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Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.
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Acil-CoA Deshidrogenasa/deficiencia , Cardiomiopatías , Carnitina O-Palmitoiltransferasa/deficiencia , Errores Innatos del Metabolismo Lipídico , Errores Innatos del Metabolismo , Proteína Trifuncional Mitocondrial/deficiencia , Tamizaje Neonatal , Rabdomiólisis , Humanos , Recién Nacido , Estudios Retrospectivos , Masculino , Femenino , Tamizaje Neonatal/métodos , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/complicaciones , Bélgica/epidemiología , Lactante , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Ácidos Grasos/metabolismo , Preescolar , Enfermedades Musculares/diagnóstico , Niño , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/complicaciones , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/diagnósticoRESUMEN
BACKGROUND: One objective of the Belgian Rare Diseases plan is to improve patients' management using phenotypic tests and, more specifically, the access to those tests by identifying the biochemical analyses used for rare diseases, developing new financing conditions and establishing reference laboratories. METHODS: A feasibility study was performed from May 2015 until August 2016 in order to select the financeable biochemical analyses, and, among them, those that should be performed by reference laboratories. This selection was based on an inventory of analyses used for rare diseases and a survey addressed to the Belgian laboratories of clinical pathology (investigating the annual analytical costs, volumes, turnaround times and the tests unavailable in Belgium and outsourced abroad). A proposal of financeable analyses, financing modalities, reference laboratories' scope and budget estimation was developed and submitted to the Belgian healthcare authorities. After its approval in December 2016, the implementation phase took place from January 2017 until December 2019. RESULTS: In 2019, new reimbursement conditions have been published for 46 analyses and eighteen reference laboratories have been recognized. Collaborations have also been developed with 5 foreign laboratories in order to organize the outsourcing and financing of 9 analyses unavailable in Belgium. CONCLUSIONS: In the context of clinical pathology and rare diseases, this initiative enabled to identify unreimbursed analyses and to meet the most crucial financial needs. It also contributed to improve patients' management by establishing Belgian reference laboratories and foreign referral laboratories for highly-specific analyses and a permanent surveillance, quality and financing framework for those tests.
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Pruebas Diagnósticas de Rutina , Enfermedades Raras , Bélgica , Presupuestos , Humanos , Laboratorios , Enfermedades Raras/diagnósticoRESUMEN
Zellweger spectrum disorders (ZSD) are inborn errors of metabolism caused by mutations in PEX genes that lead to peroxisomal biogenesis disorder (PBD). No validated treatment is able to modify the dismal progression of the disease. ZSD mouse models used to develop therapeutic approaches are limited by poor survival and breeding restrictions. To overcome these limitations, we backcrossed the hypomorphic Pex1 p.G844D allele to NMRI background. NMRI mouse breeding restored an autosomal recessive Mendelian inheritance pattern and delivered twice larger litters. Mice were longitudinally phenotyped up to 6 months of age to make this model suitable for therapeutic interventions. ZSD mice exhibited growth retardation and relative hepatomegaly associated to progressive hepatocyte hypertrophy. Biochemical studies associated with RNA sequencing deciphered ZSD liver glycogen metabolism alterations. Affected fibroblasts displayed classical immunofluorescence pattern and biochemical alterations associated with PBD. Plasma and liver showed very long-chain fatty acids, specific oxysterols and C27 bile acids intermediates elevation in ZSD mice along with a specific urine organic acid profile. With ageing, C26 fatty acid and phytanic acid levels tended to normalize in ZSD mice, as described in patients reaching adulthood. In conclusion, our mouse model recapitulates a mild ZSD phenotype and is suitable for liver-targeted therapies evaluation.
