Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

metabolomics; +19 new citations

Fri, 12/04/2019 - 12:52
19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/12PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +21 new citations

Thu, 11/04/2019 - 15:41
21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/11PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +21 new citations

Thu, 11/04/2019 - 12:39
21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/11PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +22 new citations

Wed, 10/04/2019 - 15:26
22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/10PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +22 new citations

Wed, 10/04/2019 - 12:24
22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/10PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +26 new citations

Tue, 09/04/2019 - 15:03
26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/09PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +26 new citations

Tue, 09/04/2019 - 12:02
26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/09PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Saliva and urine metabolic profiling reveals altered amino acid and energy metabolism in male farmers exposed to pesticides in Madhya Pradesh State, India.

Mon, 08/04/2019 - 14:48
Related Articles Saliva and urine metabolic profiling reveals altered amino acid and energy metabolism in male farmers exposed to pesticides in Madhya Pradesh State, India. Chemosphere. 2019 Mar 27;226:636-644 Authors: Ch R, Singh AK, Pathak MK, Singh A, Kesavachandran CN, Bihari V, Mudiam MKR Abstract Globally, the human population is exposed to low doses of pesticides due to its extensive use in agriculture. The chronic exposure to pesticides can lead to cancer, depression, anxiety, Parkinson's and Alzheimer's diseases etc. Here, we have made an attempt to use mass spectrometry based metabolomics to investigate the metabolic perturbations induced by the pesticides in the urine and saliva samples of farmers from the Madhya Pradesh State of India. The study was aimed to establish non-invasive matrices like urine and saliva as alternative diagnostic matrices to the occupational exposure studies. Saliva and urine samples were collected from 51 pesticides applicators and acquired metabolic profiles of urine and saliva samples using gas chromatography-mass spectrometry (GC-MS). Multivariate pattern recognition and pathway analysis were used to analyze and interpret the data. Investigation of endogenous metabolic profiles revealed remarkable discrimination in both saliva and urine samples of the exposed population strongly suggesting the changes in metabolic composition within the identified metabolites (for urine samples: accuracy 0.9766, R2 = 0.9130, Q2 = 0.8703; for saliva samples, an accuracy of 0.9961, R2 = 0.9698, Q2 = 0.9637). Thirteen metabolites of urine samples and sixteen metabolites of saliva samples were identified as differential metabolites specific to pesticide exposure. Pathway analysis of differential metabolites revealed that amino acid metabolism, energy metabolism (glycolysis and TCA cycle) and glutathione metabolism (oxidative stress) were found to affect in pesticide exposed population. The present study suggested that GC-MS based metabolomics can help to reveal the metabolic perturbations in human population after pesticides exposure. PMID: 30954898 [PubMed - as supplied by publisher]

Alterations in the metabolism of phospholipids, bile acids and branched-chain amino acids predicts development of type 2 diabetes in black south African women: a prospective cohort study.

