved in the first step in the conversion of proline to glutamate. Diverse phenotypes were described in patients with HPI, prior to the identification of the POX gene (PRODH): whereas various patients were asymptomatic, others had neurological and extraneurological defects. The PRODH gene is located in the region deleted in velocardiofacial syndrome (VCFS). Heterozygous and homozygous mutations have been identified in patients with variable hyperprolinemia and various features (patients with schizophrenia, chromosome 22q11 microdeletions and/or neurological defects). A functional study has divided the PRODH missense mutations into three groups: those leading to mild, moderate, or severe reduction of POX activity. In this study, we report four unrelated children with HPI and a homogeneous severe neurological phenotype. We identified biallelic abnormalities in PRODH in these patients that led to severe reduction of POX activity. These included missense and non-sense mutations, deletions of PRODH and a 22q11 microdeletion. Four other children have been reported with severe biallelic PRODH mutations. The phenotype of these eight patients associates early psychomotor development delay with predominant cognitive defects, autistic features and epilepsy. Their values of hyperprolinemia ranged from 400 to 2200 micromol/L. Patients with biallelic PRODH alterations resulting in severely impaired POX activity had an early onset and severe neurological features. Thus, children with this phenotype and those with a microdeletion in chromosome 22q11, especially those with mental retardation and autistic features, should be tested for hyperprolinemia. Hyperprolinemic patients should be screened for PRODH mutations.
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Unité(s) :
Biochimie Métabolique
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Very Low Oral Doses of Vitamin B-12 Increase Serum Concentrations in Elderly Subjects with Food-Bound Vitamin B-12 Malabsorption
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BLACHER J, CZERNICHOW S, RAPHAEL M, ROUSSEL C, CHADEFAUX-VEKEMANS B, MORINEAU G, GIRAUDIER S, TIBI A, HENRY O, VAYSSIERE M, OUDJHANI M, NADAI S, VINCENT JP, BODAK A, DI MENZA C, MENARD J, ZITTOUN J, DUCIMETIERE P
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2007 - J. Nutr. 137(2):373-378 |
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The BOSSANOVA study, a randomized double-blind trial, was designed to test the ability of very low oral doses of vitamin B-12 to increase the serum vitamin B-12 concentration in elderly subjects with food-bound vitamin B-12 malabsorption, and to determine whether there was a dose response. We also aimed to quantitatively assess the most efficient dose to be added to flour in addition to folic acid (flour cofortification with vitamin B-12 and folic acid). Sixty-seven patients were randomly assigned to 1 of 6 groups receiving various daily oral doses of vitamin B-12 (i.e., 2.5, 5, 10, 20, 40, or 80 mug/d) for 30 d. The dose-response was tested for different biological variables using a mixed model, taking into account the variable's initial value (between-subject effect), a linear log-dose effect, and a linear log (dose x time) interaction, where time was d 15 or d 30. We planned to determine the amount of oral vitamin B-12 that would increase the serum vitamin B-12 concentration by 37 pmol/L (50 ng/L). Significant between-subject effects were found for serum vitamin B-12, plasma homocysteine, and methylmalonic acid concentrations, but a log-dose effect was found only for vitamin B-12 (P < 0.001). The slope of the line tended to be higher (P = 0.07) at d 30 than at d 15. For a mean serum vitamin B-12 increase of 37 pmol/L, a dose of 5.9 (95% CI, 0.9-12.1) mug/d was needed. We concluded that very low oral doses of vitamin B-12 increased serum vitamin B-12 concentrations in elderly subjects with subclinical vitamin B-12 deficiency, following a log-dose pattern. Our results could be beneficial in the design of a public health program for safe flour cofortification with folic acid.
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Unité(s) :
Biochimie Métabolique
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Measurement of cystine in granulocytes using liquid chromatography-tandem mass spectrometry
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CHABLI A, AUPETIT J, RAEHM M, RICQUIER D, CHADEFAUX-VEKEMANS B
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2007 - Clin. Biochem. 40(9-10):692-698 |
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BACKGROUND:: Cystinosis is a rare autosomal recessive disorder characterized by an accumulation of intralysosomal cystine due to a defect in cystine transport across the lysosomal membrane. This disorder can be treated specifically using high doses of cysteamine. Accurate measurement of intracellular cystine content is necessary for the diagnosis and monitoring of treatment with cysteamine. Here we describe a new method to measure intracellular cystine. It relies on a liquid chromatography-tandem mass spectrometry assay. We compare this novel method with the cystine-binding protein assay. METHOD:: Cells were isolated and lysed in the presence of N-ethylmaleimide to avoid interference from cysteine. After deproteinization, addition of stable isotope d(6) cystine and butylation, cystine was measured using an API 3000 MSMS. RESULTS:: The cystine assay was linear to at least 50 mumol/L. Within-run and between-run coefficients of variation were 2.9% and 5.7% respectively. CONCLUSION:: It is possible to measure very low concentrations of intracellular cystine with liquid chromatography-tandem mass spectrometry. The results obtained with this novel method correlate very well with those obtained using the cystine-binding protein assay.
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Unité(s) :
Biochimie Métabolique
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Oxidative stress-inducible antioxidant adaptive response during prostaglandin F2alpha-induced luteal cell death in vivo
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GARREL C, CEBALLOS-PICOT I, GERMAIN G, AL-GUBORY KH
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2007 - Free Radical Res. 41(3):251-259 |
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Oxidative stress-induced antioxidant adaptive response would be particularly important to cells in high reactive oxygen species (ROS) environments. We aimed to determine the dynamic adaptive response of antioxidant enzymatic systems in sheep corpus luteum (CL) during PGF2alpha-induced luteal cell death. Activities of superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GSR), and in situ DNA fragmentation were determined in CL at day 10 of the estrous cycle (0 h) and at 12, 24 or 48 h after PGF2alpha injection. A decrease in plasma progesterone concentration was first observed at 6 h after treatment (P < 0.05). Apoptotic cells were rarely observed in the CL at 0 h (less than 0.7%), and their incidence increased (P < 0.01) by 12 h post-PGF2alpha (11.7%) and remained thereafter elevated through 48 h. Activities of SOD1, SOD2, GPX and GSR were not changed at any time points after PGF2alpha treatment. CAT activity increased at 12 h (P < 0.01) and at 24 h (P < 0.05) after PGF2alpha treatment as compared to that at 0 h. These findings demonstrate that PGF2alpha induce luteal cell death without depressing the activity of antioxidant enzymes. It is suggested that transient increase in CAT activity is an adaptive response of the CL to oxidative stress induced by PGF2alpha.
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Unité(s) :
Biochimie Métabolique
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Experimental acute pancreatitis in PAP/HIP knock-out mice
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GIRONELLA M, FOLCH-PUY E, LEGOFFIC A, GARCIA S, CHRISTA L, SMITH A, TEBAR L, HUNT SP, BAYNE R, SMITH AJ, DAGORN JC, CLOSA D, IOVANNA JL
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2007 - Gut 56(8):1091-1097 |
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BACKGROUND AND AIMS: PAP/HIP was first reported as an additional pancreatic secretory protein expressed during the acute phase of pancreatitis. It was shown in vitro to be anti-apoptotic and anti-inflammatory. This study aims to look at whether PAP/HIP plays the same role in vivo. METHODS: A model of caerulein-induced pancreatitis was used to compare the outcome of pancreatitis in PAP/HIP(-/-) and wild-type mice. RESULTS: PAP/HIP(-/-) mice showed the normal phenotype at birth and normal postnatal development. Caerulein-induced pancreatic necrosis was, however, less severe in PAP/HIP(-/-) mice than in wild-type mice, as judged by lower amylasemia and lipasemia levels and smaller areas of necrosis. On the contrary, pancreas from PAP/HIP(-/-) mice was more sensitive to apoptosis, in agreement with the anti-apoptotic effect of PAP/HIP in vitro. Surprisingly, pancreatic inflammation was more extensive in PAP/HIP(-/-) mice, as judged from histological parameters, increased myeloperoxidase activity and increased pro-inflammatory cytokine expression. This result, in apparent contradiction with the limited necrosis observed in these mice, is, however, in agreement with the anti-inflammatory function previously reported in vitro for PAP/HIP. This is supported by the observation that activation of the STAT3/SOCS3 pathway was strongly decreased in the pancreas of PAP/HIP(-/-) mice and by the reversion of the apoptotic and inflammatory phenotypes upon administration of recombinant PAP/HIP to PAP/HIP(-/-) mice. CONCLUSION: The anti-apoptotic and anti-inflammatory functions described in vitro for PAP/HIP have physiological relevance in the pancreas in vivo during caerulein-induced pancreatitis.
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Unité(s) :
Biochimie Métabolique
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Which gene, Reg2 or Reg3 beta, was targeted that affected liver regeneration ? Reply
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HUNT SP, KIYAMA H, SMITH AJH, CHRISTA L
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2007 - Hepatology 45(6):1585-1586 |
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Unité(s) :
Biochimie Métabolique
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A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element
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MINÉ M, CHEN JM, BRIVET M, DESGUERRE I, MARCHANT D, DE LONLAY P, BERNARD A, FEREC C, ABITBOL M, RICQUIER D, MARSAC C
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2007 - Hum. Mutat. 28(2):137-142 |
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The long interspersed element-1 (LINE-1 or L1) retrotransposition has altered the human genome in many ways. In particular, recent in vitro studies have demonstrated that the retrotranspositional insertion of L1 elements has resulted in significant genomic deletions. Here we provide evidence for its operation in the human genome by identifying a approximately 46-kb pathological genomic deletion in the PDHX gene directly linked to the insertion of a full-length L1 element, in a patient with pyruvate dehydrogenase complex (PDHc) deficiency. Both the deduced bottom and top strand cleavage sites in the PDHX gene coincide with the consensus L1 endonuclease (EN) target sequence 5'-TTTT/A-3', while the full-length L1 element is followed by a 67-bp poly(A) tail. Interestingly, two hairpin structures, potentially formed by the inverted repeats present immediately 5' to the top strand nick site and 3' to the bottom strand nick site, may have facilitated the accessibility of L1 EN to the target sequences and also brought the two otherwise distantly located sequences into close proximity. Since the L1 element inserted in the PDHX gene is full-length, we favor the model of the template jumping as opposed to that of the microhomology-mediated end-joining for linking the 5' end of the nascent L1 copy to its genomic target. Our finding not only serves as an important complement to the in vitro approaches to studying L1 retrotransposition, but also reveals a novel mechanism causing human genetic disease.
