RESUMEN
Fabry disease (FD) is an X-linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti-drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45- and CD45 + CCR7-CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA-CCR7-CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers.
Asunto(s)
Linfocitos T CD4-Positivos , Enfermedad de Fabry , Trihexosilceramidas , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Humanos , Enfermedad de Fabry/inmunología , Masculino , Trihexosilceramidas/metabolismo , Adulto , Linfocitos T CD4-Positivos/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Persona de Mediana Edad , Adulto Joven , Adolescente , Esfingolípidos/metabolismo , Estudios de Casos y Controles , Antígenos Comunes de Leucocito , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Citometría de Flujo , Antígenos CD28 , Memoria Inmunológica , Receptores CCR7/metabolismo , GlucolípidosRESUMEN
OBJECTIVE: To assess spatial aggregates of amyotrophic lateral sclerosis (ALS) incident cases, using a solid geo-epidemiological statistical method, in France. METHODS: This population-based study (2003-2011) investigated 47.1 million person-years of follow-up (PYFU). Case ascertainment of incident ALS cases was based on multiple sources (ALS referral centers, hospital centres and health insurance data). Neurologists confirmed all ALS diagnoses. Exhaustiveness was estimated through capture-recapture. Aggregates were investigated in four steps: (a) geographical modelling (standardized incidence ratio (SIR) calculation), (b) analysis of the spatial distribution of incidence (Phothoff-Winttinghill's test, Global Moran's Index, Kulldorf's spatial scan statistic, Local Moran's Index), (c) classification of the level of certainty of spatial aggregates (i.e. definite cluster; probable over-incidence area; possible over-incidence area) and (d) evaluation of the robustness of the results. RESULTS: The standardized incidence of ALS was 2.46/100,000 PYFU (95% CI 2.31-2.63, European population as reference) based on 1199 incident cases. We identified 13 areas of spatial aggregates: one cluster (stable in robustness analysis), five probable over-incidence areas (2 stable in robustness analysis) and seven possible over-incidence areas (including 4 stable areas in robustness analysis). A cluster was identified in the Rhône-Alpes region: 100 observed vs 54.07 expected cases for 2,411,514 PYFU, SIR: 1.85 (95% CI 1.50-2.25). CONCLUSION: We report here one of the largest investigations of incidence and spatial aggregation of ALS ever performed in a western country. Using a solid methodology framework for case ascertainment and cluster analysis, we identified 13 areas that warrant further investigation.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/epidemiología , Incidencia , Análisis por Conglomerados , Métodos Epidemiológicos , Francia/epidemiologíaRESUMEN
Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16-86). Eighty-nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD-6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life-threatening condition. Physicians working in adult care must be aware of late-onset presentations given the implications for patients and their families.
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Trastornos Innatos del Ciclo de la Urea/diagnóstico , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Aciduria Argininosuccínica/diagnóstico , Femenino , Francia , Humanos , Hiperamonemia/diagnóstico , Masculino , Persona de Mediana Edad , Ornitina/deficiencia , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Estudios Retrospectivos , Factores Sexuales , Trastornos Innatos del Ciclo de la Urea/mortalidad , Adulto JovenRESUMEN
Many similarities between tryptophan (Trp) and phenylalanine (Phe) metabolisms exist. It is possible that a modification of Trp metabolism might be seen in phenylketonuria (PKU). As some of these metabolites have neuroactive properties, they should be consider in neurological impairment seen in this pathology and not totally explained by blood Phe concentrations. One hundred and fifty-one adult PKU patients (mean age 26.8 years) were included for this study. Plasma Trp, kynurenine (KYN), 3-hydroxykynurenic acid (3HK), and kynurenic acid (KA) were analyzed by liquid chromatography coupled with tandem mass spectrometry. KYN and 3HK were significantly lower in PKU patients compared to general population (P < .0001), and KA was significantly enhanced is this population (P = .009). Furthermore, 3HK concentration was significantly different between PKU patients underwent controlled low-Phe diet compared to PKU patients without this diet (P = .0016). In PKU patients with diet, taking AA substitute enable higher plasma 3HK concentration than without (P = .0008) but still not reaching general population level (P < .0001). Although further study has to be done, it is clear that Trp metabolism is modified in adult PKU patients. An exploration of complete Trp metabolism, and not only Trp concentration, is needed in PKU population, but also in other inborn error of metabolism treated with hypoprotidic diet.