Mon, 08/04/2019 - 14:48
Related Articles Alterations in the metabolism of phospholipids, bile acids and branched-chain amino acids predicts development of type 2 diabetes in black south African women: a prospective cohort study. Metabolism. 2019 Apr 04;: Authors: Zeng Y, Mtintsilana A, Goedecke JH, Micklesfield LK, Olsson T, Chorell E Abstract BACKGROUND: South Africa (SA) has the highest global projected increase in diabetes risk. Factors typically associated with insulin resistance and type 2 diabetes risk in Caucasians are not significant correlates in black African populations. Therefore, we aimed to identify circulating metabolite patterns that predict type 2 diabetes development in this high-risk, yet understudied SA population. METHODS: We conducted a prospective cohort study in black SA women with normal glucose tolerance (NGT). Participants were followed for 13 years and developed (i) type 2 diabetes (n = 20, NGT-T2D), (ii) impaired glucose tolerance (IGT) (n = 27, NGT-IGT), or (iii) remained NGT (n = 28, NGT-NGT). Mass-spectrometry based metabolomics and multivariate analyses was used to elucidate metabolite patterns at baseline and at follow-up that were associated with type 2 diabetes development. RESULTS: Metabolites of phospholipid, bile acid and branched-chain amino acid (BCAA) metabolism, differed significantly between the NGT-T2D and NGT-NGT group. At baseline: the NGT-T2D group had i) a higher lysophosphatidylcholine:lysophosphatidylethanolamine ratio containing linoleic acid (LPC(C18:2):LPE(C18:2)), ii) lower proliferation-related bile acids (ursodeoxycholic- and chenodeoxycholic acid), iii) higher levels of leucine and its catabolic intermediates (ketoleucine and C5-carnitine), compared to the NGT-NGT group. At follow-up: the NGT-T2D group had i) lower LPC(C18:2) levels, ii) higher apoptosis-related bile acids (deoxycholic- and glycodeoxycholic acid), and iii) higher levels of all BCAAs and their catabolic intermediates. CONCLUSIONS: Changes in lysophospholipid metabolism and the bile acid pool occur during the development of type 2 diabetes in black South African women. Further, impaired leucine catabolism precedes valine and isoleucine catabolism in the development of type 2 diabetes. These metabolite patterns can be useful to identify and monitor type 2 diabetes risk >10 years prior to disease onset and provide insight into the pathophysiology of type 2 diabetes in this high risk, but under-studied population. PMID: 30954560 [PubMed - as supplied by publisher]

Blood-based molecular signature of Alzheimer's disease via spectroscopy and metabolomics.

Mon, 08/04/2019 - 14:48
Related Articles Blood-based molecular signature of Alzheimer's disease via spectroscopy and metabolomics. Clin Biochem. 2019 Apr 04;: Authors: Habartová L, Hrubešová K, Syslová K, Vondroušová J, Fišar Z, Jirák R, Raboch J, Setnička V Abstract OBJECTIVES: With over 35 million cases worldwide, Alzheimer's disease (AD) represents the main cause of dementia. The differentiation of AD from other types of dementia is challenging and its early diagnosis is complicated. The established biomarkers are not only based on the invasive collection of cerebrospinal fluid, but also lack sufficient sensitivity and specificity. Therefore, much current effort is aimed at the identification of new biomarkers of AD in peripheral blood. DESIGN AND METHODS: We focused on blood-based analyses using chiroptical spectroscopy (Raman optical activity, electronic circular dichroism) supplemented with conventional vibrational spectroscopy (infrared, Raman) and metabolomics (high-performance liquid chromatography with a high-resolution mass detection). RESULTS: This unique approach enabled us to identify the spectral pattern of AD and variations in metabolite levels. Subsequent linear discriminant analysis of the spectral data resulted in differentiation between the AD patients and control subjects. CONCLUSIONS: It may be stated that this less invasive approach has strong potential for the identification of disease-related changes within essential plasmatic biomolecules and metabolites. PMID: 30954438 [PubMed - as supplied by publisher]

Corrigendum to "Herb-drug interaction: A case study of effects and involved mechanisms of cisplatin on the pharmacokinetics of ginsenoside Rb1 in tumor-bearing mice" [Biomed. Pharmacother. 110 (2019) 95-104].

Mon, 08/04/2019 - 14:48
Related Articles Corrigendum to "Herb-drug interaction: A case study of effects and involved mechanisms of cisplatin on the pharmacokinetics of ginsenoside Rb1 in tumor-bearing mice" [Biomed. Pharmacother. 110 (2019) 95-104]. Biomed Pharmacother. 2019 Apr 04;:108827 Authors: Zhou J, Wu J, Wu CY, Long F, Shen H, Zhang W, Li SL PMID: 30954310 [PubMed - as supplied by publisher]

The effects of hexaconazole and epoxiconazole enantiomers on metabolic profile following exposure to zebrafish (Danio rerio) as well as the histopathological changes.