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ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Síndrome de Zellweger/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , Alelos , Animales , Ácidos y Sales Biliares/metabolismo , Membrana Celular/metabolismo , Femenino , Glucosa-6-Fosfatasa/metabolismo , Hepatocitos/metabolismo , Estudios Longitudinales , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Oxiesteroles/metabolismo , RNA-Seq , Síndrome de Zellweger/genéticaRESUMEN
5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH (ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA-riboside in urine. AICA-ribosiduria had been reported in only one individual, 15 years ago. In this article, we report three novel cases of AICA-ribosiduria from two independent families, with two novel pathogenic variants in ATIC. We also provide a clinical update on the first patient. Based on the phenotypic features shared by these four patients, we define AICA-ribosiduria as the syndromic association of severe-to-profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features were observed in all four cases, especially neonatal/infancy coarse facies with upturned nose. Early-onset epilepsy is frequent and can be pharmacoresistant. Less frequently observed features are aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis. Alteration of the transformylase activity of ATIC might result in a more severe impairment than the alteration of the cyclohydrolase activity. Data from literature points toward a cytotoxic mechanism of the accumulated AICA-riboside.
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Anomalías Congénitas/genética , Epilepsia/genética , Transferasas de Hidroximetilo y Formilo/deficiencia , Discapacidad Intelectual/genética , Complejos Multienzimáticos/genética , Nucleótido Desaminasas/deficiencia , Aminoimidazol Carboxamida/metabolismo , Niño , Preescolar , Femenino , Humanos , Transferasas de Hidroximetilo y Formilo/genética , Transferasas de Hidroximetilo y Formilo/metabolismo , Lactante , Recién Nacido , Masculino , Complejos Multienzimáticos/metabolismo , Mutación , Nucleótido Desaminasas/genética , Nucleótido Desaminasas/metabolismo , Fenotipo , Ribonucleósidos/metabolismoRESUMEN
Idiopathic hyperammonemia is a rare but potentially fatal complication occurring in patients with acute leukemia or bone marrow transplantation. The role of some specific anticancer drugs may be discussed, but the etiology of hyperammonemia is often multifactorial. We report the case of a 40-year-old woman who developed fatal idiopathic hyperammonemia two weeks after induction chemotherapy with idarubicin-aracytine for acute myeloid leukemia. Despite intensive care management and extrarenal epuration, the patient was declared brain dead two days after hyperammonemia onset.
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BACKGROUND: Deletions or inactivating mutations of the cystinosin gene CTNS lead to cystine accumulation and crystals at acidic pH in patients with nephropathic cystinosis, a rare lysosomal storage disease and the main cause of hereditary renal Fanconi syndrome. Early use of oral cysteamine to prevent cystine accumulation slows progression of nephropathic cystinosis but it is a demanding treatment and not a cure. The source of cystine accumulating in kidney proximal tubular cells and cystine's role in disease progression are unknown. METHODS: To investigate whether receptor-mediated endocytosis by the megalin/LRP2 pathway of ultrafiltrated, disulfide-rich plasma proteins could be a source of cystine in proximal tubular cells, we used a mouse model of cystinosis in which conditional excision of floxed megalin/LRP2 alleles in proximal tubular cells of cystinotic mice was achieved by a Cre-LoxP strategy using Wnt4-CRE. We evaluated mice aged 6-9 months for kidney cystine levels and crystals; histopathology, with emphasis on swan-neck lesions and proximal-tubular-cell apoptosis and proliferation (turnover); and proximal-tubular-cell expression of the major apical transporters sodium-phosphate cotransporter 2A (NaPi-IIa) and sodium-glucose cotransporter-2 (SGLT-2). RESULTS: Wnt4-CRE-driven megalin/LRP2 ablation in cystinotic mice efficiently blocked kidney cystine accumulation, thereby preventing lysosomal deformations and crystal deposition in proximal tubular cells. Swan-neck lesions were largely prevented and proximal-tubular-cell turnover was normalized. Apical expression of the two cotransporters was also preserved. CONCLUSIONS: These observations support a key role of the megalin/LRP2 pathway in the progression of nephropathic cystinosis and provide a proof of concept for the pathway as a therapeutic target.