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Fenilcetonurias/sangre , Triptófano/metabolismo , Adulto , Análisis Químico de la Sangre/métodos , Cromatografía Liquida , Femenino , Francia , Humanos , Masculino , Fenilcetonurias/diagnóstico , Fenilcetonurias/metabolismo , Estudios Prospectivos , Espectrometría de Masas en TándemRESUMEN
BACKGROUD: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity. METHODS: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients. RESULTS: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI. CONCLUSION: Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
Asunto(s)
Enfermedad de Fabry/clasificación , Adulto , Estudios de Cohortes , Córnea/diagnóstico por imagen , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/diagnóstico por imagen , Femenino , Francia , Humanos , Persona de Mediana Edad , Parestesia/etiología , Fenotipo , Estudios Prospectivos , Sistema de Registros , Adulto JovenRESUMEN
BACKGROUND: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients' ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus. METHODS: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH. FINDINGS: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75-55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the 'Biopterin_H' domain (OR = 6·45; 95% CI: 1·99-20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively. INTERPRETATION: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH. FUNDING: French National Institute of Health and Medical Research (INSERM) UMR_S 1256.
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Evolución Biológica , Etnicidad/genética , Genética de Población , Fenilalanina Hidroxilasa/genética , Fenilcetonurias/genética , Exoma/genética , Femenino , Francia , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Sitios Genéticos , Geografía , Haplotipos/genética , Humanos , Masculino , Filogenia , Análisis de Componente PrincipalRESUMEN
Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism.
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Enfermedades de los Ganglios Basales , Encefalopatías Metabólicas Innatas , Glutatión/metabolismo , Adulto , Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/genética , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Cerebrotendineous xanthomatosis (CTX) is an autosomal recessive disorder of bile acids synthesis. Patients may present with a variety of clinical manifestations: bilateral cataract and chronic diarrhea during childhood, then occurrence of neurological debilitating symptoms in adulthood (cognitive decline, motor disorders). Plasma cholestanol is used as a diagnostic marker of CTX, and to monitor the response to the treatment. Current treatment for CTX is chenodeoxycholic acid (CDCA), which was reported to improve and/or stabilize clinical status and decrease levels of plasma cholestanol. Rare published reports have also suggested a potential efficacy of cholic acid (CA) in patients with CTX. In this retrospective Franco-Belgian multicentric study, we collected data from 12 patients treated with CA, evaluating their clinical status, cholestanol levels and adverse effects during the treatment period. The population was divided in two subgroups: treatment-naive (who never had CDCA prior to CA) and non-treatment-naive patients (who had CDCA prior to CA introduction). We found that treatment with CA significantly and strongly reduced cholestanol levels in all patients. Additionally, 10 out of 12 patients clinically improved or stabilized with CA treatment. Worsening was noted in one treatment-naïve patient and one non-treatment-naïve patient, but both patients experienced similar outcomes with CDCA treatment as well. No adverse effects were reported from patients with CA treatment, whereas elevated transaminases were observed in some patients while they were treated with CDCA. In conclusion, these findings suggest that CA may be a suitable alternative treatment for CTX, especially in patients with side effects related to CDCA.
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Colestanol/antagonistas & inhibidores , Colestanol/sangre , Ácido Cólico/uso terapéutico , Xantomatosis Cerebrotendinosa/sangre , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Adulto , Colesterol/sangre , Ácido Cólico/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Xantomatosis Cerebrotendinosa/diagnósticoAsunto(s)
Seudoobstrucción Intestinal/diagnóstico , Distrofia Muscular Oculofaríngea/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Precoz , Terapia de Reemplazo Enzimático , Femenino , Francia , Predisposición Genética a la Enfermedad , Humanos , Seudoobstrucción Intestinal/genética , Seudoobstrucción Intestinal/terapia , Masculino , Persona de Mediana Edad , Distrofia Muscular Oculofaríngea/genética , Distrofia Muscular Oculofaríngea/terapia , Mutación , Oftalmoplejía/congénito , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Timidina Fosforilasa/genética , Adulto JovenRESUMEN
BACKGROUND: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. RESULTS: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 µg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005). CONCLUSION: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.