Sun, 07/04/2019 - 14:34
Related Articles The effects of hexaconazole and epoxiconazole enantiomers on metabolic profile following exposure to zebrafish (Danio rerio) as well as the histopathological changes. Chemosphere. 2019 Mar 26;226:520-533 Authors: Jia M, Wang Y, Wang D, Teng M, Yan J, Yan S, Meng Z, Li R, Zhou Z, Zhu W Abstract Hexaconazole and epoxiconazole are the worldwidely used fungicides. However, limited information is known about the toxicological effects of their enantiomers on aquatic organisms. In this study, zebrafish were separately exposed to 100 and 1000 μgL-1 hexaconazole and epoxiconazole enantiomers for 21 d 1H NMR-based metabolomics analysis showed that the exposure of low and high dose of hexaconazole enantiomers altered energy metabolism, lipid metabolism and amino acid metabolism of zebrafish, with the different metabolic profiles resulted from the same dose of (+)-hexaconazole and (-)-hexaconazole. Similar to hexaconazole enantiomers, the metabolic profiles, including the changes related to energy metabolism, lipid metabolism and amino acid metabolism, were demonstrated in low and high dose epoxiconazole enantiomers treatment groups. There are differences in the metabolic profiles of zebrafish between exposed to (+)-epoxiconazole and (-)-epoxiconazole of the same dose. The results of histological examination revealed that the exposure of both enantiomers for hexaconazole and epoxiconazole resulted in the similar histopathological changes. The exposure of hexaconazole and epoxiconazole enantiomers at low and high dose resulted the vacuolization and swell in the liver of the female and male zebrafish. Compared to female zebrafish, more liver damage was found in male zebrafish in the hexaconazole enantiomers exposure groups. The reduction of spermatids was observed in hexaconazole and epoxiconazole enantiomers treatment groups of both doses. Hexaconazole enantiomers exposure of low and high dose resulted the increase in the number of mature eggs, while such effect was not observed in epoxiconazole enantiomers exposure groups. Hexaconazole and epoxiconazole enantiomers exposure resulted in no changes in brains of female and male zebrafish. As a result, both triazole-based chiral bactericides, hexaconazole and epoxiconazole, have similar toxicological effects but their mechanisms of action are not exactly the same. The above results will play an important part in making the differences in toxic effects of hexaconazole and epoxiconazole enantiomers clear. What's more, it is an indispensable part for an integrated environmental risk assessment. PMID: 30953897 [PubMed - as supplied by publisher]

Chronic paradoxical sleep deprivation-induced depression-like behavior, energy metabolism and microbial changes in rats.

Sun, 07/04/2019 - 14:34
Related Articles Chronic paradoxical sleep deprivation-induced depression-like behavior, energy metabolism and microbial changes in rats. Life Sci. 2019 Apr 04;: Authors: Ma W, Song J, Wang H, Shi F, Zhou N, Jiang J, Xu Y, Zhang L, Yang L, Zhou M Abstract AIMS: Given the lasting impact of chronic paradoxical sleep deprivation (PSD) on behavior and organism metabolic alternations, along with the role of the microbiome in neurobehavioral development and metabolism, we sought to examine the relationship between the microbiota and chronic PSD-induced behavioral and metabolic changes. MATERIALS AND METHODS: Psychological status of 7-day PSD (7d-PSD) male rats was tested by behavioral method, serum inflammatory cytokines and hypothalamic-pituitary-adrenal (HPA) axis-related hormones. In addition, GC-MS based urine metabolomics and 16S rRNA gene sequencing approaches were applied to estimate the influences of chronic PSD on host metabolism and gut-microbiota. Furtherly, microbial functional prediction and Spearman's correlation analysis were implemented to manifest the relations between the differential urinary metabolites and gut microbiota. KEY FINDINGS: 7d-PSD rats displayed depression-like behavior, metabolic and microbial changes. By integrating differential gut bacteria with indicators of depression and differential metabolites, we found that the alterations of Akkermansia, Oscillospira, Ruminococcus, Parabacteroides, Aggregatibacter and Phascolarctobacterium were closely related to abnormalities of depression symptoms and inflammatory cytokines. These bacteria also had close connections with host energy metabolism concerning arginine and proline metabolism, glycine, serine and threonine metabolism, and glyoxylate and dicarboxylate metabolism, pyruvate metabolism, which overlapped with the results of 16S rRNA gene function annotation. SIGNIFICANCE: These data suggest that a specific situation of circadian disturbance, chronic PSD-induced alterations in gut microbiota and related host changes in metabolism may be the pathogenesis of depression. PMID: 30953642 [PubMed - as supplied by publisher]

Novel Metabolites Are Associated with Augmentation Index and Pulse Wave Velocity: Findings from the Bogalusa Heart Study.

