RESUMO
Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Mutação , RiluzolRESUMO
Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category 'probable' PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.
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Esclerose Lateral Amiotrófica , Doença dos Neurônios Motores , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/genética , Consenso , Humanos , Doença dos Neurônios Motores/diagnóstico por imagem , Doença dos Neurônios Motores/genética , Neurônios Motores/fisiologiaRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by upper and lower motor neuron damage in the bulbar and spinal territories. Although the pathophysiology of ALS is still unknown, the involvement of genetic factors is no longer a subject of debate. Familial ALS (fALS) accounts for 10-20% of cases. Since the identification of the SOD1 gene, more than 20 genes have been described, of which four can explain >50% of familial cases. This review is an update focused on major aspects of the field of ALS genetics concerning both causative and susceptibility factors.
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Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Humanos , Superóxido Dismutase-1/genéticaRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. Alongside identification of aetiologies, development of biomarkers is a foremost research priority. Metabolomics is one promising approach that is being utilized in the search for diagnosis and prognosis markers. Our aim is to provide an overview of the principal research in metabolomics applied to ALS. References were identified using PubMed with the terms 'metabolomics' or 'metabolomic' and 'ALS' or 'amyotrophic lateral sclerosis' or 'MND' or 'motor neuron disorders'. To date, nine articles have reported metabolomics research in patients and a few additional studies examined disease physiology and drug effects in patients or models. Metabolomics contribute to a better understanding of ALS pathophysiology but, to date, no biomarker has been validated for diagnosis, principally due to the heterogeneity of the disease and the absence of applied standardized methodology for biomarker discovery. A consensus on best metabolomics methodology as well as systematic independent validation will be an important accomplishment on the path to identifying the long-awaited biomarkers for ALS and to improve clinical trial designs.
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Esclerose Lateral Amiotrófica/metabolismo , Metabolômica/métodos , Humanos , Metabolômica/normasRESUMO
BACKGROUND AND PURPOSE: The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined clinical and metabolomic parameters and independently to validate predictive models. METHODS: In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with (1)H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1-year prospective follow-up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort. RESULTS: The best-fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS. CONCLUSION: Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Progressão da Doença , Metaboloma/fisiologia , Idoso , Biomarcadores/líquido cefalorraquidiano , Seguimentos , Humanos , Metabolômica , Pessoa de Meia-Idade , Prognóstico , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system, with a median survival of 2 to 4 years and a wide variety of prognosis. Thus, there is a critical need for diagnosis and prognosis biomarkers to improve the care of patients in routine practice. In this study, we aimed to determine prognostic value of routine biochemical markers in sporadic ALS (SALS). METHODS: We retrospectively collected clinical and biological data obtained during the systematic routine monitoring of 216 sporadic ALS patients. The main outcomes were disease duration and annual decline of Revised ALS Functional Rating Scale (ALSFRS-R). Changes to these biological variables over time were assessed, in link with disease progression. RESULTS: We found that concentrations of creatinine (P=0.0166) and ferritin (P=0.0306) changed significantly during the progression of ALS. A reduction of creatinine levels and an increase of ferritin levels were associated with disease progression. Multivariate analysis showed that early variation of ferritin was an independent predictive factor of patient survival (P=0.0048). CONCLUSION: Changes to ferritin and creatinine levels with time are associated with ALS progression. This is the first study describing the changes to these biological variables during ALS progression.
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Esclerose Lateral Amiotrófica/sangue , Creatinina/sangue , Progressão da Doença , Ferritinas/sangue , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Metabolomics is an emerging field that includes ascertaining a metabolic profile from a combination of small molecules, and which has health applications. Metabolomic methods are currently applied to discover diagnostic biomarkers and to identify pathophysiological pathways involved in pathology. However, metabolomic data are complex and are usually analyzed by statistical methods. Although the methods have been widely described, most have not been either standardized or validated. Data analysis is the foundation of a robust methodology, so new mathematical methods need to be developed to assess and complement current methods. We therefore applied, for the first time, the dominance-based rough set approach (DRSA) to metabolomics data; we also assessed the complementarity of this method with standard statistical methods. Some attributes were transformed in a way allowing us to discover global and local monotonic relationships between condition and decision attributes. We used previously published metabolomics data (18 variables) for amyotrophic lateral sclerosis (ALS) and non-ALS patients. RESULTS: Principal Component Analysis (PCA) and Orthogonal Partial Least Square-Discriminant Analysis (OPLS-DA) allowed satisfactory discrimination (72.7%) between ALS and non-ALS patients. Some discriminant metabolites were identified: acetate, acetone, pyruvate and glutamine. The concentrations of acetate and pyruvate were also identified by univariate analysis as significantly different between ALS and non-ALS patients. DRSA correctly classified 68.7% of the cases and established rules involving some of the metabolites highlighted by OPLS-DA (acetate and acetone). Some rules identified potential biomarkers not revealed by OPLS-DA (beta-hydroxybutyrate). We also found a large number of common discriminating metabolites after Bayesian confirmation measures, particularly acetate, pyruvate, acetone and ascorbate, consistent with the pathophysiological pathways involved in ALS. CONCLUSION: DRSA provides a complementary method for improving the predictive performance of the multivariate data analysis usually used in metabolomics. This method could help in the identification of metabolites involved in disease pathogenesis. Interestingly, these different strategies mostly identified the same metabolites as being discriminant. The selection of strong decision rules with high value of Bayesian confirmation provides useful information about relevant condition-decision relationships not otherwise revealed in metabolomics data.