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Cistinosis/etiología , Endocitosis , Túbulos Renales Proximales/patología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/fisiología , Animales , Cistina/metabolismo , Cistinosis/prevención & control , Progresión de la Enfermedad , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiología , Proteína Wnt4/fisiologíaRESUMEN
OBJECTIVE: SLC13A3 encodes the plasma membrane Na+ /dicarboxylate cotransporter 3, which imports inside the cell 4 to 6 carbon dicarboxylates as well as N-acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes, and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a urinary excretion of α-ketoglutarate (αKG) that was markedly increased and persisted over time. In one patient, increased concentrations of cerebrospinal fluid NAA and dicarboxylates (including αKG) were observed. Extensive workup was unsuccessful, and a genetic cause was suspected. METHODS: Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher. RESULTS: WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by reverse transcriptase polymerase chain reaction performed in muscle tissue (c.1016 + 3A > G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild-type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate, and NAA. INTERPRETATION: SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy, for which SLC13A3 deficiency is a novel differential diagnosis. ANN NEUROL 2019;85:385-395.
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Ácido Aspártico/análogos & derivados , Ácidos Cetoglutáricos/metabolismo , Leucoencefalopatías/genética , Simportadores/genética , Adolescente , Ácido Aspártico/líquido cefalorraquídeo , Ácido Aspártico/metabolismo , Preescolar , Femenino , Células HEK293 , Humanos , Ácidos Cetoglutáricos/líquido cefalorraquídeo , Ácidos Cetoglutáricos/orina , Leucoencefalopatías/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Mutación Missense , Linaje , Infecciones del Sistema Respiratorio , Ácido Succínico/metabolismo , Simportadores/metabolismo , Tonsilitis , Secuenciación del ExomaRESUMEN
The case is reported of a 39-year-old severely obese woman who developed acute metabolic disorders after the administration of a short course of intravenous amiodarone. The main biological features were hypertriglyceridemia, hypoglycaemia, hyperlactatemia and hyperammonemia; all were reversible after amiodarone discontinuation. There was an associated rise in liver enzymes. However, the influence of co-factors on these metabolic disorders, such as acquired carnitine deficiency, severe obesity, a long-term course of pancreatitis, and abdominal infections, could not be excluded.
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Amoníaco/sangre , Recolección de Muestras de Sangre , Temperatura , Centrifugación , HumanosRESUMEN
INTRODUCTION: Lysinuric protein intolerance (LPI) is a form of inherited aminoaciduria caused by a deficiency in the cationic amino acid transport process on the basolateral membrane of enterocytes and renal tubular cells. Clinical signs include gastrointestinal symptoms, failure to thrive, hepatosplenomegaly, osteoporosis, episodes of coma, intellectual deficiency, lung and renal involvement, bone marrow abnormalities, as well as altered immune response. Moyamoya disease is a cerebrovascular disorder predisposing sufferers to stroke through progressive stenosis of the intracranial internal carotid arteries and their proximal branches. Patients with characteristic moyamoya vasculopathy who also exhibit well-recognized associated conditions, such as Down syndrome or sickle-cell disease, are diagnosed with moyamoya syndrome, whereas those with no known associated risk factors are said to suffer from moyamoya disease. CASE STUDY: A 5-year-old girl exhibiting aversion to protein-rich food and splenomegaly presented with a history of recurrent ischemic strokes. Cerebral angiography confirmed moyamoya vasculopathy. Metabolic investigation revealed abnormalities characteristic of LPI. This diagnosis was confirmed by the detection of a mutation within the SLC7A7 gene upon molecular investigation. CONCLUSION: To the best of our knowledge, this is the first reported case of an association between moyamoya vasculopathy and LPI. While the question of association or coincidence cannot yet be answered, several pathophysiological consequences of LPI can be defined as separate, such as links between the impact of low arginine levels on the function of vascular endothelium and brain nitric oxide metabolism, as well as hemophagocytic syndrome associated with the risk of vasculitis, thus accounting for the development of moyamoya vasculopathy.