Sun, 07/04/2019 - 14:34
Related Articles Novel Metabolites Are Associated with Augmentation Index and Pulse Wave Velocity: Findings from the Bogalusa Heart Study. Am J Hypertens. 2019 Apr 06;: Authors: Li C, He J, Li S, Chen W, Bazzano L, Sun X, Shen L, Liang L, Shen Y, Gu X, Kelly TN Abstract BACKGROUND: Metabolomics study may help identify novel mechanisms underlying arterial stiffening. METHODS: We performed untargeted metabolomics profiling among 1,239 participants of the Bogalusa Heart Study. After quality control, 1,202 metabolites were evaluated for associations with augmentation index (AI) and pulse-wave velocity (PWV), using multivariate linear regression adjusting for age, sex, race, education, smoking, drinking, body weight, body height, physical activity, and estimated glomerular filtration rate. Heart rate, blood pressure and antihypertensive medication usage, lipids, and fasting glucose were sequentially adjusted in the sensitivity analyses for significant metabolites. Weighted correlation network analysis was applied to build metabolite networks. RESULTS: Six novel metabolites were negatively associated with AI, of which, 3-methyl-2-oxobutyrate had the lowest p value and largest effect size (β=-6.67, P=5.99×10-6). Heart rate contributed to a large proportion (25%-58%) of the association for each metabolite. Twenty-one novel metabolites were identified for PWV, of which, fructose (β=0.61, P=6.18×10-10) was most significant, and histidine had the largest effect size (β=-1.09, P=2.51×10-7). Blood pressure played a major contribution (9%-54%) to the association for each metabolite. Furthermore, 16 metabolites were associated with arterial stiffness independent of traditional risk factors. Network analysis identified two modules associated with both AI and PWV (P<8.00×10-4). One was composed of metabolites from the glycerolipids synthesis and recycling pathway, and the other was involved in valine, leucine, and isoleucine metabolism. One module related to sphingomyelin metabolism was associated with PWV only (P=0.002). CONCLUSIONS: The current study has identified novel and important metabolites and metabolic networks associated with arterial stiffness. PMID: 30953049 [PubMed - as supplied by publisher]

Establishment of an induced memory response in Pseudomonas aeruginosa during infection of a eukaryotic host.

Sun, 07/04/2019 - 14:34
Related Articles Establishment of an induced memory response in Pseudomonas aeruginosa during infection of a eukaryotic host. ISME J. 2019 Apr 05;: Authors: Kordes A, Grahl N, Koska M, Preusse M, Arce-Rodriguez A, Abraham WR, Kaever V, Häussler S Abstract In a given habitat, bacterial cells often experience recurrent exposures to the same environmental stimulus. The ability to memorize the past event and to adjust current behaviors can lead to efficient adaptation to the recurring stimulus. Here we demonstrate that the versatile bacterium Pseudomonas aeruginosa adopts a virulence phenotype after serial passage in the invertebrate model host Galleria mellonella. The virulence phenotype was not linked to the acquisition of genetic variations and was sustained for several generations, despite cultivation of the ex vivo virulence-adapted P. aeruginosa cells under rich medium conditions in vitro. Transcriptional reprogramming seemed to be induced by a host-specific food source, as reprogramming was also observed upon cultivation of P. aeruginosa in rich medium supplemented with polyunsaturated long-chain fatty acids. The establishment of induced memory responses adds a time dimension and seems to fill the gap between long-term evolutionary genotypic adaptation and short-term induced individual responses. Efforts to unravel the fundamental mechanisms that underlie the carry-over effect to induce such memory responses will continue to be of importance as hysteretic behavior can serve survival of bacterial populations in changing and challenging habitats. PMID: 30952997 [PubMed - as supplied by publisher]

Comparison of Machine Learning Algorithms for Predictive Modeling of Beef Attributes Using Rapid Evaporative Ionization Mass Spectrometry (REIMS) Data.