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Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores/química , Biologia Computacional/métodos , Metabolômica/métodos , Ácido 3-Hidroxibutírico/química , Acetatos/química , Acetona/química , Idoso , Algoritmos , Teorema de Bayes , Tomada de Decisões , Análise Discriminante , Feminino , Humanos , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Componente PrincipalRESUMO
INTRODUCTION: McArdle disease, or glycogen storage disease type V (GSD 5), is a rare metabolic myopathy linked to an autosomal recessive myophosphorylase deficiency. CASE REPORT: We report the case of a 17-year-old male patient who was referred to the emergency department for the management of acute inflammatory low back pain, without traumatic context, associated with an increase of CK at 66,336 UI/L (N<192UI/L) and a CRP at 202mg/L. The immunological assessment was negative and the spinal MRI showed images in favor of necrotizing fasciitis affecting the erector spinae muscles, among others. Faced with the description of difficulties in practicing physical activities since childhood and a non-ischaemic forearm exercise test showing no elevation in lactacidemia, genetic tests were carried out, finding two heterozygous variants in the PYGM gene: c.1963G>A (p.Glu655Lys) class 5 and c.2178-1G>A class 4, confirming the diagnosis of McArdle disease. DISCUSSION: GSD 5 is a disease characterized essentially by muscular fatigability during exercise. The case reported here is original in the clinical circumstances leading to the diagnosis, i.e., inaugural acute low back pain with rhabdomyolysis. This symptomatology had already been described before, but in a patient whose diagnosis was already known. Spinal MRI showed non-specific muscle inflammation and necrosis. Muscle biopsy only found necrosis but no pathological elements typical of the diagnosis. If the symptoms are suggestive, it may be preferable to directly perform a non-ischaemic forearm exercise test, in order to go directly to molecular genetic analysis. There is no specific curative treatment of GSD 5. However, some measures can be implemented to limit the symptoms, such as learning physical exercises, limiting intense efforts and adopting dietary recommendations.
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Doença de Depósito de Glicogênio Tipo V , Dor Lombar , Humanos , Doença de Depósito de Glicogênio Tipo V/diagnóstico , Doença de Depósito de Glicogênio Tipo V/complicações , Doença de Depósito de Glicogênio Tipo V/genética , Masculino , Dor Lombar/etiologia , Dor Lombar/diagnóstico , Adolescente , Doença AgudaAssuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Mutação/fisiologia , Substituição de Aminoácidos/genética , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/epidemiologia , Causalidade , Progressão da Doença , Projetos de Pesquisa Epidemiológica , Europa (Continente)/epidemiologia , Humanos , Proteína FUS de Ligação a RNA/genéticaRESUMO
BACKGROUND: Glomerular filtration rate (GFR) measurement is a major issue in kidney transplant recipients for clinicians. GFR can be determined by estimating the plasma clearance of iohexol, a nonradiolabeled compound. For practical and convenient application for patients and caregivers, it is important that a minimal number of samples are drawn. The aim of this study was to develop and validate a Bayesian model with fewer samples for reliable prediction of GFR in kidney transplant recipients. METHODS: Iohexol plasma concentration-time curves from 95 patients were divided into an index (n = 63) and a validation set (n = 32). Samples (n = 4-6 per patient) were obtained during the elimination phase, that is, between 120 and 270 minutes. Individual reference values of iohexol clearance (CL(iohexol)) were calculated from k (elimination slope) and V (volume of distribution from intercept). Individual CL(iohexol) values were then introduced into the Bröchner-Mortensen equation to obtain the GFR (reference value). A population pharmacokinetic model was developed from the index set and validated using standard methods. For the validation set, we tested various combinations of 1, 2, or 3 sampling time to estimate CL(iohexol). According to the different combinations tested, a maximum a posteriori Bayesian estimation of CL(iohexol) was obtained from population parameters. Individual estimates of GFR were compared with individual reference values through analysis of bias and precision. A capability analysis allowed us to determine the best sampling strategy for Bayesian estimation. RESULTS: A 1-compartment model best described our data. Covariate analysis showed that uremia, serum creatinine, and age were significantly associated with k(e), and weight with V. The strategy, including samples drawn at 120 and 270 minutes, allowed accurate prediction of GFR (mean bias: -3.71%, mean imprecision: 7.77%). With this strategy, about 20% of individual predictions were outside the bounds of acceptance set at ± 10%, and about 6% if the bounds of acceptance were set at ± 15%. CONCLUSIONS: This Bayesian approach can help to reduce the number of samples required to calculate GFR using Bröchner-Mortensen formula with good accuracy.