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Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Enfermedad de Moyamoya/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/genética , Sistema de Transporte de Aminoácidos y+L , Preescolar , Femenino , Cadenas Ligeras de la Proteína-1 Reguladora de Fusión/genética , Humanos , MutaciónRESUMEN
Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial protein involved in oxidative phosphorylation complex I biogenesis. This protein also exhibits acyl-CoA dehydrogenase (ACAD) activity. ACAD9-mutated patients have been reported to suffer from primarily heart, muscle, liver, and nervous system disorders. ACAD9 mutation is suspected in cases of elevated lactic acid levels combined with complex I deficiency, and confirmed by ACAD9 gene analysis. At least 18 ACAD9-mutated patients have previously been reported, usually displaying severe cardiac involvement. We retrospectively studied nine additional patients from three unrelated families with a wide spectrum of cardiac involvement between the families as well as the patients from the same families. All patients exhibited elevated lactate levels. Deleterious ACAD9 mutations were identified in all patients except one for whom it was not possible to recover DNA. To our knowledge, this is one of the first reports on isolated mild ventricular hypertrophy due to ACAD9 mutation in a family with moderate symptoms during adolescence. This report also confirms that dilated cardiomyopathy may occur in conjunction with ACAD9 mutation and that some patients may respond clinically to riboflavin treatment. Of note, several patients suffered from patent ductus arteriosus (PDA), with one exhibiting a complex congenital heart defect. It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild.
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Acil-CoA Deshidrogenasas/genética , Cardiopatías/genética , Ácido Láctico/sangre , Mutación , Acil-CoA Deshidrogenasas/metabolismo , Adulto , Niño , Femenino , Predisposición Genética a la Enfermedad , Cardiopatías/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Estudios Retrospectivos , Riboflavina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
The purpose of the present work was to progress in our understanding of the pathophysiology of L-2-hydroxyglutaric aciduria, due to a defect in L-2-hydroxyglutarate dehydrogenase, by creating and studying a mouse model of this disease. L-2-hydroxyglutarate dehydrogenase-deficient mice (l2hgdh-/-) accumulated L-2-hydroxyglutarate in tissues, most particularly in brain and testis, where the concentration reached ≈ 3.5 µmol/g. Male mice showed a 30% higher excretion of L-2-hydroxyglutarate compared to female mice, supporting that this dicarboxylic acid is partially made in males by lactate dehydrogenase C, a poorly specific form of this enzyme exclusively expressed in testes. Involvement of mitochondrial malate dehydrogenase in the formation of L-2-hydroxyglutarate was supported by the commensurate decrease in the formation of this dicarboxylic acid when down-regulating this enzyme in mouse l2hgdh-/- embryonic fibroblasts. The concentration of lysine and arginine was markedly increased in the brain of l2hgdh-/- adult mice. Saccharopine was depleted and glutamine was decreased by ≈ 40%. Lysine-α-ketoglutarate reductase, which converts lysine to saccharopine, was inhibited by L-2-hydroxyglutarate with a Ki of ≈ 0.8 mM. As low but significant activities of the bifunctional enzyme lysine-α-ketoglutarate reductase/saccharopine dehydrogenase were found in brain, these findings suggest that the classical lysine degradation pathway also operates in brain and is inhibited by the high concentrations of L-2-hydroxyglutarate found in l2hgdh-/- mice. Pathological analysis of the brain showed significant spongiosis. The vacuolar lesions mostly affected oligodendrocytes and myelin sheats, as in other dicarboxylic acidurias, suggesting that the pathophysiology of this model of leukodystrophy may involve irreversible pumping of a dicarboxylate in oligodendrocytes. Neurobehavioral testing indicated that the mice mostly suffered from a deficit in learning capacity. In conclusion, the findings support the concept that L-2-hydroxyglutaric aciduria is a disorder of metabolite repair. The accumulation of L-2-hydroxyglutarate exerts toxic effects through various means including enzyme inhibition and glial cell swelling.