Sun, 07/04/2019 - 14:34
Related Articles Comparison of Machine Learning Algorithms for Predictive Modeling of Beef Attributes Using Rapid Evaporative Ionization Mass Spectrometry (REIMS) Data. Sci Rep. 2019 Apr 05;9(1):5721 Authors: Gredell DA, Schroeder AR, Belk KE, Broeckling CD, Heuberger AL, Kim SY, King DA, Shackelford SD, Sharp JL, Wheeler TL, Woerner DR, Prenni JE Abstract Ambient mass spectrometry is an analytical approach that enables ionization of molecules under open-air conditions with no sample preparation and very fast sampling times. Rapid evaporative ionization mass spectrometry (REIMS) is a relatively new type of ambient mass spectrometry that has demonstrated applications in both human health and food science. Here, we present an evaluation of REIMS as a tool to generate molecular scale information as an objective measure for the assessment of beef quality attributes. Eight different machine learning algorithms were compared to generate predictive models using REIMS data to classify beef quality attributes based on the United States Department of Agriculture (USDA) quality grade, production background, breed type and muscle tenderness. The results revealed that the optimal machine learning algorithm, as assessed by predictive accuracy, was different depending on the classification problem, suggesting that a "one size fits all" approach to developing predictive models from REIMS data is not appropriate. The highest performing models for each classification achieved prediction accuracies between 81.5-99%, indicating the potential of the approach to complement current methods for classifying quality attributes in beef. PMID: 30952873 [PubMed - in process]

Autophagy regulates lipid metabolism through selective turnover of NCoR1.

Sun, 07/04/2019 - 14:34
Related Articles Autophagy regulates lipid metabolism through selective turnover of NCoR1. Nat Commun. 2019 Apr 05;10(1):1567 Authors: Saito T, Kuma A, Sugiura Y, Ichimura Y, Obata M, Kitamura H, Okuda S, Lee HC, Ikeda K, Kanegae Y, Saito I, Auwerx J, Motohashi H, Suematsu M, Soga T, Yokomizo T, Waguri S, Mizushima N, Komatsu M Abstract Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production. PMID: 30952864 [PubMed - in process]

Glutaminolysis and lipoproteins are key factors in late immune recovery in successfully treated HIV-infected patients.

Sun, 07/04/2019 - 14:34
Related Articles Glutaminolysis and lipoproteins are key factors in late immune recovery in successfully treated HIV-infected patients. Clin Sci (Lond). 2019 Apr 05;: Authors: Rosado-Sánchez I, Rodríguez-Gallego E, Peraire J, Viladés C, Herrero P, Fanjul F, Gutiérrez F, Bernal E, Pelazas R, Leal M, Veloso S, López-Dupla M, Blanco J, Vidal F, Pacheco YM, Rull A Abstract The immunological, biochemical and molecular mechanisms associated with poor immune recovery are far from known, and metabolomic profiling offers additional value to traditional soluble markers. Here, we present novel and relevant data that could contribute to better understanding of the molecular mechanisms preceding a discordant response and HIV progression under suppressive cART. Integrated data from NMR-based lipoprotein profiles, MS-based metabolomics and soluble plasma biomarkers help to build prognostic and immunological progression tools that enable the differentiation of HIV-infected subjects based on their immune recovery status after 96 weeks of suppressive cART. The metabolomic signature of ART-naïve HIV subjects with a subsequent late immune recovery is the expression of pro-inflammatory molecules and glutaminolysis, which is likely related to elevate T-cell turnover in these patients. The knowledge about how these metabolic pathways are interconnected and regulated provides new targets for future therapeutic interventions not only in HIV infection but also in other metabolic disorders such as human cancers where glutaminolysis is the alternative pathway for energy production in tumor cells to meet their requirement of rapid proliferation. PMID: 30952809 [PubMed - as supplied by publisher]

Towards a Personalized Approach in Pancreatic Cancer Diagnostics Through Plasma Amino Acid Analysis.