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Unité(s) :
Biochimie Métabolique, CERTO, Neurologie
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Allogeneic bone marrow transplantation in mevalonic aciduria
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NEVEN B, VALAYANNOPOULOS V, QUARTIER P, BLANCHE S, PRIEUR AM, DEBRE M, ROLLAND MO, RABIER D, CUISSET L, CAVAZZANA-CALVO M, DE LONLAY P, FISCHER A
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2007 - N. Engl. J. Med. 356(26):2700-2703 |
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Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.
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Unité(s) :
Immuno-Hématologie-Rhumatologie Pédiatriques, Biochimie Métabolique, Biothérapie, Métabolisme, U768
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Biomarkers identified in inborn errors for lysine, arginine, and ornithine
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SAUDUBRAY JM, RABIER D
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2007 - J. Nutr. 137(6):1669.S-1672.S |
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Inborn errors of lysine, arginine, and ornithine metabolism are very rare: only a few patients affected with these disorders have been carefully investigated, and very few reports on long-term outcome are available. These rare data make it difficult to define safety limits of these amino acids and useful biomarkers from these disorders. Only 4 disorders give rise to an important increase of the plasma amino acid concentration proximal to the metabolic block: lysine in 2-aminoadipic semialdehyde synthase deficiency, arginine in arginase deficiency, ornithine in ornithine amino transferase deficiency, and hyperammonemia hyperornithinemia homocitrullinuria syndrome. There is an obvious discrepancy between the important physiological role of these amino acids in cell metabolism and nutrition and the clinical consequences that are actually observed in these disorders.
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Unité(s) :
Biochimie Métabolique, Pédiatrie Générale
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A human neuronal tissue culture model for Lesch-Nyhan disease
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SHIRLEY TL, LEWERS JC, EGAMI K, MAJUMDAR A, KELLY M, CEBALLOS-PICOT I, SEIDMAN MM, JINNAH HA
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2007 - J. Neurochem. 101(3):841-853 |
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Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, the key pathophysiological changes that accompany loss of purine recycling are unclear. To facilitate delineating the consequences of HPRT deficiency, four independent HPRT-deficient sublines of the human dopaminergic neuroblastoma, SK-N-BE(2) M17, were isolated by targeted mutagenesis with triple helix-forming oligonucleotides. As a group, these HPRT-deficient cells showed several significant abnormalities: (i) impaired purine recycling with accumulation of hypoxanthine, guanine, and xanthine, (ii) reduced guanylate energy charge and GTP:GDP ratio, but normal adenylate energy charge and no changes in any adenine nucleotide ratios, (iii) increased levels of UTP and NADP+, (iv) reduced DOPA decarboxylase, but normal monoamines, and (v) reduction in cell soma size. These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency.
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Unité(s) :
Biochimie Métabolique
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Reconsideration of the proposed luteotropic and luteoprotective actions of ovine placental lactogen in sheep: in vivo and in vitro studies
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AL-GUBORY KH, CAMOUS S, GERMAIN G, BOLIFRAUD P, NICOLE A, CEBALLOS-PICOT I
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2006 - J. Endocrinol. 188(3):559-568 |
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Ovine placental lactogen (oPL) is produced by the conceptus trophectoderm and is secreted into both the maternal and fetal circulations. The present study was designed to examine in vivo the luteotropic effect of recombinant oPL (roPL), as determined by monitoring progesterone concentration and cycle length (experiment 1), and the antioxidative and antiapoptotic effects of roPL, as determined respectively by monitoring antioxidant enzymatic activity and apoptosis in the corpus luteum (CL) of cyclic ewes (experiment 2). We also studied whether roPL is capable of stimulating progesterone secretion in vitro by cultured luteal tissue of functionally active CL obtained from day-10 cyclic ewes (experiment 3) and day-60 pregnant ewes (experiment 4). Circulating concentrations of progesterone and cycle length were not affected by treatment of ewes with 80 mug/kg body weight per day of roPL (n = 4 ewes) for 10 days beginning on day 11 post-estrus, as compared with saline-treated ewes (n = 4 ewes). Luteolysis occurred between days 15 and 16 post-estrus in the four saline-treated ewes and in 3/4 roPL-treated ewes. The activities of the key antioxidant enzymes copper-zinc superoxide dismutase (Cu,Zn-SOD), manganese SOD (Mn-SOD), glutathione peroxidase (GPX), glutathione reductase (GSR) and glutathione S-transferase (GST) were unaffected by treatment of ewes with 80 mug/kg per day of roPL (n = 4 ewes) for 3 days, between days 11 and 14 post-estrus, as compared with saline-treated ewes (n = 4 ewes). In situ TUNEL method revealed that the number of apoptotic cells was not different between the two groups of ewes. There was no significant change in progesterone secretion by explants from day-10 estrous cycle (n = 3 ewes) or day-60 pregnancy (n = 3 ewes) CL cultured with different concentrations (10, 100 and 1000 ng/ml) of roPL, whereas treatment with oLH at the concentration of 100 or 1000 ng/ml caused a significant increase in progesterone secretion by explants from day-10 estrous cycle CL (P < 0.05) and by explants from day-60 pregnancy CL (P < 0.01). In conclusion, our results demonstrate that oPL has no luteotropic and/or luteoprotective actions in sheep, either in vivo or in vitro.
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Unité(s) :
Biochimie Médicale
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The incidence of Rett syndrome in France
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BIENVENU T, PHILIPPE C, DE ROUX N, RAYNAUD M, BONNEFOND JP, PASQUIER L, LESCA G, MANCINI J, JONVEAUX P, MONCLA A, FEINGOLD J, CHELLY J, VILLARD L
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2006 - Pediat. Neurol. 34(5):372-375 |
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Since the description of Rett syndrome, only a handful of epidemiologic studies based only on clinical investigation have been reported. Mutations in the MECP2 gene are associated with Rett syndrome and French laboratories have organized a clinical and molecular network to investigate the incidence of Rett syndrome in France including the results of molecular investigations. The present study, based on a large cohort of 424 patients with Rett syndrome, found that the incidence of this disease with a MECP2 mutation varied between 0.43 to 0.71 per 10,000 females. The total population of females aged 4-15 years in November 2004 in France was estimated to be 4,337,627. The data presented here indicate a prevalence of Rett syndrome of 0.558 per 10,000 females aged 4-15 years in France. The incidence of Rett syndrome is in accordance with other European epidemiologic studies based on clinical examination. Given that this is a minimum incidence because complete inventory was not possible, this study of patients with Rett syndrome reinforces the fact that the great majority of patients with Rett syndrome have a MECP2 mutation.
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Unité(s) :
Génétique Médicale Pédiatrique, Biochimie Médicale
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Prenatal diagnosis of some metabolic diseases using early amniotic fluid samples: report of a 15 years, experience
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CHADEFAUX-VEKEMANS B, RABIER D, CADOUDAL N, LESCOAT A, CHABLI A, AUPETIT J, DUMEZ Y, OURY JF
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2006 - Prenatal Diag. 26(9):814-818 |
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BACKGROUND: In the present study, we report the results of 132 prenatal diagnoses performed on chorionic villi and cell-free amniotic fluid obtained simultaneously at 12-13 weeks of gestation. In addition, we report the result of 59 prenatal diagnoses performed at 12-13th week using amniotic fluid only. METHODS AND RESULTS: A total of one fetal loss (1/191) was observed when a sample of amniotic fluid was obtained at around 12-13 weeks, whereas three losses (3/82) were observed after midtrimester amniocentesis. We attribute this finding to the fact that only a very small volume of amniotic fluid was sampled using a very small needle. CONCLUSION: From these data it appears that when a couple is facing a high risk of recurrence of some metabolic diseases, the study of chorionic villus and amniotic fluid sampled simultaneously offers a safe and reliable method of early prenatal diagnosis. Copyright (c) 2006 John Wiley & Sons, Ltd.
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Unité(s) :
Biochimie Médicale, Obstétrique
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Delineation of the motor disorder of Lesch-Nyhan disease
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JINNAH HA, VISSER JE, HARRIS JC, VERDU A, LAROVERE L, CEBALLOS-PICOT I, GONZALEZ-ALEGRE P, NEYCHEV V, TORRES RJ, DULAC O, DESGUERRE I, SCHRETLEN DJ, ROBEY KL, BARABAS G, BLOEM BR, NYHAN W, DE KREMER R, EDDEY GE, PUIG JG, REICH SG
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2006 - Brain 129(Pt 5):1201-1217 |
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Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.
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Unité(s) :
Biochimie Médicale, Département de Pédiatrie, Métabolisme-Neurologie
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Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice
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LIEU HT, SIMON MT, NGUYEN-KHOA T, KEBEDE M, CORTES A, TEBAR L, SMITH AJ, BAYNE R, HUNT SP, BRECHOT C, CHRISTA L
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2006 - Hepatology 44(6):1452-1464 |
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Reg2/RegIIIbeta is the murine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2-/- mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 microg/g), only 50% of the Reg2-/- mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2-/- mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-alpha/IL-6 priming signaling by exerting a negative feed-back on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-alpha/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver.