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Meios de Contraste/metabolismo , Iohexol/metabolismo , Transplante de Rim/fisiologia , Rim/metabolismo , Adulto , Idoso , Teorema de Bayes , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Transplante de Rim/métodos , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Fish odor syndrome (FOS) is a rare metabolic disorder that manifests as "rotten fish" body odor and is caused by the excretion of trimethylamine (TMA) in body fluids. This disease can have a negative impact on the social life of affected patients. CASE REPORTS: We report the case of two female patients complaining about unpleasant body odor. The diagnosis of FOS was confirmed by the demonstration of trimethylaminuria by NMR spectroscopy and by molecular analysis of the FMO3 gene. A restrictive choline diet combined with digestive decontamination reduced odor symptoms and improved the social life of these 2 patients. CONCLUSIONS: Fish odor syndrome is a rare and unrecognized disease that can affect the quality of life of affected persons. Following laboratory diagnosis, treatment is often effective.
Assuntos
Doenças Metabólicas , Erros Inatos do Metabolismo , Feminino , Humanos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia , Metilaminas/urina , Oxigenases/genética , Qualidade de VidaRESUMO
OBJECTIVE: Several association studies have identified possible susceptibility factors for sporadic amyotrophic lateral sclerosis (SALS). Studies on the APOE gene provided conflicting results, especially about the effect on bulbar onset. We assessed the possible role of APOE gene in a large cohort of patients with ALS and matched controls. METHODS: The APOE alleles were determined in 1482 patients with SALS and 955 controls and analysed by univariate and multivariate statistics, taking into account gender, site-of-onset and age-at-onset. RESULTS: Patients with bulbar onset were more likely to be women [odds ratio (OR)=2.17; 95% CI: 1.74-2.72] and to be older (OR=3.47; 95% CI: 2.58-4.67). The ε4-carriers were more frequent in the bulbar-onset group than in the limb-onset group (OR=1.39 bulbar onset versus limb onset; 95% CI: 1.08-1.80) but this association was observed amongst men (OR=1.78; 95% CI: 1.25-2.53) and not women (OR=1.09; 95% CI: 0.75-1.59). CONCLUSION: Our study provides evidence for a contribution of the ε4 allele in the occurrence of bulbar-onset ALS amongst men. We propose that men are normally protected by androgens against bulbar onset and that the ε4 allele inhibits this protection, perhaps by interfering with the androgen pathway.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Apolipoproteína E4/genética , Paralisia Bulbar Progressiva/epidemiologia , Paralisia Bulbar Progressiva/genética , Predisposição Genética para Doença/genética , Idoso , Androgênios/deficiência , Androgênios/genética , Androgênios/fisiologia , Estudos de Casos e Controles , Estudos de Coortes , Citoproteção/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Transdução de Sinais/genéticaRESUMO
OBJECTIVES: To assess the predictive role of several measures obtained by transcranial magnetic stimulation (TMS) in patients with clinically isolated syndrome (CIS) for the risk of conversion to multiple sclerosis (MS) during the first 2 years. MATERIALS AND METHODS: We investigated 34 patients with CIS. After 2 years of follow-up and classification into two groups according to MS diagnosis, initial TMS measures were compared to determine their predictive values for conversion to MS. RESULTS: Sixteen patients developed MS. We observed a significant difference between the two groups for contralateral silent period and no significant difference for the central motor conduction time, amplitude ratio, motor threshold, ipsilateral silent period, and the transcallosal conduction time. CONCLUSIONS: Contralateral silent period (SP) seems to be a valuable parameter to early distinguish patients who will develop MS or not. This result about SP during CIS has never been described until now. An increased contralateral silent period would predict a conversion to MS with a positive predictive value of 75%, but this result needs to be confirmed in larger groups.