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Anticuerpos/sangre , Enfermedad de Fabry/inmunología , Enfermedad de Fabry/patología , alfa-Galactosidasa/antagonistas & inhibidores , Adulto , Terapia de Reemplazo Enzimático , Ensayo de Inmunoadsorción Enzimática , Enfermedad de Fabry/sangre , Enfermedad de Fabry/tratamiento farmacológico , Femenino , Glucolípidos/sangre , Humanos , Inmunoglobulina G/sangre , Enfermedades por Almacenamiento Lisosomal/sangre , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico , Enfermedades por Almacenamiento Lisosomal/inmunología , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Esfingolípidos/sangre , alfa-Galactosidasa/inmunologíaRESUMEN
This work presents the performances of silicon micro-preconcentrators chips for breath sampling. The silicon chips were coupled to a handheld battery powered system for breath sampling and direct injection in a laboratory gas chromatography mass spectrometry system through thermal desorption (TD). Performances of micro-preconcentrators were first compared to commercial TD for benzene trapping. Similar chromatographic peaks after gas chromatographic separation were observed while the volume of sample needed was reduced by a factor of 5. Repeatability and day to day variability of the micro-preconcentrators were then studied for a 500 ppb synthetic model mixture injected three times a day four days in a row: 8% and 12% were measured respectively. Micro-preconcentrator to micro-preconcentrator variability was not significant compared to day to day variability. In addition, micro-preconcentrators were tested for breath samples collected in Tedlar® bags. Three analyses of the same breath sample displayed relative standard deviations values below 16% for eight of the ten most intense peaks. Finally, the performances of micro-preconcentrators for breath sampling on a single expiration were illustrated with the example of volatile tobacco markers tracking. The signals of three smoking markers in breath, benzene, 2,5-dimethylfuran, and toluene were studied. Concentrations of benzene and toluene were found to be 10 to 100 higher in the breath of smokers. 2,5-dimethylfuran was only found in the breath of smokers. The elimination kinetics of the markers were followed as well during 4 h: a fast decrease of the signal of the three markers in breath was observed 20 min after smoking in good agreement with what is described in the literature. Those results demonstrate the efficiency of silicon chips for breath sampling, compared to the state of the art techniques. Thanks to miniaturization and lower sample volumes needed, micro-preconcentrators could be in the future a key technology towards portable breath sampling and analysis.
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Biomarcadores/análisis , Pruebas Respiratorias/instrumentación , Miniaturización/instrumentación , Nicotiana/química , Silicio/química , Compuestos Orgánicos Volátiles/análisis , Benceno/análisis , Furanos/análisis , Cromatografía de Gases y Espectrometría de Masas , Humanos , Fumar , Tolueno/análisisRESUMEN
The efficacy of intravenous immunoglobulins (IVIg) in patients with autoimmune diseases (AID) has been known for several decades. Majority of these patients received IVIg in hospital. A retrospective study was conducted in 22 centers in France to evaluate the feasibility of the administration of Tegeline, an IVIg from LFB Biomedicaments, and assess its safety at home, compared to in hospital, in patients with AID. The included patients were at least 18 years old, suffering from AID, and treated with at least 1 cycle of Tegeline at home after receiving 3 consecutive cycles of hospital-based treatment with Tegeline at a dose between 1 and 2 g/kg/cycle. Forty-six patients with AID, in most cases immune-mediated neuropathies, received a total of 138 cycles of Tegeline in hospital and then 323 at home. Forty-five drug-related adverse events occurred in 17 patients who received their cycles at home compared to 24 adverse events in hospital in 15 patients. Serious adverse events occurred in 3 patients during home treatment, but they were not life-threatening and did not lead to discontinuation of Tegeline. Forty-five patients continued their treatment with Tegeline at home or in hospital; 39 (84.8%) were still receiving home treatment at the end of the study. In conclusion, the study demonstrates the good safety profile of Tegeline administered at home at high doses in patients with AID who are eligible for home administration of Tegeline.