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Unité(s) :
Biochimie Médicale, Biochimie Générale
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Contribution of Fetal MR Imaging in the Prenatal Diagnosis of Zellweger Syndrome
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MOCHEL F, GREBILLE AG, BENACHI A, MARTINOVIC J, RAZAVI F, RABIER D, SIMON I, BODDAERT N, BRUNELLE F, SONIGO P
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2006 - Amer. J. Neuroradiol. 27(2):333-336 |
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Summary: Zellweger syndrome (ZS), or cerebrohepatorenal syndrome, was the first described peroxisomal biogenesis disorder. It represents the most severe phenotype, and some of its multiple congenital anomalies can manifest prenatally. Fetal hypokinesia, renal hyperechogenicity, and cerebral ventricular enlargement are the most common reported fetal features. Single and/or late detectable manifestations account for most of the difficulties of prenatal diagnosis, as well as the limitations of ultrasonography itself. Prenatal diagnosis, however, can be achieved through (1) assays of concentrations of peroxisomal metabolites (very-long-chain fatty acids, bile acids, intermediates, plasmalogens), (2) activities of peroxisomal enzymes (dihydroacetone-phosphate acyltransferase), or (3) molecular screening techniques, if available. We report on the contribution of MR imaging to the diagnosis of ZS in 2 unrelated fetuses. MR imaging was performed in the third trimester because of cerebral ventricular enlargement diagnosed on routine sonography examinations. In both cases, MR imaging revealed ZS-characteristic abnormal cortical gyral patterns, impaired myelination, and cerebral periventricular pseudocysts. In addition, MR imaging revealed renal microcysts and hepatosplenomegaly in one case. The high level of resolution of MR imaging, which allows analysis of cerebral gyration and myelination, facilitates the prenatal diagnosis of complex polymalformative syndromes such as ZS.
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Unité(s) :
Biochimie Médicale, Histo-Embryologie & Cytogénétique, Obstétrique, Radiologie Pédiatrique
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Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update
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PHILIPPE C, VILLARD L, DE ROUX N, RAYNAUD M, BONNEFOND JP, PASQUIER L, LESCA G, MANCINI J, JONVEAUX P, MONCLA A, CHELLY J, BIENVENU T
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2006 - Eur. J. Med. Genet 49(1):9-18 |
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Mutations in the MECP2 (Methyl-CpG-binding protein) gene have been reported to cause Rett syndrome (RTT), an X-linked progressive encephalopathy. Recent studies have identified large gene rearrangements that escape the common PCR-based mutation screening strategy and mutations in a novel MeCP2 isoform (named MECP2B). We have collected the results of MECP2 mutational analysis concerning 424 RTT patients conducted in eight laboratories in France. In total, 121 different MECP2 mutations were identified. R168X (11.5%) is the most common of MECP2 mutations, followed by R270X (9%), R255X (8.7%), T158 M (8.3%) and R306C (6.8%). Only eight mutations had relative frequency>3%. Large and complex rearrangements not previously detected using only a PCR-based strategy represent 5.8% of MECP2 mutations. On the contrary, mutation in exon 1 appears to be rare (less than 0.5%). These data demonstrate the high allelic heterogeneity of RTT in France and suggest that routine mutation screening in MECP2 should include quantitative analysis of the MECP2 gene. This study represents an important instrument for molecular diagnosis strategy and genetic counseling in RTT families.
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Unité(s) :
Biochimie Médicale, Génétique Médicale Pédiatrique
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Myeloperoxidase promoter polymorphism -463G is associated with more severe clinical expression of cystic fibrosis pulmonary disease
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REYNOLDS WF, SERMET-GAUDELUS I, GAUSSON V, FEUILLET MN, BONNEFONT JP, LENOIR G, DESCAMPS-LATSCHA B, WITKO-SARSAT V
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2006 - Mediat. Inflamm. .(7):36735 |
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The severity of cystic fibrosis (CF) pulmonary disease is not directly related to CFTR genotype but depends upon several parameters, including neutrophil-dominated inflammation. Identification of agents modulating inflammation constitutes a relevant goal. Myeloperoxidase (MPO) is involved in both microbicidal and proinflammatory neutrophil activities. The aim of this study was to evaluate whether the -463GA MPO promoter polymorphism is linked to clinical severity of CF-associated pulmonary inflammation. This polymorphism significantly affects the level of MPO gene expression in leukocytes and the G allele is more expressing than the A allele. We show that MPO genotype significantly influences the severity of pulmonary disease in early stages, prior to the development of chronic lung infections, with GG genotype being associated with more severe CF disease. Our findings indicate that the level of MPO gene expression influences the CF pathogenesis, presumably reflecting cellular damage by MPO-generated oxidants or other activity of MPO in airway inflammation.
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Unité(s) :
Biochimie Médicale, Pédiatrie Générale, U507
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Treatment of Lesch-Nyhan disease in France: survey on 16 patients
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ROULEAU E, CEBALLOS-PICOT I, PERIGNON JL
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2006 - Archives Pédiatrie 13(9):1266-1267 |
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Unité(s) :
Biochimie Médicale
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Atypical Gilles de la Tourette Syndrome with beta-mannosidase deficiency
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SEDEL F, FRIDERICI K, NUMMY K, CAILLAUD C, CHABLI A, DURR A, LUBETZKI C, AGID Y
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2006 - Arch. Neurol. 63(1):129-131 |
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BACKGROUND: beta-Mannosidosis is a rare inborn error of metabolism with various phenotypes, including mental retardation, behavioral problems, hearing loss, and recurrent airway infections in childhood. To our knowledge, there is no published description of Gilles de la Tourette syndrome in association with this enzymatic deficiency. OBJECTIVE: To describe a unique case of Gilles de la Tourette syndrome associated with beta-mannosidosis. SETTING: University hospital.Patient An 18-year-old man exhibited motor and vocal tics since childhood, attention-deficit/hyperactivity disorder, impulsivity, and aggressiveness compatible with Gilles de la Tourette syndrome. A screen for inborn errors of metabolism was made because of the atypical association with slight mental retardation and bilateral perceptive hypoacousia. RESULTS: Urinary analysis showed disacchariduria, and leukocyte analysis revealed a profound deficit in beta-mannosidase activity. Two novel mutations in the beta-mannosidase gene were found: a new splice mutation in one allele, and a unique 10-base-pair insertion in the other. CONCLUSIONS: This case illustrates the phenotypic variability of inborn errors of metabolism in adults and demonstrates the need to screen inborn errors of metabolism in atypical Gilles de la Tourette syndrome.
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Unité(s) :
Biochimie Médicale
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Methylmalonic and propionic acidurias: Management without or with a few supplements of specific amino acid mixture
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TOUATI G, VALAYANNOPOULOS V, MENTION K, DE LONLAY P, JOUVET P, DEPONDT E, ASSOUN M, SOUBERBIELLE JC, RABIER D, OGIER DE BAULNY H, SAUDUBRAY JM
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2006 - J. Inherit. Metab. Dis. 29(2-3):288-298 |
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In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.
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Unité(s) :
Métabolisme-Neurologie, Explorations Fonctionnelles, Biochimie Médicale, Réanimation Pédiatrique - N
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Changes in activities of superoxide dismutase, nitric oxide synthase, glutathione-dependent enzymes and the incidence of apoptosis in sheep corpus luteum during the estrous cycle
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AL-GUBORY KH, CEBALLOS-PICOT I, NICOLE A, BOLIFRAUD P, GERMAIN G, MICHAUD M, MAYEUR C, BLACHIER F
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2005 - Biochim. Biophys. Acta - Gen. Subjects 1725(3):348-357 |
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Anti-oxidative enzymes play a role in protecting cells from oxidative stress-induced cell death. The present study was conducted to evaluate whether the anti-oxidant and pro-oxidant enzymatic capacities of the sheep corpus luteum (CL) are correlated with steroidogenic and structural status of the gland during the estrous cycle. Steroidogenic activity, apoptosis and superoxide dismutase (SOD1 and SOD2), nitric oxide synthase (NOS), glutathione peroxidase (GPX), glutathione reductase (GSR) and glutathione S-transferase (GST) activities were determined in the CL at specific developmental stages of the luteal phase. The intensity of apoptotic DNA fragmentation, characteristic of physiological cell death, was much greater in CL at late luteal phase than at early and mid-luteal phase, concomitantly with the diminution in the plasma progesterone concentrations from mid-to late luteal phase. SOD1 and GPX activities increased from early to mid-luteal phase, and increased further at late luteal phase. SOD2 and GST activities were not different between early and mid-luteal phase, but increased at late luteal phase. GSR activity was not different between any luteal phase examined. NOS activity decreased from early to mid- and late luteal phase. These results show that the activities of SOD1, SOD2, NOS, GPX, GSR and GST in the sheep CL are subject to major changes during the estrous cycle, and that the anti-oxidant and pro-oxidant enzymatic capacities of luteal cells are not correlated with cell steroidogenic status and integrity during the late luteal phase.
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Unité(s) :
Biochimie Médicale
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Delta(1)-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline
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BAUMGARTNER MR, RABIER D, NASSOGNE MC, DUFIER JL, PADOVANI JP, KAMOUN P, VALLE D, SAUDUBRAY JM
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2005 - Eur. J. Pediat. 164(1):31-36 |
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Delta(1)-pyrroline-5-carboxylate synthase (P5CS) catalyses the reduction of glutamate to Delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine. Recently, we reported a newly recognised inborn error due to deficiency of P5CS in two sibs, one presenting at birth with hypotonia, dysmorphic signs, pes planus and clonic seizures. Both developed progressive neurodegeneration and peripheral neuropathy, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes mild hyperammonaemia, hypo-ornithinaemia, hypocitrullinaemia, hypo-argininaemia and hypoprolinaemia. Incorporation of (3)H-proline into protein was deficient in fibroblasts incubated with (3)H-glutamate. Both patients are homozygous for the missense mutation R84Q in P5CS. Here, we describe the clinical phenotype of the sibs in detail and show that a relative deficiency of urea cycle intermediates (ornithine, citrulline and arginine) during fasting periods results in a paradoxical hyperammonaemia. Furthermore, we show the results of ornithine loading tests and indirect enzyme studies corroborating the biological significance of the defect in P5CS in vivo. CONCLUSION:The metabolic phenotype of Delta(1)-pyrroline-5-carboxylate synthase deficiency is easily missed. The combination of low levels of ornithine, citrulline, arginine and proline plus a tendency to hyperammonaemia or one of the above together with a clinical phenotype of neurodegeneration with peripheral neuropathy and/or cataracts and connective tissue manifestations should suggest this disorder. Early recognition would allow a therapeutic trial with citrulline and proline.