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Doenças Desmielinizantes/fisiopatologia , Potencial Evocado Motor/fisiologia , Esclerose Múltipla/diagnóstico , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Valor Preditivo dos Testes , Estimulação Magnética Transcraniana , Adulto JovemRESUMO
Inherited metabolic disorders (IMDs) have been observed in individuals with hearing loss (HL), but IMDs are rarely the cause of syndromic HL. With early diagnosis, management of HL is more effective and cortical reorganization is possible with hearing aids or cochlear implants. This review describes relationships between IMDs and HL in terms of incidence, etiology of HL, pathophysiology, and treatment. Forty types of IMDs are described in the literature, mainly in case reports. Management and prognosis are noted where existing. We also describe IMDs with HL given age of occurrence of HL. Reviewing the main IMDs that are associated with HL may provide an additional clinical tool with which to better diagnose syndromic HL.
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Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/patologia , Animais , Implante Coclear/métodos , Surdez/complicações , Surdez/patologia , Auxiliares de Audição , Perda Auditiva/complicações , Humanos , Incidência , Doenças Metabólicas/etiologiaRESUMO
In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.
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Esclerose Lateral Amiotrófica/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Quimiocina CCL2/sangue , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/imunologia , Fatores de Crescimento de Fibroblastos/fisiologia , Interleucina-6/sangue , Leptina/sangue , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Resistina/sangue , Teste de Desempenho do Rota-Rod , Transdução de Sinais , Transcriptoma , Fator de Necrose Tumoral alfa/sangueRESUMO
INTRODUCTION: Amino acid (AA) analysis in plasma is essential for diagnosis and monitoring of inborn errors of metabolism (IEM). The efficacy of patient management is governed by the rapidity of AA profile availability, along with the robustness of the method. French quality guidelines and progress made in analytical techniques have led biologists to develop AA profile exploration via mass spectrometry (MS). OBJECTIVES: The aim of this study was to validate an analytical method with a single quadrupole mass spectrometer (MS) and to suggest reference values in regard to French quality and IEM society recommendations. DESIGN AND METHODS: Plasma samples from patients were deproteinised and derivatised with AccqTag™ reagent. Analysis was performed by reverse-phase chromatography coupled to QDA detector. We evaluated accuracy, intra-days and inter-days precision and limit of quantification by the ß-expectation tolerance interval method for 27 AA. Method comparison was performed with the standard method (ion exchange chromatography, IEC) on Jeol Aminotac® and to tandem MS. Reference values were established on AA concentrations of the cohort of patients who had no IEM. RESULTS: Our method allowed the separations of almost all amino acids with a total run time of 12 min. Separation of isoleucine and alloisoleucine was incomplete (R = 0.55) but without impact on biological interpretation. Precision, accuracy and quantification were satisfactory (intra-days coefficient of variation (CV) was <5%, inter-days precision CV <10% and accuracy <15%). The limits of quantification were validated between 1 and 900 µmol/L. Results were comparable between the new method and IEC. CONCLUSION: Ultimately, we validated a rapid method on plasma for quantifying 27 amino acids that can be used in routine practice, according to French quality laboratories and SFEIM (French Society of Inborn Error of Metabolism) recommendations. Furthermore, estimated reference values were similar to those found in published studies focusing on other methods. Despite a lower specificity compared to tandem MS, the simplicity and rapidity of our method are the main advantage of this technique and place it as a major tool in IEM diagnosis and management.
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Aminoácidos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Erros Inatos do Metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/diagnóstico , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy. AREAS COVERED: The authors discuss the two approved drugs, as well as several examples of drug candidates whose clinical trials did not demonstrate efficacy in phase III. Post-hoc analyses reveal that future clinical trials should include disease-staging procedures, longer-term trials to correctly assess survival, genetic studies of participants to aid in stratification, and more similarity between the protocols on preclinical models and clinical trials. Finally, they discuss the trials in process that demonstrate some of these suggestions and improvements. EXPERT OPINION: The approval of riluzole and edaravone was essentially a desperate attempt to provide urgent pharmacotherapy to the ALS community. To evolve toward more efficient therapies, we must conduct clinical trials with optimal stratification based on rapid/slow progressors and cognitive decline. Pharmaco-metabolomics should allow for the identification of biomarkers that are adapted for a given drug.
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
The biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection. We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of viral diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day. Plasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy > 74%, sensitivity, specificity > 75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution. Here, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.