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Enfermedades Autoinmunes/tratamiento farmacológico , Inmunoglobulinas Intravenosas/administración & dosificación , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Adulto , Anciano , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Femenino , Francia , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1). If untreated, the disease leads to an important intellectual disability (IQ <50). Although many facts are common between phenylalanine (Phe) and tryptophan (Trp) metabolism, little is known about Trp metabolism modification in PKU. Our aim was to evaluate the modifications of Trp metabolism in a phenylketonuric population. A monocentric study was conducted between October 2016 and March 2017. Every phenylketonuric fasting adults were included during their annual follow up. For each patient, 9 analytes of Trp metabolism were quantified in peripheral blood using liquid chromatography coupled with tandem mass spectrometry. Mann and Whitney tests (p <0.05) were carried out in StatView 5.0 software. A total of 6 PKU patients were studied. Significant modification of Trp metabolism was shown. Indeed, three analytes, i.e. tryptophan, kynurenine and 3-hydroxykynurenic acid, were significantly lower in phenylketonuric than in healthy population (p-value <0.05), without known confounding factors. This study shows a significant modification of Trp metabolism in peripheral blood of phenylketonuric patients. Nevertheless, more investigations are necessary to confirm the modification of Trp metabolism in PKU and to determine how this metabolism is involved in neurological symptoms.
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Análisis Químico de la Sangre/métodos , Fenilcetonurias/sangre , Triptófano/metabolismo , Adulto , Análisis Químico de la Sangre/normas , Estudios de Casos y Controles , Cromatografía Liquida , Femenino , Humanos , Masculino , Metaboloma , Persona de Mediana Edad , Fenilcetonurias/diagnóstico , Fenilcetonurias/metabolismo , Valor Predictivo de las Pruebas , Valores de Referencia , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masas en Tándem/normas , Adulto JovenRESUMEN
Guillain-Barré syndrome (GBS) is an immune-mediated disorder which can be triggered by cytomegalovirus (CMV) infection. GBS following CMV primary infection is a rare event during pregnancy, which raises the question of maternal and fetal management. We describe an unusual case of GBS after CMV primary infection in a pregnant woman. The mother was successfully treated with standard immunoglobulins but in utero fetal death caused by CMV congenital infection unfortunately occurred. Similar cases have rarely been reported in the literature.
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Infecciones por Citomegalovirus/complicaciones , Síndrome de Guillain-Barré/epidemiología , Síndrome de Guillain-Barré/etiología , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/etiología , Adulto , Antivirales/uso terapéutico , Femenino , Muerte Fetal , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Embarazo , Resultado del TratamientoRESUMEN
BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. METHODS: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. RESULTS: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. CONCLUSIONS: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.
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Biopterinas/análogos & derivados , Estudios de Asociación Genética/métodos , Genotipo , Fenotipo , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/genética , Biopterinas/uso terapéutico , Estudios de Cohortes , Femenino , Francia/epidemiología , Humanos , Masculino , Fenilcetonurias/epidemiología , Resultado del TratamientoRESUMEN
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease. It occurs in two forms: (1) familial cases, for which several genes have been identified and (2) sporadic cases, for which various hypotheses have been formulated. Notably, the ß-N-methylamino-L-alanine (L-BMAA) toxin has been postulated to be involved in the occurrence of sporadic ALS. The objective of the French BMAALS programme is to study the putative link between L-BMAA and ALS. METHODS AND ANALYSIS: The programme covers the period from 1 January 2003 to 31 December 2011. Using multiple sources of ascertainment, all the incident ALS cases diagnosed during this period in the area under study (10 counties spread over three French regions) were collected. First, the standardised incidence ratio will be calculated for each municipality under concern. Then, by applying spatial clustering techniques, overincidence and underincidence zones of ALS will be sought. A case-control study, in the subpopulation living in the identified areas, will gather information about patients' occupations, leisure activities and lifestyle habits in order to assess potential risk factors to which they are or have been exposed. Specimens of drinking water, food and biological material (brain tissue) will be examined to assess the presence of L-BMAA in the environment and tissues of ALS cases and controls. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the French ethical committee of the CPP SOOM IV (Comité de Protection des Personnes Sud-Ouest & Outre-Mer IV). The results will be published in peer-reviewed journals and presented at national and international conferences.
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Aminoácidos Diaminos/análisis , Esclerosis Amiotrófica Lateral/epidemiología , Exposición a Riesgos Ambientales/estadística & datos numéricos , Neurotoxinas/análisis , Sistema de Registros , Encéfalo , Química Encefálica , Estudios de Casos y Controles , Análisis por Conglomerados , Toxinas de Cianobacterias , Agua Potable/análisis , Exposición a Riesgos Ambientales/análisis , Análisis de los Alimentos , Francia/epidemiología , Humanos , Actividades Recreativas , Exposición Profesional/estadística & datos numéricos , Ocupaciones/estadística & datos numéricosRESUMEN
The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n = 468) and matched-controls (n = 394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio = 2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.