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Unité(s) :
Métabolisme-Neurologie, Ophtalmologie, Biochimie Médicale
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Urea cycle defects: Management and outcome
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NASSOGNE MC, HERON B, TOUATI G, RABIER D, SAUDUBRAY JM
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2005 - J. Inherit. Metab. Dis. 28(3):407-414 |
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This paper reviews the clinical presentation of 217 patients with urea cycle defects, including 121 patients with neonatal-onset forms and 96 patients with late-onset forms. Long-term outcome of these patients is also reported with the severity of the neonatal forms of these disorders, mostly for ornithine carbamoyltransferase-deficient males. Patients with late-onset forms may present at any age and carry a 28% mortality rate and a subsequent risk of subsequent disabilities.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie
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Methylmalonic and propionic acidaemias: Management and outcome
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OGIER DE BAULNY H, BENOIST JF, RIGAL O, TOUATI G, RABIER D, SAUDUBRAY JM
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2005 - J. Inherit. Metab. Dis. 28(3):415-423 |
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Organic acidurias comprise many various disorders. Methylmalonic aciduria (MMA) and propionic aciduria (PA) are the most frequent diseases and the two organic acidurias for which we have better knowledge of the long-term outcome.Comparing the outcome of patients born before and after 1990, it appears that better neonatal and long-term management have improved the survival rate. Less than 20% of the patients died in either the neonatal period or before the age of 10 years. However, most surviving patients showed poor nutritional status with growth retardation and about 40% present some kind of visceral or neurological impairment. The developmental outcome may have improved in MMA patients, with IQ higher than 75 in about 40% patients aged more than 4 years. Conversely, poor intellectual development is the rule in PA patterns, with 60% having an IQ less than 75 and requiring special education. Successful liver and/or renal transplantations, in a few patients, have resulted in better quality of life but have not necessarily prevented neurological and various visceral complications. These results emphasize the need for permanent metabolic follow-up whatever the therapeutic strategy.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie
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Inherited metabolic diseases : benefits of metabolomics
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RICQUIER D
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2005 - M S-Méd. Sci. 21(5):512-516 |
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Both hope and illusion, the recent progress in biology has raised our expectations that one day it will be possible to introduce a biological sample into an apparatus which will then deliver in a few minutes thousands of qualitative and quantitative data concerning the genome, transcriptome, proteome and metabolome, thereby contributing to diagnosis and follow-up of diseases which are now difficult to identify. Such machines do not exist yet and, in any case, should be associated with the appropriate and adequate clinical work on the disease and with the patient. This << total >> approach is of course being pushed by the recent decoding of the genomes of several species (genomics), the development of high throughput analysis of mRNAs (transcriptomics), and the efforts to identify the protein products on a large scale (proteomics). Wide sectors of medicine are waiting for the results of these new medium and high throughput technological approaches, for example, in order to identify early markers of diseases. The object of this article is to present a biochemist's point of view on hereditary metabolic diseases (also referred to as inborn errors of metabolism), a field of medicine and research covering very diverse clinical and biochemical aspects. Significant advances will be made possible by improving the present methods of analysis of the metabolome which establishes a link between genotypes and phenotypes, an area now called metabolomics. The contribution of proteomics will be important as well but will still require some time.
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Unité(s) :
Biochimie Médicale
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Antioxidant enzymatic defence systems in sheep corpus luteum throughout pregnancy
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AL-GUBORY KH, BOLIFRAUD P, GERMAIN G, NICOLE A, CEBALLOS-PICOT I
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2004 - Reproduction 128(6):767-774 |
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The activities of copper, zinc-superoxide dismutase (SOD1), manganese SOD (SOD2), glutathione peroxidase (GPX), glutathione reductase (GSSG-R) and glutathione S-transferase (GST) were studied in sheep corpora lutea (CL) obtained on days 15, 40, 60, 80 and 128 of pregnancy. Maintained enzymatic activity of SOD1, SOD2, GPX, GSSG-R and GST were found in the sheep CL throughout pregnancy. Enzymatic activity of SOD1, GPX and GST increased significantly from day 15 to day 40 of pregnancy, and thereafter remained constant until day 128. SOD2 and GSSG-R activities were not different between any days of pregnancy examined. Apoptotic luteal cells identified by the terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelling were very rarely observed, and their incidence (less than 0.5%) was not different between days of pregnancy. These results showed that the activities of antioxidant enzymes in the sheep CL are subject to major changes during early pregnancy, suggesting that the CL of early pregnancy may be rescued from luteolysis through increasing activities of key antioxidant enzymes and inhibition of apoptosis. Maintained levels of antioxidant enzymes in the CL throughout pregnancy may be linked to reactive oxygen species continuously generated in the steroidogenically active luteal cells, and may be involved in the maintenance of luteal steroidogenic activity and cellular integrity.
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Unité(s) :
Biochimie Médicale
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H2S, a new neuromodulator
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KAMOUN P
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2004 - M S-Méd. Sci. 20(6-7):697-700 |
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The formation of H2S from cyst(e)ine is catalyzed by three enzymes, cystathionine beta synthase, cystathionase, and 3-mercaptopyruvate sulfurtransferase. In the liver, kidney, enterocytes and vascular smooth muscle cells, H2S is principally synthesized by cystathionase. In contrast, it is synthesized by cystathionine beta synthase in the brain and partially by 3-mercaptopyruvate sulfurtransferase in cardiac tissue. H2S is catabolized, essentially in mitochondria by thiosulfate reductase. The sulfite generated is then oxidized to sulfate by sulfite oxidase. The amount of thiosulfate excreted in the urine is the best indicator of H2S biosynthesis, together with sulfhemoglobin determination in erythrocytes. H2S acts as a neuromodulator in the brain, increasing responses mediated by NMDA receptors, facilitating the induction of long-term potentialization in the hippocampus. H2S also acts as a vasodilator, acting directly on ATP-dependent potassium channels in vascular smooth muscle cells. The concentration of H2S is abnormally low in the brains of subjects with Alzheimer's disease, due to changes in the concentration of the physiological activator of cystathionine beta synthase. The overproduction of H2S described in subjects with Down's syndrome probably results from the overproduction of cystathionine beta synthase, as the gene encoding this protein is located on chromosome 21.
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Unité(s) :
Biochimie Médicale
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Endogenous production of hydrogen sulfide in mammals
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KAMOUN P
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2004 - Amino Acids 26(3):243-254 |
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Hydrogen sulfide is one of three gases involved in biological functions and synthesized in vivo. Like NO and CO, it seems to act as a neuromodulator: it modulates NMDA glutamate receptor function. CBS seems to be the only source of hydrogen sulfide in the brain, whereas the liver synthesizes hydrogen sulfide via cystathionase. In the heart, the third pathway for the hydrogen sulfide synthesis, the 3-mercaptopyruvate pathway is used. Only two diseases characterized by alterations of hydrogen sulfide metabolism have been described: decreased hydrogen sulfide synthesis in the brains of Alzheimers disease patients and increased hydrogen sulfide synthesis due to the overexpression of CBS in Down syndrome patients.
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Unité(s) :
Biochimie Médicale
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Hyperpipecolic acidaemia: a diagnostic tool for peroxisomal disorders
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PEDUTO A, BAUMGARTNER MR, VERHOEVEN NM, RABIER D, SPADA M, NASSOGNE MC, POLL-THE BT, BONETTI G, JAKOBS C, SAUDUBRAY JM
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2004 - Mol. Genet. Metab. 82(3):224-230 |
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Peroxisomal disorders include a complex spectrum of diseases, characterized by a high heterogeneity from both the clinical and the biochemical points of view. Specific assays are required for the study of peroxisome metabolism. Among these, pipecolic acid evaluation is considered as a supplementary test. We have established the diagnostic role of pipecolic acid in 30 patients affected by a peroxisomal defect (5 Zellweger syndromes, 10 Infantile Refsum diseases, 1 neonatal adrenoleukodystrophy, 6 patients affected by a peroxisomal biogenesis disorder with unclassified phenotype, 1 case of rhizomelic chondrodysplasia punctata (RCDP), 2 acyl-CoA oxidase deficiencies, 2 bifunctional enzyme deficiencies, 2 Refsum diseases, and 1 beta-oxidation deficiency). Pipecolic acid was increased in all generalized peroxisomal disorders, while normal pipecolic acid with abnormal very long chain fatty acid concentrations was strong evidence for a single peroxisomal enzyme deficiency. Unexpectedly, hyperpipecolic acidaemia was found also in a child affected by RCDP and in two patients with Refsum disease. In six patients the suggestion of a peroxisomal disorder was raised by the fortuitous finding of a pipecolic acid peak in amino acid chromatography, routinely performed as a general metabolic screening. For all patients, pipecolic acid proved to be a useful parameter in the biochemical classification of peroxisomal disorders.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie Génétique Pédiatrique
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The neuronal SAPK/JNK pathway is altered in a murine model of hyperhomocysteinemia
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ROBERT K, SANTIARD-BARON D, CHASSE JF, PALY E, AUPETIT J, KAMOUN P, LONDON J, JANEL N
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2004 - J. Neurochem. 89(1):33-43 |
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Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases. Various neuronal diseases have been associated with hyperhomocysteinemia, but the molecular mechanisms of homocysteine toxicity are unknown. We investigated the pathways involved in the pathological process, by analyzing differential gene expression in neuronal tissues. We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both plasma and brain homocysteine concentrations were high. Several genes were found to be differentially expressed in the brains of CBS-deficient mice, and the identities of some of these genes suggested that the SAPK/JNK pathway was altered in the brains of CBS-deficient mice. We therefore investigated the activation of proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway may play an important role in the development of neuronal defects associated with hyperhomocysteinemia.