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Oxidorreductasas de Alcohol/genética , Encefalopatías Metabólicas Innatas/patología , Encéfalo/patología , Modelos Animales de Enfermedad , Glutaratos/metabolismo , Testículo/metabolismo , Oxidorreductasas de Alcohol/metabolismo , Animales , Arginina/metabolismo , Encéfalo/metabolismo , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Células Cultivadas , Femenino , Cetona Oxidorreductasas/metabolismo , Lisina/metabolismo , Masculino , Ratones , Ratones NoqueadosRESUMEN
Ganciclovir is widely prescribed in renal transplant patients for the prevention or treatment of herpes and cytomegalovirus (CMV) infections. Side-effects are usually represented by hematological disorders, and particularly leucopenia. We report a case of severe and fatal lactic acidosis developing in a 76-year-old renal transplant woman, a few days after ganciclovir has been introduced to treat CMV pneumonia. Usual etiologies of lactic acidosis were ruled out. A high lactate/pyruvate molecular ratio was suggestive of a respiratory chain dysfunction. With the analogy to nucleoside analogues-related lactic acidosis, we suggest that ganciclovir may exceptionally be responsible for respiratory chain dysfunction and subsequent lactic acidosis, and we discuss potential risk factors in our patient.
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OBJECTIVES: Little is known about the correlation between the inosine-monophosphate dehydrogenase (IMPDH) activity and mycophenolic acid (MPA) concentrations in peripheral-blood-mononuclear cells (PBMCs), where the drug is acting. The aim of this study was to analyze the relationship between plasma or PBMC MPA levels, as pharmacokinetic (PK) markers, and the intracellular IMPDH enzyme activity, as a pharmacodynamic (PD) biomarker, in kidney transplantation. DESIGN AND METHODS: Forty de novo renal transplant patients were enrolled in this prospective study. The sampling was performed on the day before transplantation and at T0, T1.5 and T3.5 following the morning dose, on days 2, 4 and 10 post-transplantation. All subjects were treated with a fixed MMF dose (500 mg twice-a-day). IMPDH activities were determined by HPLC, and MPA plasma or PBMC concentrations were obtained by LC-MSMS. RESULTS: Important inter-patient variability was observed both for the PK and PD biomakers. Pre-dose IMPDH activity, surprisingly, increased during the 10 days post-transplantation. As expected, a significant inverse relationship was found between IMPDH activities and MPA concentrations in both plasma and PBMCs. A significant correlation was found between plasma and PBMC MPA values. Maximum IMPDH inhibition was found mostly at T1.5, before returning to its pre-dose levels at T3.5. IMPDH inhibition at T1.5 better correlated with plasma MPA AUC(0-3.5) (p=0.027) than with PBMC AUC(0-3.5) (p=0.323). Mean MPA plasma concentrations paralleled the enzyme inhibition profiles and decreased strongly at T3.5, whereas the decreasing slope of MPA concentrations in PBMCs appeared slower. CONCLUSIONS: These findings suggest that PBMC MPA concentrations do not provide any better correlation with the IMPDH activity than plasma MPA values, most likely due to the correlation between plasma and PBMC MPA levels and to the important interpatient variability both in MPA levels and enzyme activities.
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Inhibidores Enzimáticos/farmacocinética , Ácido Micofenólico/farmacocinética , Adulto , Anciano , Área Bajo la Curva , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , IMP Deshidrogenasa/antagonistas & inhibidores , IMP Deshidrogenasa/metabolismo , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/enzimología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Leucocitos Mononucleares/enzimología , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Estudios Prospectivos , Distribución Tisular , Adulto JovenRESUMEN
UNLABELLED: (18)F-FDG PET/CT can be used to detect arterial atherosclerotic plaque inflammation. However, avid myocardial glucose uptake may preclude its use for visualizing coronary plaques. Fatty acid loading or calcium channel blockers could decrease myocardial (18)F-FDG uptake, thus assisting coronary plaque inflammation identification. The present prospective randomized trial compared the efficacies of different interventions for suppressing myocardial (18)F-FDG uptake. We also investigated whether circulating free fatty acid (cFFA) levels predicted the magnitude of myocardial (18)F-FDG uptake. METHODS: Thirty-six volunteers ate a high-fat low-carbohydrate meal, followed by a 12-h fasting period. They were then randomized to 1 of 4 intervention groups. Group 1 received no additional preparation and served as a reference. Groups 2 and 3, respectively, received a commercial high-fat solution containing 43.8 g of lipids or 50 mL of olive oil 1 h before (18)F-FDG injection to evaluate the impact of fatty acid loading on myocardial (18)F-FDG uptake. Group 4 received verapamil to evaluate the effect of calcium channel blockers. Cardiac PET/CT was performed after administration of 370 MBq of (18)F-FDG. Myocardial uptake suppression was assessed using a qualitative visual scale and by measuring the myocardial maximum standardized uptake value (SUV(max)). Insulin, glucose, and cFFA were serially measured. RESULTS: The qualitative visual scale showed good myocardial (18)F-FDG uptake suppression in 8 of 9, 5 of 9, 4 of 9, and 8 of 9 subjects of groups 1, 2, 3, and 4, respectively (P = 0.09). SUV(max) did not significantly differ between groups (P = 0.17). Interestingly, cFFA levels were higher in volunteers with good suppression (0.80 ± 0.31 mmol/L) than in those with poor suppression (0.53 ± 0.15 mmol/L; P = 0.011). We found an inverse correlation between cFFA level (measured at (18)F-FDG injection) and the SUV(max) (R = 0.61). Receiver-operating-characteristic curve analysis identified 0.65 mmol/L cFFA as the best cutoff value to predict adequate (18)F-FDG uptake suppression (positive predictive value, 89%). CONCLUSION: A high-fat low-carbohydrate meal followed by a 12-h fasting period effectively suppressed myocardial (18)F-FDG uptake in most subjects. Neither complementary fatty acid loading nor verapamil administered 1 h before (18)F-FDG injection conferred any additional benefit. Myocardial (18)F-FDG uptake was inversely correlated with cFFA level, representing an interesting way to predict myocardial (18)F-FDG uptake suppression.
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Vasos Coronarios/patología , Fluorodesoxiglucosa F18/farmacocinética , Placa Aterosclerótica/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Adulto , Dieta , Ácidos Grasos no Esterificados/sangre , Femenino , Voluntarios Sanos , Humanos , Inflamación , Lípidos/administración & dosificación , Masculino , Aceite de Oliva , Aceites de Plantas/administración & dosificación , Aceites de Plantas/química , Estudios Prospectivos , Reproducibilidad de los Resultados , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodos , Verapamilo/administración & dosificaciónRESUMEN
A 31-year-old pregnant woman (32 + 3 weeks) was admitted with extreme tachypnea. She had a previous history of congenital muscular dystrophy (Ullrich's disease) and isolated glucosuria. The patient had reduced food intake during the last 24 hours prior to admission and vomited twice. Serum glucose level was normal (112 mg/dL), while urinalysis revealed glucosuria 4+ and ketonuria 4+. ABG revealed pH 7.06, PCO2 9 mm Hg, and bicarbonate 2 mmol/L. Anion gap was 28 mmol/L. Tachypnea was a compensatory mechanism for a severe nonlactic metabolic acidosis. The diagnosis of starvation ketoacidosis was established. The patient received supplemental dextrose 10% intravenously and sodium bicarbonate. As fetal heart monitoring was pathological, an emergency caesarean section was performed. Umbilical cord venous pH was 7.01, with PCO2 34 mm Hg and bicarbonate 8 mmol/L. Starvation ketoacidosis is a rare metabolic disorder that may occur mainly in the third trimester of pregnancy. Muscular dystrophy and renal glucosuria were precipitating factors.
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It has been proposed that neonatal thyroid-stimulating hormone (TSH) concentrations are a good indicator of iodine deficiency in the population. A frequency of neonatal TSH concentrations above 5 mU/L below 3% has been proposed as the threshold indicating iodine sufficiency. The objective of the present study was to evaluate feasibility and usefulness of nation-wide neonatal TSH concentration screening results to assess iodine status in Belgium. All newborns born in Belgium during the period 2009-2011 (n = 377713) were included in the study, except those suffering from congenital hypothyroidism and premature neonates. The frequency of neonatal TSH concentrations above 5 mU/L from 2009 to 2011 in Belgium fluctuated between 2.6 and 3.3% in the centres using the same TSH assay. There was a significant inverse association between neonatal TSH level and birth weight. The longer the duration between birth and screening, the lower the TSH level. Neonatal TSH levels were significantly lower in winter than in spring or autumn and significantly lower in spring and summer than in autumn while significantly higher in spring compared to summer. In conclusion, despite that pregnant women in Belgium are mildly iodine deficient, the frequency of neonatal TSH concentrations above 5 mU/L was very low, suggesting that the neonatal TSH threshold proposed for detecting iodine deficiency needs to be re-evaluated. Although neonatal TSH is useful to detect severe iodine deficiency, it should not be recommended presently for the evaluation of iodine status in mildly iodine deficient regions.