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Esclerosis Amiotrófica Lateral/genética , Neuronas Motoras/metabolismo , Proteínas Musculares/genética , Mutación Missense , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/etnología , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Axones/metabolismo , Muerte Celular/genética , Células Cultivadas , Femenino , Francia/epidemiología , Humanos , Masculino , Ratones , Neuronas Motoras/citología , Suecia/epidemiologíaRESUMEN
Clinical features at onset of Creutzfeldt-Jakob disease (CJD) may mimic symptoms of Lewy bodies dementia. Clinical evolution, neuroimaging, metabolism exploration, and cerebrospinal fluid investigations may help establishing the diagnosis. However, CJD definite diagnosis requires postmortem autopsy. This symptom overlap led us to successfully prescribe an anticholinesterasic treatment, rivastigmine, to a patient for whom a probable CJD disease was finally diagnosed.
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Inhibidores de la Colinesterasa/uso terapéutico , Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Alucinaciones/tratamiento farmacológico , Fenilcarbamatos/uso terapéutico , Anciano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/fisiopatología , Femenino , Alucinaciones/etiología , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Rivastigmina , Resultado del TratamientoRESUMEN
The role of influenzalike illnesses and influenza vaccination in the development of Guillain-Barré syndrome (GBS), particularly the role of A/H1N1 epidemics and A/H1N1 vaccination, is debated. Data on all incident GBS cases meeting the Brighton Collaboration criteria that were diagnosed at 25 neurology centers in France were prospectively collected between March 2007 and June 2010, covering 3 influenzavirus seasons, including the 2009-2010 A/H1N1 outbreak. A total of 457 general practitioners provided a registry of patients from which 1,080 controls were matched by age, gender, index date (calendar month), and region to 145 cases. Causal relations were assessed by multivariate case-control analysis with adjustment for risk factors (personal and family history of autoimmune disorders, among others), while matching on age, gender, and calendar time. Influenza (seasonal or A/H1N1) or influenzalike symptoms in the 2 months preceding the index date was associated with GBS, with a matched odds ratio of 2.3 (95% confidence interval (CI): 0.7, 8.2). The difference in the rates of GBS occurring between influenza virus circulation periods and noncirculation periods was highly statistically significant (P = 0.004). Adjusted odds ratios for GBS occurrence within 6 weeks after seasonal and A/H1N1 vaccination were 1.3 (95% CI: 0.4, 4.1) and 0.9 (95% CI: 0.1, 7.6), respectively. Study results confirm that influenza virus is a likely risk factor for GBS. Conversely, no new concerns have arisen regarding influenza vaccination.
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Síndrome de Guillain-Barré/epidemiología , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Estudios de Casos y Controles , Niño , Preescolar , Intervalos de Confianza , Brotes de Enfermedades/estadística & datos numéricos , Femenino , Francia/epidemiología , Síndrome de Guillain-Barré/etiología , Humanos , Vacunas contra la Influenza/efectos adversos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Factores Sexuales , Adulto JovenRESUMEN
We examined oxidative stress markers of 31 patients suffering from ALS, 24 patients suffering from PD and 30 healthy subjects were included. We determined the plasma levels of lipid peroxidation (malondialdehyde, MDA), of protein oxidative lesions (plasma glutathione, carbonyls and thiols) and the activity of antioxidant enzymes i.e. erythrocyte Cu,Zn-Superoxide dismutase (SOD), Glutathione peroxidase (GSH-Px) and catalase. MDA and thiols were significantly different in both neurodegenerative diseases versus control population. A trend for an enhancement of oxidized glutathione was noted in ALS patients. Univariate analysis showed that SOD activity was significantly decreased in ALS and GSH-Px activity was decreased in PD. After adjusting for demographic parameters and enzyme cofactors, we could emphasize a compensatory increase of SOD activity in PD. Different antioxidant systems were not involved in the same way in ALS and PD, suggesting that oxidative stress may be a cause rather than a consequence of the neuronal death.