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Unité(s) :
Biochimie Médicale
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Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients
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EDERY P, CHABRIER S, CEBALLOS-PICOT I, MARIE S, VINCENT MF, TARDIEU M
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2003 - Amer. J. Med. Genet. 120A(2):185-190 |
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We report on the striking variable expression of adenylosuccinate lyase (ADSL) deficiency in three patients belonging to a family which originates from Portugal. ADSL deficiency is a rare autosomal recessive disorder of the de novo purine synthesis which results in accumulation of succinylpurines in body fluids. As a result, patients may have variable combinations of psychomotor retardation and/or regression, seizures, autistic features and cerebellar vermis hypoplasia. However, intrafamilial variable expression of the phenotype has not been documented to date in this disease and is not commonly observed in metabolic disorders. Here, while the proband had marked psychomotor regression and progressive cerebellar vermis atrophy, the other two affected patients presented mainly autistic features. Mutation analysis of the ADSL gene revealed the presence of a homozygous R426H mutation in this family. Finally, although ADSL deficiency is a rare disorder, this diagnosis should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in any patient with mental retardation of unexplained origin.
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Unité(s) :
U383, Biochimie Médicale
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Endogenous hydrogen sulfide overproduction in Down syndrome
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KAMOUN P, BELARDINELLI MC, CHABLI A, LALLOUCHI K, CHADEFAUX-VEKEMANS B
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2003 - Amer. J. Med. Genet. 116(3):310-311 |
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Unité(s) :
Biochimie Médicale
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Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia
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ROBERT K, CHASSÉ JF, SANTIARD-BARON D, VAYSSETTES C, CHABLI A, AUPETIT J, MAEDA N, KAMOUN P, LONDON J, JANEL N
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2003 - J. Biol. Chem. 278(34):31504-31511 |
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Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.
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Unité(s) :
Biochimie Médicale
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Prenatal diagnosis of carnitine palmitoyltransferase 2 deficiency in chorionic villi: a novel approach
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VEKEMANS BC, BONNEFONT JP, AUPETIT J, ROYER G, DROIN V, ATTIE-BITACH T, SAUDUBRAY JM, THUILLIER L
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2003 - Prenatal Diag. 23(11):884-887 |
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Carnitine palmitoyltransferase 2 (CPT2) deficiency, the most common autosomal recessive inherited disease of the mitochondrial long-chain fatty acid (LCFA) beta-oxidation, may result in three distinct clinical phenotypes, namely, a mild adult muscular form, a severe infantile hepatocardiomuscular disease, and a neonatal form, which includes dysmorphic features in addition to hepatocardiomuscular symptoms. Both the latter forms are life-threatening diseases, and prenatal diagnosis (PND) can be offered to couples at a one-fourth risk of having an affected child. PND of CPT2 deficiency hitherto relied mostly on mutation detection from fresh chorionic villi (10 weeks' gestation), since CPT2 activity could be assayed on cultured amniocytes only (16-17 weeks' gestation).We devised a CPT2 activity assay from 10 mg of chorionic villi sampling (CVS). Combining this enzymatic assay to haplotype study using polymorphic markers linked to the CPT2 gene, we were able to carry out within 2 days, CPT2 deficiency PND, in two unrelated families, using a CVS performed at the 11th week of gestation.
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Unité(s) :
Génétique Médicale Pédiatrique, Biochimie Médicale
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Improving the prenatal diagnosis of citrullinemia using citrulline/ornithine plus arginine ratio in amniotic fluid
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CHADEFAUX-VEKEMANS B, RABIER D, CHABLI A, BLANC A, AUPETIT J, BARDET J, KAMOUN P
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2002 - Prenat. Diag. 22(6):456-458 |
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Prenatal diagnosis of citrullinemia is performed using a direct argininosuccinate synthetase (ASS) assay oil chorionic villi (CV) and citrulline concentration measurement in early amniotic fluid (AF). Here we report the results of 40 prenatal diagnoses performed using this method, discuss the difficulties encountered ill interpreting the results, and propose the use of the citrulline/ornithine+arginine ratio (which is more discriminatory than citrulline concentration alone) when performing prenatal diagnosis of citrullillemia. Copyright (C) 2002 John Wiley Sons. Ltd.
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Unité(s) :
Biochimie Médicale
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Quality internal audit questionnaire in the LABM in health services
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GUEZ P, VASSAULT A, AURIGNAC R, BRACONNIER F, DIZAZZO M, MARION S, ROUX A, RUELLE C, SIGLER D, TRIADOU P
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2002 - Ann. Biol. Clin. 60(1):111-122 |
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Unité(s) :
Biochimie Médicale
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Towards a suggestive facial dysmorphism in adenylosuccinate lyase deficiency?
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HOLDER-ESPINASSE M, MARIE S, BOURROUILLOU G, CEBALLOS-PICOT I, NASSOGNE MC, FAIVRE L, AMIEL J, MUNNICH A, VINCENT MF, CORMIER-DAIRE V
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2002 - J. Med. Genet. 39(6):440-442 |
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Unité(s) :
Biochimie Médicale, U393, Génétique Médicale Pédiatrique
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KAMOUN P, BRAUNER R, FEILLET F, ROBERT JJ, SOUBERBIELLE JC, TOUATI G, TRIVIN C
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Unité(s) :
Biochimie Médicale, Endocrinologie et Croissance, Explorations Fonctionnelles, Métabolisme-Neurologi
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Guide des examens de laboratoire (4e Edition)
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KAMOUN P, FRÉJAVILLE JP
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Unité(s) :
Biochimie Médicale
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A risk factor for chronic mild hyperammonaemia
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KAMOUN P, RABIER D, SAUDUBRAY JM
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2002 - Eur. J. Pediat. 161(4):221 |
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Unité(s) :
Biochimie Médicale, Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique
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Plasma lysine concentration and availability of 2-ketoglutarate in liver mitochondria
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KAMOUN P, RICHARD V, RABIER D, SAUDUBRAY JM
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2002 - J. Inherit. Metab. Dis. 25(1):1-6 |
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Defects of lysine metabolism are rare, but hyperlysinemia is a concomitant of many inborn errors of metabolism, including urea cycle abnormalities, pyruvate carboxylase deficiency and L-2-hydroxyglutaric aciduria. We have hypothesized that mitochondrial lysine degradation is regulated by bioavailability of 2-oxoglutarate in the same compartment, and our studies in physiologic fluid derived from patients with the above described disorders supports our hypothsis. Our data further suggest that patients with isolated L-2-hydroxyglutaric aciduria may have a defect in 2-ketoglutarate metabolism. The current report summarizes our studies.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie Génétique Pédiatrique
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Long-chain 3-hydroxyacylCoA dehydrogenase deficiency: a new case presenting with liver dysfunction, cholestasis and fibrosis
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ODIEVRE MH, SEVIN C, LAURENT J, LABOUREAU JP, RABIER D, BRIVET M, ROE C, WANDERS RJ, SAUDUBRAY JM
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2002 - Acta Paediatr. 91(6):719-722 |
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A cholestatic 6-mo-old girl was admitted to our department because she recently presented with hypotonia and lethargy, apparently due to moderate and transient hypoglycaemia. Her urine contained 3-hydroxy-dicarboxylic acids of 12 to 14 carbons in length and her plasma acylcarnitine profile was consistent with long-chain 3-hydroxyacylCoA dehydrogenase deficiency. This diagnosis was confirmed by enzyme studies. This deficiency was due to a G1528C mutation on the paternal allele (mutation on the maternal allele as yet not identified). The patient improved dramatically with medium-chain triglyceride supplementation. CONCLUSION: Early cholestasis and hepatic fibrosis must lead to search for long-chain 3-hydroxyacylCoA dehydrogenase deficiency, particularly when hypoketotic hypoglycaemia is present.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie Génétique Pédiatrique
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Vascular complications of homocystinuria: a retrospective multicenter study
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SIMORRE B, QUERE I, BERRUT G, CHASSE JF, BELLET H, KAMOUN P, LE HELLO C, SAUDUBRAY JM, JANBON C
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2002 - Rev. Méd. Interne 23(3):267-272 |
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PURPOSE: Arterial or venous thromboses are frequent in patients with homocystinuria. Because severe homocystinuria is rare, prevalence of thrombosis, especially in France, is still unknown. METHODS: Review of the clinical outcome of 37 patients with homocystinuria due to cystathionine-cystathionine beta-synthase deficiency (34) and 5,10-methylenetetrahydrofolate reductase (three) lead us to describe vascular complications occurring in 12 (32%) of them. RESULTS: Venous thromboembolism is the earlier and the most frequent one and is mainly found in untreated late-diagnosed cases. Under specific treatment of homocystinuria, thromboses are rare and always a complication of surgery associated with high thromboembolic risk. Association with factor V Leiden increased the risk of venous thrombosis.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie Génétique Pédiatrique