Sun, 07/04/2019 - 14:34
Related Articles Towards a Personalized Approach in Pancreatic Cancer Diagnostics Through Plasma Amino Acid Analysis. Anticancer Res. 2019 Apr;39(4):2035-2042 Authors: Tumas J, Baskirova I, Petrenas T, Norkuniene J, Strupas K, Sileikis A Abstract BACKGROUND/AIM: Body fluid biomarkers may provide means for early pancreatic cancer diagnosis, patient stratification, application of personalized approaches and, finally, improved outcomes. Amino acids are the most frequently distinguished metabolite class in the metabolomics of pancreatic cancer patients. They have been identified as pre-diagnostic and diagnostic markers and associated with pancreatic cancer risk factors. MATERIALS AND METHODS: Deep phenotyping and quantitative amino acid analysis were performed in patients scheduled for pancreatic surgery due to pancreatic tumors (n=75). RESULTS: Significant differences in plasma amino acid concentrations were observed between diagnostic categories (malignant vs. benign lesions and histological cancer types) and pancreatic ductal adenocarcinoma stages. Characteristic patterns of plasma amino acid concentration dynamics according to cancer stage were identified. CONCLUSION: Standardization of metabolomics methods and deep phenotyping may provide means for improved patient stratification and effective personalized approaches in pancreatic cancer prevention, early diagnosis and treatment. PMID: 30952747 [PubMed - in process]

Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook.

Sun, 07/04/2019 - 14:34
Related Articles Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019 Mar 27;: Authors: Himmelreich N, Montioli R, Bertoldi M, Carducci C, Leuzzi V, Gemperle C, Berner T, Hyland K, Thöny B, Hoffmann GF, Voltattorni CB, Blau N Abstract Aromatic-l-amino acid decarboxylase (AADC) deficiency is an ultra-rare inherited autosomal recessive disorder characterized by sharply reduced synthesis of dopamine as well as other neurotransmitters. Symptoms, including hypotonia and movement disorders (especially oculogyric crisis and dystonia) as well as autonomic dysfunction and behavioral disorders, vary extensively and typically emerge in the first months of life. However, diagnosis is difficult, requiring analysis of metabolites in cerebrospinal fluid, assessment of plasma AADC activity, and/or DNA sequence analysis, and is frequently delayed for years. New metabolomics techniques promise early diagnosis of AADC deficiency by detection of 3-O-methyl-dopa in serum or dried blood spots. A total of 82 dopa decarboxylase (DDC) variants in the DDC gene leading to AADC deficiency have been identified and catalogued for all known patients (n = 123). Biochemical and bioinformatics studies provided insight into the impact of many variants. c.714+4A>T, p.S250F, p.R347Q, and p.G102S are the most frequent variants (cumulative allele frequency = 57%), and c.[714+4A>T];[714+4A>T], p.[S250F];[S250F], and p.[G102S];[G102S] are the most frequent genotypes (cumulative genotype frequency = 40%). Known or predicted molecular effect was defined for 79 variants. Most patients experience an unrelenting disease course with poor or no response to conventional medical treatments, including dopamine agonists, monoamine oxidase inhibitors, and pyridoxine derivatives. The advent of gene therapy represents a potentially promising new avenue for treatment of patients with AADC deficiency. Clinical studies based on the direct infusion of engineered adeno-associated virus type 2 vectors into the putamen have demonstrated acceptable safety and tolerability and encouraging improvement in motor milestones and cognitive symptoms. The success of gene therapy in AADC deficiency treatment will depend on timely diagnosis to facilitate treatment administration before the onset of neurologic damage. PMID: 30952622 [PubMed - as supplied by publisher]

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