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Hipotiroidismo Congénito/diagnóstico , Tirotropina , Bélgica , Hipotiroidismo Congénito/sangre , Femenino , Humanos , Recién Nacido , Análisis de los Mínimos Cuadrados , Embarazo , Estaciones del Año , Tirotropina/sangreRESUMEN
Tyrosinemia Type III is caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), an enzyme involved in the catabolic pathway of tyrosine. To our knowledge, only a few patients presenting with this disease have been described in the literature, and the clinical phenotype remains variable and unclear. We report the case of a boy with tyrosinemia Type III detected using neonatal screening, who is homozygous for the splice donor mutation IVS11+1G>A in intron 11 of the HPD gene. At the age of 30 months, the boy's outcome under mild protein restriction was characterized by normal growth and psychomotor development.
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4-Hidroxifenilpiruvato Dioxigenasa/genética , Dieta con Restricción de Proteínas , Tirosina/metabolismo , Tirosinemias/dietoterapia , 4-Hidroxifenilpiruvato Dioxigenasa/deficiencia , Preescolar , Manejo de la Enfermedad , Homocigoto , Humanos , Recién Nacido , Intrones , Masculino , Mutación , Tamizaje Neonatal , Desempeño Psicomotor , Resultado del Tratamiento , Tirosinemias/genética , Tirosinemias/metabolismoRESUMEN
PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.
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Tamizaje Neonatal/métodos , Programas Informáticos , Espectrometría de Masas en Tándem/métodos , Biología Computacional , Interpretación Estadística de Datos , Bases de Datos Factuales , Diagnóstico Diferencial , Reacciones Falso Positivas , Humanos , Recién Nacido , Cooperación Internacional , Metaboloma , Minnesota , Análisis Multivariante , Reconocimiento de Normas Patrones Automatizadas , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
A limited number of enzymes are known that play a role analogous to DNA proofreading by eliminating non-classical metabolites formed by side activities of enzymes of intermediary metabolism. Because few such "metabolite proofreading enzymes" are known, our purpose was to search for an enzyme able to degrade ethylmalonyl-CoA, a potentially toxic metabolite formed at a low rate from butyryl-CoA by acetyl-CoA carboxylase and propionyl-CoA carboxylase, two major enzymes of lipid metabolism. We show that mammalian tissues contain a previously unknown enzyme that decarboxylates ethylmalonyl-CoA and, at lower rates, methylmalonyl-CoA but that does not act on malonyl-CoA. Ethylmalonyl-CoA decarboxylase is particularly abundant in brown adipose tissue, liver, and kidney in mice, and is essentially cytosolic. Because Escherichia coli methylmalonyl-CoA decarboxylase belongs to the family of enoyl-CoA hydratase (ECH), we searched mammalian databases for proteins of uncharacterized function belonging to the ECH family. Combining this database search approach with sequencing data obtained on a partially purified enzyme preparation, we identified ethylmalonyl-CoA decarboxylase as ECHDC1. We confirmed this identification by showing that recombinant mouse ECHDC1 has a substantial ethylmalonyl-CoA decarboxylase activity and a lower methylmalonyl-CoA decarboxylase activity but no malonyl-CoA decarboxylase or enoyl-CoA hydratase activity. Furthermore, ECHDC1-specific siRNAs decreased the ethylmalonyl-CoA decarboxylase activity in human cells and increased the formation of ethylmalonate, most particularly in cells incubated with butyrate. These findings indicate that ethylmalonyl-CoA decarboxylase may correct a side activity of acetyl-CoA carboxylase and suggest that its mutation may be involved in the development of certain forms of ethylmalonic aciduria.