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Trinucleotide repeat contraction: a pitfall in prenatal diagnosis of myotonic dystrophy
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AMIEL J, RACLIN V, JOUANNIC JM, MORICHON N, HOFFMAN-RADVANYI H, DOMMERGUES M, FEINGOLD J, MUNNICH A, BONNEFONT JP
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2001 - J. Med. Genet. 38(12):850-852 |
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Unité(s) :
Biochimie Médicale, Génétique Médicale Pédiatrique, U393
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Urinary sulfur compounds in down syndrome
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BELARDINELLI MC, CHABLI A, CHADEFAUX-VEKEMANS B, KAMOUN P
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2001 - Clin. Chem. 47(8):1500-1501 |
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Unité(s) :
Biochimie Médicale, UMR 8602
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Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients
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DE LONLAY P, BENELLI C, FOUQUE F, GANGULY A, ARAL B, DIONISI-VICI C, TOUATI G, HEINRICHS C, RABIER D, KAMOUN P, ROBERT JJ, STANLEY C, SAUDUBRAY JM
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2001 - Pediat. Res. 50(3):353-357 |
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Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene. resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 mu mol/L, normal < 50 mu mol/L) was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC50, or concentrations required for 50% inhibition of GDH activity. ranging from 140 to 580 nM, compared with control IC50 value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were per-formed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene. [References: 22]
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Unité(s) :
Biochimie Médicale, Fédération de Pédiatrie, U530, Génétique Médicale Pédiatrique
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Combined nutritional support and continuous extracorporeal removal therapy in the severe acute phase of maple syrup urine disease
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JOUVET P, JUGIE M, RABIER D, DESGRES J, HUBERT P, SAUDUBRAY JM, MAN NK
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2001 - Intens. Care Med. 27(11):1798-1806 |
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Objective: The authors assessed the efficiency, tolerance and outcome of neonates and children with maple syrup urine disease (MSUD) in acute decompensation managed by endogenous and extra- corporeal removal of accumulated MSUD metabolites. Design: Single center cohort study. Setting: Pediatric and neonatal intensive care unit in a tertiary care hospital. Patients: Between January, 1991, and June, 1999, six neonates and six children in acute decompensation of MSUD were included in the study. Each of them had two of the three following criteria: comatose state, gastrointestinal intolerance, leucine plasma levels over 1700 mu mol/l. Interventions: Patients were treated by combined nutrition manipulation and continuous venovenous extracorporeal removal therapies (CECRT) including hemofiltration, hemodialysis or hemodiafiltration. A clinical and biological evaluation was performed before., during and following the treatment. Results: Eleven out of the 12 patients survived. One child had two acute episodes at 6.5 and 9 years old. Eight patients recovered a normal cerebral performance category score. In all cases, plasma leucine level decreased according to a logarithmic mode within 11-24 h hemodiafiltration combined with nutritional support whereas, with nutrition alone after stopping CECRT, the decrease in leucine plasma levels was slower, following a linear mode. Eight patients were supplemented with valine and isoleucine for mean plasma values of 177 +/- 92 and 68 +/- 66, respectively. Conclusion: In severe acute decompensation of MSUD. CECRT combined with nutritional support limit central nervous system damage, by dramatically decreasing branched chain amino and keto acid levels. [References: 23]
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Unité(s) :
Métabolisme-Neurologie Génétique Pédiatrique, Réanimation Pédiatrique, U507, Biochimie Médicale
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Mental retardation in down syndrome: a hydrogen sulfide hpothesis
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KAMOUN P
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2001 - Med. Hypotheses 57(3):389-392 |
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Mental retardation is progressive in Down syndrome: individuals are born with normal intelligence which starts to decline linearly within the first year. This phenomenon can be observed with phenylalanine in patients with phenylketonuria, therefore it is compatible with metabolic intoxication. The toxic compound could be hydrogen sulfide. The amount of the compound is probably increased in Down syndrome by increasing active cystathionine beta synthase. This heuristic hypothesis requires further investigation. (C) 2001 Harcourt Publishers Ltd. [References: 33]
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Unité(s) :
Biochimie Médicale, UMR 8602
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Aide-mémoire de biochimie et biologie moléculaire
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KAMOUN P
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Unité(s) :
Biochimie Médicale
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Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1a mutation in the hutterite community
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PRIP BUUS C, THUILLIER L, ABADI N, PRASAD C, DILLING L, KLASING J, DEMAUGRE F, GREENBERG CR, HAWORTH JC, DROIN V, KADHOM N, GOBIN S, KAMOUN P, GIRARD J, BONNEFONT JP
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2001 - Mol. Genet. Metab. 73(1):46-54 |
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Hepatic carnitine palmitoyltransferase 1 (CPT1A) deficiency is a rare disorder of mitochondrial fatty acid oxidation inherited as an autosomal recessive trait. Symptomatology comprises attacks of hypoketotic hypoglycemia with risk of sudden death or neurological sequelae, Only one CPT1A mutation has been reported so far. Identification of the disease-causing mutations allows both insights into the structure-function relationships of CPT1A and management of the patients and their relatives, The molecular analysis of CPT1A deficiency in a large Hutterite kindred illustrates this point. Both cDNA and genomic DNA analysis demonstrate that the affected patients are homozygous for a 2129G>A mutation predicting a G710E substitution, Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein. By con contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A. Finally, due to a strongly suspected founder effect for the origin of CPT1A deficiency in this Hutterite kindred, identification of this disease-causing mutation allows the setup of a targeted DNA-based newborn screening in this at-risk population, (C) 2001 Academic Press. [References: 33]
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Unité(s) :
Biochimie Médicale, U370, U393
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Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase
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BAUMGARTNER MR, HU CAA, ALMASHANU S, STEEL G, OBIE C, ARAL B, RABIER D, KAMOUN P, SAUDUBRAY JM, VALLE D
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2000 - Hum. Mol. Genet. 9(19):2853-2858 |
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Delta (1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to Delta (1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine, Recently, we reported the cloning and expression of human and murine P5CS cDNAs, Previously, we showed that mammalian P5CS undergoes alternative splicing to generate two isoforms differing only by a 2 amino acid insert at the N-terminus of the gamma -glutamyl kinase active site, The short isoform has high activity In the gut, where it participates in arginine biosynthesis and is inhibited by ornithine, The long isoform, expressed in multiple tissues, is necessary for the synthesis of proline from glutamate and is insensitive to ornithine, Here, we describe a newly recognized inborn error due to the deficiency of P5CS in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts, Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia. Both are homozygous for the missense mutation, R84Q, which alters a conserved residue in the! P5CS gamma -glutamyl kinase domain, R84Q is not present in 194 control chromosomes and dramatically reduces the activity of both P5CS isoforms when expressed in mammalian cells, Additionally, R84Q appears to destabilize the long isoform, This; is the first documented report of an inborn error of P5CS and suggests that this disorder should be considered in the differential diagnosis in patients with neurodegeneration and/or cataracts and connective tissue disease. [References: 26]
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Unité(s) :
Métabolisme-Neurologie Génétique Pédiatrique, Biochimie Médicale
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Mutation analysis of the hamartin gene using denaturing high performance liquid chromatography
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BENIT P, KARA-MOSTEFA A, BERTHELON M, SENGMANY K, MUNNICH A, BONNEFONT JP
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2000 - Hum. Mutat. 16(5):417-421 |
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Denaturing high performance liquid chromatography (DHPLC) is a novel high-capacity technique for gene mutation scanning. We have assessed the sensitivity and specificity of this method for analysis of the full coding sequence of the hamartin (TSC1) gene in 20 tuberous sclerosis patients, whose TSC1 genes previously had been studied by single strand conformation polymorphism analysis and protein truncation assay. All eight sequence variants previously identified were adequately detected by DHPLC. Additionally, this approach picked up three polymorphisms, one of which (IVS13-55 C>G) was hitherto unreported, therefore serving as proof of principle for this technique. Thus, DHPLC appears to be a highly sensitive method with advantages in terms of flexibility, fragments size analysis, cost and time and labor sparing, compared to classical approaches of mutation scanning. Copyright 2000 Wiley-Liss, Inc.
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Unité(s) :
IRNEM, Génétique Médicale Pédiatrique, Biochimie Médicale, U393
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Ifcc recommended reference method for the determination of the substance concentration of ionized calcium in undiluted serum, plasma or whole blood
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BURNETT RW, CHRISTIANSEN TF, COVINGTON AK, FOGH-ANDERSEN N, KULPMANN WR, LEWENSTAM A, MAAS AHJ, MULLER-PLATHE O, SACHS C, SIGGAARD-ANDERSEN O, VANKESSEL AL, ZIJLSTRA WG
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2000 - Clin. Chem. Lab. Med. 38(12):1301-1314 |
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A reference method is described for the determination of the substance concentration of ionized calcium in plasma by which ionized calcium (free or unbound) may be reliably determined on the basis of calibration with aqueous solutions with known concentration of ionized calcium. The composition of the calibration solutions is chosen such that the activity coefficient of the calcium ion is assumed to be identical both in the calibration solutions and in "normal" plasma, i.e. by convention, the ionic strength (I-m) is 0.160 mol/kg. The convention is adopted of reporting ionized calcium measurements as concentration expressed as mmol/l. The proposed reference method for ionized calcium measurement in plasma is based on the use of a cell consisting of an external reference electrode with a saturated potassium chloride liquid/liquid junction in combination with a calcium ion-selective membrane electrode of defined construction and performance. Procedures for using the reference cell and a protocol for sample measurement are described. The preparation of the calibration solutions to be used are described in detail in Appendix A, secondary calibration solutions and check standards in Appendix B, and reference cell vessel design in Appendix C. [References: 50]
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Unité(s) :
Biochimie Médicale
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Recommendations for measurement of and conventions for reporting sodium and potassium by ion-selective electrodes in undiluted serum, plasma or whole blood
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BURNETT RW, COVINGTON AK, FOGH-ANDERSEN N, KULPMANN WR, LEWENSTAM A, MAAS AHJ, MULLER-PLATHE O, SACHS C, SIGGAARD-ANDERSEN O, VANKESSEL AL, ZIJLSTRA WG
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2000 - Clin. Chem. Lab. Med. 38(10):1065-1071 |
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Ion-selective electrodes (ISEs) respond to ion-activity and therefore do not sense substance concentration directly. However, it is recognized that sodium and potassium in plasma will continue to be expressed for clinical purposes in terms of substance concentration (mmol/l). A convention is proposed whereby for routine clinical purposes results of ISE measurements of sodium and potassium in undiluted plasma should be reported in terms of substance concentration (mmol/l). In specimens with normal concentrations of plasma water, total CO2, lipids, protein and pH, the values will concur with the total substance concentration as determined for example by flame atomic emission spectrometry (FAES) or ISE measurements on diluted samples. In specimens with abnormal concentrations of plasma water, the results will differ. However, under these circumstances, measurements of sodium and potassium by ISE in the undiluted sample will more appropriately reflect the activity of sodium and potassium and are therefore clinically more relevant than the determination in diluted samples. Detailed recommendations are made about practical procedures to achieve this. The recommended name for this quantity is the substance concentration of ionized sodium or ionized potassium in plasma, as opposed to total sodium or total potassium determined by, e.g. FAES, or ISE measurements on diluted samples. [References: 17]
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Unité(s) :
Biochimie Médicale
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Identification of a novel mutation, 1087delT, in exon 7 of the CFTR gene in a patient with cystic fibrosis
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FEUILLET-FIEUX MN, SERMET I, EDELMAN A, TOROSSI T, FERREC M, GUILLOT M, LENOIR G, BONNEFONT JP, THUILLIER L
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2000 - Hum. Mutat. 16(1):95 |
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Unité(s) :
U467, Département de Pédiatrie, Biochimie Médicale
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Genetic hypoglycaemia in infancy and childhood: pathophysiology and diagnosis
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SAUDUBRAY JM, DE LONLAY P, TOUATI G, MARTIN D, NASSOGNE MC, CASTELNAU P, SEVIN C, LABORDE C, BAUSSAN C, BRIVET M, VASSAULT A, RABIER D, BONNEFONT JP, KAMOUN P
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2000 - J. Inherit. Metab. Dis. 23(3):197-214 |
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Unité(s) :
Métabolisme-Neurologie Génétique Pédiatrique, Biochimie Médicale
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Genotype/phenotype correlation in carnitine palmitoyl transferase II deficiency: lessons from a compound heterozygous patient
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THUILLIER L, SEVIN C, DEMAUGRE F, BRIVET M, RABIER D, DROIN V, AUPETIT J, ABADI N, KAMOUN P, SAUDUBRAY JM, BONNEFONT JP
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2000 - Neuromuscular Disord. 10(3):200-205 |
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Carnitine palmitoyl transferase II deficiency, an inherited disorder of long-chain fatty acid oxidation, may result in either a mild form (muscle disease in adults) or a severe form (hepatocardiomuscular syndrome in infants). The difference in severity between these two forms is related to a difference in levels of residual carnitine palmitoyl transferase II activity and long-chain fatty acid oxidation and in genotypes. Few data are, however, available regarding compound heterozygotes for a 'mild' and a 'severe' carnitine palmitoyl transferase II mutation. We report on such a patient carrying both the 'mild' S113L substitution and the 'severe' Y628S mutation. The patient's clinical picture (cardiac arrest at 6 years) was markedly more serious than usually observed in S113L homozygotes, and suggested that 'mild'/'severe' compound heterozygosity makes patients at risk from life-threatening events. Palmitate oxidation and carnitine palmitoyl transferase II activity were lower in lymphocytes from the S113L/Y628S patient than in those from a S113L homozygote. Thus, assessment of carnitine palmitoyl transferase II mutations, long-chain fatty acid oxidation, and carnitine palmitoyl transferase II activity, may help in predicting the potential severity of the muscular form of carnitine palmitoyl transferase II deficiency.
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Unité(s) :
Métabolisme-Neurologie Génétique Pédiatrique, Biochimie Médicale
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Protein truncation test for screening hamartin gene mutations and report of new disease-causing mutations
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BENIT P, KARA-MOSTEFA A, HADJ-RABIA S, MUNNICH A, BONNEFONT JP
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1999 - Hum. Mutat. 14(5):428-432 |
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Considering the prevalence of truncating mutations in the tuberous sclerosis (TSC) hamartin gene (TSC1), we devised a protein truncation rest (PTT) to analyze the full length coding sequence of TSC1, Studying 12 sporadic cases and three familial forms by a combination of MT and single-strand conformation polymorphism analysis (SSCA), we found 5/15 mutations while PTT alone detected 4/15 truncating mutations, two of which escaped SSCA analysis. SSCA alone picked up one missense mutation and two mutations also detected by PTT. Interestingly, a TSC1 mutation was identified in all three familial forms (3/3) while the rate of mutation detection was lower in sporadic cases (2/12). Zn conclusion, PTT proves to be a useful technique for the rapid detection of disease-causing mutations in the TSC1 gene. Hum Mutat 14:428-432, 1999. (C) 1999 Wiley Liss, Inc. [References: 11]
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Unité(s) :
U393, Biochimie Médicale
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Carnitine palmitoyltransferase deficiencies
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BONNEFONT JP, DEMAUGRE F, PRIPBUUS C, SAUDUBRAY JM, BRIVET M, ABADI N, THUILLIER L
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1999 - Mol. Genet. Metab. 68(4):424-440 |
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Carnitine palmitoyltransferase (CPT) deficiencies are common disorders of mitochondrial fatty acid oxidation, The CPT system is made up of two separate proteins located in the outer- (CPT1) and inner- (CPT2) mitochondrial membranes. While CPT2 is a ubiquitous protein, two tissue- specific CPT1 isoforms-the so-called ''liver'' (L) and ''muscle'' (M) CPT1s-have been shown to exist. Amino acid and cDNA nucleotide sequences have been identified for all of these proteins. L-CPT1 deficiency (13 families reported) presents as recurrent attacks of fasting hypoketotic hypoglycemia, Two L-CPT1 mutations have been reported to date. M-CPT1 deficiency has not been hitherto identified. CPT2 deficiency has several clinical presentations, The ''benign'' adult form (more than 150 families reported) is characterized by episodes of rhabdomyolysis triggered by prolonged exercise. The prevalent S113L mutation is found in about 50% of mutant alleles, The infantile-type CPT2 deficiency (10 families reported) presents as severe attacks of hypoketotic hypoglycemia, occasionally associated with cardiac damage commonly responsible for sudden death before 1 year of age. In addition to these symptoms, features of brain and kidney dysorganogenesis are frequently seen in the neonatal-onset CPT2 deficiency (13 families reported), almost always lethal during the first month of life. More than 25 CPT2 mutations (private missense or truncating mutations) have hitherto been detected. Treatment is based upon avoidance of fasting and/or exercise, a low-fat diet enriched with medium chain triglycerides and carnitine (''severe'' CPT2 deficiency), Prenatal diagnosis may be offered for pregnancies at a 1/4 risk of infantile/severe- type CPT2 deficiency. (C) 1999 Academic Press.
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Unité(s) :
Biochimie Médicale, Métabolisme-Neurologie Génétique Pédiatrique
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Improved fluorescent PCR-based assay for sizing CGG repeats at the FRAXA locus
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HOUDAYER C, LEMONNIER A, GERARD M, CHAUVE C, TREDANO M, DE VILLEMEUR TB, AYMARD P, BONNEFONT JP, FELDMANN D
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1999 - Clin. Chem. Lab. Med. 37(4):397-402 |
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Fragile X syndrome is the most frequent heritable genetic disease involving mental retardation and is usually caused by an expanded CGG repeat in the first exon of the FMR1 gene. Therefore, searching for CGG expansion at the FRAXA locus among the mentally retarded has become a routine investigation in neuropaediatric practice. Consequently, we have developed a fluorescent PCR-based assay for sizing repeats as an alternative to laborious and time-consuming Southern blot. The procedure utilises a reverse fluorescent labelled primer, and the Expand Long Template PCR system(TM) (Roche) with addition of dimethylsulfoxide and 7-deaza-dGTP. It allows precise determination of the CGG repeat number in males and females for alleles from normal to premutation size range and detection of full mutations in males. We believe that this PCR protocol, allowing a high sample throughput, is useful for first-line screening among mentally retarded males, possibly complemented by Southern blot analysis to assess the methylation status of large mutated alleles. [References: 19]
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Unité(s) :
Biochimie Médicale
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Cystathionine beta-synthase mutations in homocystinuria
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KRAUS JP, JANOSIK M, KOZICH V, MANDELL R, SHIH V, SPERANDEO MP, SEBASTIO G, DE FRANCHIS R, ANDRIA G, KLUIJTMANS LAJ, BLOM H, BOERS GHJ, GORDON RB, KAMOUN P, TSAI MY, KRUGER WD, KOCH HG, OHURA T, GAUSTADNES M
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1999 - Hum. Mutat. 13(5):362-375 |
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The major cause of homocystinuria is mutation of the gene encoding the enzyme cystathionine beta-synthase (CBS), Deficiency of CBS activity results in elevated levels of homocysteine as well as methionine in plasma and urine and decreased levels of cystathionine and cysteine, Ninety-two different disease associated mutations have been identified in the CBS gene in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations are missense, and the vast majority of these are private mutations. The two most frequently encountered of these mutations are the pyridoxine responsive I278T and the pyridoxine nonresponsive G307S, Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene. Hum Mutat 13:362-375, 1999, (C) 1999 Wiley-Liss, Inc. [References: 48]
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Unité(s) :
Biochimie Médicale
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Evaluation of gonadal function in 107 intersex patients by means of serum antimullerian hormone measurement
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REY RA, BELVILLE C, NIHOUL-FEKETE C, MICHEL-CALEMARD L, FOREST MG, LAHLOU N, JAUBERT F, MOWSZOWICZ I, DAVID M, SAKA N, BOUVATTIER C, BERTRAND AM, LECOINTRE C, SOSKIN S, CABROL S, CROSNIER H, LEGER J, LORTAT-JACOB S, NICOLINO M, RABL W, TOLEDO SPA, BAS F, GOMPEL A, CZERNICHOW P, CHATELAIN P, ET AL
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1999 - J. Clin. Endocrinol. Metabol. 84(2):627-631 |
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Fetal male sexual differentiation is driven by two testicular hormones: testosterone (synthesized by interstitial Leydig cells) and antimullerian hormone (AMH; produced by Sertoli cells present in the seminiferous tubules). Intersex states result either from gonadal dysgenesis, in which both Leydig and Sertoli cell populations are affected, or from impaired secretion or action of either testosterone or AMH. Until now, only Leydig cell function has been assessed in children with ambiguous genitalia, by means of testosterone assay.
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Unité(s) :
Chirurgie Pédiatrique, Anatomo-Pathologie, Biochimie Médicale, Endocrinologie et Croissance, Endocri
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Blood dissemination of colonic epithelial cells during no-touch surgery for rectosigmoid cancer
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SALES JP, WIND P, DOUARD R, CUGNENC P, LORIC S
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1999 - Lancet 354(9176):392 |
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No-touch surgery is used to minimise spread of malignant cells during surgery for colorectal cancer, We looked for cell dissemination in mesenteric blood during no-touch surgery and showed such spillage in 12.5% of patients. [References: 5]
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Unité(s) :
Biochimie Médicale
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Recognition and management of fatty acid oxidation defects: A series of 107 patients
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SAUDUBRAY JM, MARTIN D, DE LONLAY P, TOUATI G, POGGI-TRAVERT F, BONNET D, JOUVET P, BOUTRON M, SLAMA A, VIANEY-SABAN C, BONNEFONT JP, RABIER D, KAMOUN P, BRIVET M
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1999 - J. Inherit. Metab. Dis. 22(4):488-502 |
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In recent years tremendous progress has been made with respect to the enzymology of the mitochondrial fatty acid beta-oxidation machinery and defects therein. Firstly, a number of new mitochondrial beta-oxidation enzymes have been identified, including very-long-chain acyl-CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (MTP). Secondly, the introduction of tandem MS for the analysis of plasma acylcarnitines has greatly facilitated the identification of patients with a defect in fatty acid oxidation (FAO). These two developments explain why the number of defined FAO disorders has increased dramatically, making FAO disorders the most rapidly growing group of inborn errors of metabolism. In this review we describe the current state of knowledge of the enzymes involved in the mitochondrial oxidation of straight-chain, branched-chain and (poly)unsaturated fatty acyl-CoAs as well as disorders of fatty acid oxidation. The laboratory diagnosis of these disorders is described, with particular emphasis on the methods used to identify the underlying enzyme defect and the molecular mutations. In addition, a simple flowchart is presented as a guide to the identification of mitochondrial FAO-disorders. Finally, treatment strategies are discussed briefly. [References: 59]
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Unité(s) :
Biochimie Médicale, Département de Pédiatrie
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Liver transplantation in urea cycle disorders
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SAUDUBRAY JM, TOUATI G, DE LONLAY P, JOUVET P, NARCY C, LAURENT J, RABIER D, KAMOUN P, JAN D, REVILLON Y
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1999 - Eur. J. Pediat. 158(Suppl 2):S55-S59 |
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We report here our experience in the long-term management of 28 patients with citrullinaemia, 13 patients with carbamoyl phosphate synthase deficiency and 15 patients with argininosuccinic aciduria. In addition, we report a national French survey of 119 patients with ornithine transcarbamylase (OTC) deficiency enzymatically characterized in our laboratory. We also include in this report four personal patients (two with OTC and two with citrullinaemia) who were liver transplanted, and one OTC patient from the National French survey. Although this retrospective series is not really representative of the modern treatment combining low protein diet and arginine, sodium benzoate and sodium phenylbutyrate, it is obvious that the long-term outcome of all urea cycle disorders remains very guarded. We highlight the severity of the neonatal forms of such disorders, and mostly for OTC-deficient males. According to this evidence, our policy is not to treat such severely affected patients in the neonatal period who die anyway spontaneously within 2 to 3 days. At the present time, we only have three patients with neonatal citrullinaemia, aged 1, 6 and 10 years respectively, who are still doing well. One of them has been successfully liver transplanted at 5 years. Another transplanted patient died in the post-surgical phase. We emphasize the unexpected severity of argininosuccinic aciduria in which there is no one patient doing well. This is a rather surprising finding as this disorder is easy to manage and rarely presents with recurrent attacks of hyperammonaemia when it is treated by arginine supplementation. This consideration would suggest to extend the indication of orthotopic liver transplantation in this disorder. Finally, the most difficult indication is in the late onset symptomatic female OTC group. In this last group, despite a significant residual activity due to heterozygote status, even with a variable lyonisation, only seven girls are still mentally and neurologically normal. Interestingly, three of these seven were liver-transplanted before the constitution of irreversible neurological damage. These three girls and their family declare their well-being, their feeling to be cured and enjoy their normal life. [References: 18]
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Unité(s) :
Fédération de Pédiatrie, Biochimie Médicale
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Liver transplantation in propionic acidaemia
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SAUDUBRAY JM, TOUATI G, DE LONLAY P, JOUVET P, SCHLENZIG J, NARCY C, LAURENT J, RABIER D, KAMOUN P, JAN D, REVILLON Y
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1999 - Eur. J. Pediat. 158(Suppl 2):S65-S69 |
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Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Good results can be obtained at a very high price in terms of medical attention, family burden and high cost. In most early onset forms of PA, the intake of natural protein must be rigidly restricted to 8-12 g/day for the first 3 years of life, and then slowly increased to 15-20 g/day by the age of 6-8 years. Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg protein per day is generally recommended, although remains controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding or gastrostomy. Metronidazole is very effective in reducing the excretion of propionate metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically given to promote propionylcarnitine synthesis and excretion. We report here a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital. Of them, 2 have been liver transplanted. In these two patients who presented frequent severe and unexpected metabolic decompensations despite good compliance with the dietary therapy, orthotopic liver transplantation (OLT) was done at 7 and 9 years respectively. One child died 15 months after transplantation due to a severe lymphoproliferative disorder; the other child now aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she is under normal moderate daily protein intake (40-50 g/day) and still on carnitine supplementation. Interestingly, another patient who filled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions to the intensive care unit despite excellent dietary management) was also placed on the list for OLT. From the time he was registered onward, he experienced no further episodes of metabolic decompensation, there was almost no interruption in his daily intake and he gained height and weight and developed well. He was finally removed from the list and is still doing very well 2 years thereafter. Correction of propionylCoA carboxylase deficiency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical phenotype. Liver transplanted PA patients still require slight protein restriction and carnitine treatment. We consider that at the moment OLT should only be performed in severe forms of PA, mostly characterised by frequent and unexpected episodes of metabolic decompensation despite good dietary therapy. However, a strict appreciation of these criteria is difficult. A more generalised indication for OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors or transplantation of isolated allogenic hepatocytes, genetically modified or not. [References: 28]
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Unité(s) :
Fédération de Pédiatrie, Biochimie Médicale
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Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy
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TOUAM M, ZINGRAFF J, JUNGERS P, CHADEFAUX-VEKEMANS B, DRUEKE T, MASSY ZA
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1999 - Kidney Int. 56(6):2292-2296 |
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Background. Folic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients.
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Unité(s) :
U507, Biochimie Médicale
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D-2-hydroxyglutaric aciduria: Further clinical delineation
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VAN DER KNAAP MS, JAKOBS C, HOFFMANN GF, DURAN M, MUNTAU AC, SCHWEITZER S, KELLEY RI, PARROT-ROULAUD F, AMIEL J, DE LONLAY P, RABIER D, EEG-OLOFSSON O
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1999 - J. Inherit. Metab. Dis. 22(4):404-413 |
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It has recently been recognized that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with a severe and a mild phenotype. Whereas the clinical and neuroimaging findings of the severe phenotype were homogeneous among the patients, the findings in the mild phenotype were much more variable, leaving the clinical picture poorly defined. We were able to collect the clinical, biochemical and neuroimaging data on an additional 8 patients with D-2-hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. With the new information, it becomes clear that the mild phenotype shares the essential characteristics of the severe phenotype. The most frequent findings, regardless of the clinical phenotype, are epilepsy, hypotonia and psychomotor retardation. Additional findings, mainly occurring in the severe phenotype, are episodic vomiting, cardiomyopathy, inspiratory stridor and apnoeas. The most consistent MRI finding is enlargement of the lateral ventricles, occipital more than frontal. Regardless of the clinical phenotype, early MRI shows in addition subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal multifocal cerebral white-matter abnormalities. Two patients had vascular abnormalities, but it is as yet unclear whether these are related to D-2-hydroxyglutaric aciduria or are incidental findings. [References: 11]
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Unité(s) :
Biochimie Médicale
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Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia: Wide variations in phenotypic expression
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WILLIG TN, DRAPTCHINSKAIA N, DIANZANI I, BALL S, NIEMEYER C, RAMENGHI U, ORFALI K, GUSTAVSSON P, GARELLI E, BRUSCO A, TIEMANN C, PERIGNON JL, BOUCHIER C, CICCHIELLO L, DAHL N, MOHANDAS N, TCHERNIA G
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1999 - Blood 94(12):4294-4306 |
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Mutations of the ribosomal protein S19 (RPS19) gene were recently identified in 10 patients with Diamond Blackfan anemia (DBA). To determine the prevalence of mutations in this gene in DBA and to begin to define the molecular basis for the observed variable clinical phenotype of this disorder, the genomic sequence of the 6 exons and the 5' untranslated region of the RPS19 gene was directly assessed in DBA index cases from 172 new families. Mutations affecting the coding sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas mutations in noncoding regions were found in 8 patients (4.6%). Mutations included nonsense, missense, splice sites, and frameshift mutations. A hot spot for missense mutations was identified between codons 52 and 62 of the RPS19 gene in a new sequence consensus motif W-[YFW][YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No correlation between the nature of mutations and the different patterns of clinical expression, including age at presentation, presence of malformations, and therapeutic outcome, could be documented. Moreover, RPS19 mutations were also found in some first-degree relatives presenting only with isolated high erythrocyte adenosine deaminase activity and/or macrocytosis. The lack of a consistent relationship between the nature of the mutations and the clinical phenotype implies that yet unidentified factors modulate the phenotypic expression of the primary genetic defect in families with RPS19 mutations. (C) 1999 by The American Society of Hematology. [References: 37]
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Unité(s) :
Biochimie Médicale
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