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1
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Gao X, Liu C, Zhao X. Isomer-resolved characterization of acylcarnitines reveals alterations in type 2 diabetes. Anal Chim Acta 2025; 1351:343856. [PMID: 40187868 DOI: 10.1016/j.aca.2025.343856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Acylcarnitines (CARs) are metabolites of fatty acids that play crucial roles in various cellular energy metabolism pathways. The structural diversity of CAR species arises from several modifications localized on the fatty acyl chain and there is currently a lack of reports characterizing these detailed structures. High-performance liquid chromatography (HPLC)-electrospray mass spectrometry (ESI-MS) is the common tool for CARs analysis. RESULTS In this study, we improved the MS detection signals of CARs by adding NH4HCO3 as buffer in the mobile phase of LC system. We demonstrated that electron activated dissociation (EAD) on the ZenoTOF 7600 system is capable of localizing the hydroxyl group and methyl branching position in CARs. The benzophenone Paternò-Büchi (PB) reaction was used for derivatizing the carbon-carbon double bond (CC). The capability of profiling CARs with detailed structural information was demonstrated by analyzing complex lipid extracts from mouse plasma. Our results also provided visualization of isomers composition, including branched chain isomers of CAR 4:0 and CAR 5:0 and CC location isomers of unsaturated CARs. Notably, we observed significant changes in the relative compositions of branched-chain isomers of CAR 5:0 and CC location isomers of several unsaturated CARs in mouse plasma samples from type 2 diabetes (T2D) compared to normal controls, suggesting their potential as diagnostic indicators for T2D. SIGNIFICANCE In this work, we enhanced the limit of detection for acylcarnitine species by incorporating ammonium bicarbonate into the LC system. The CC positions in the acyl chain of CARs were identified using Paternò-Büchi (PB) derivatization coupled with tandem mass spectrometry. Modifications such as methyl branching and hydroxyl groups along the acyl chain were localized through Electron-Activated Dissociation (EAD) on the Zeno-TOF 7600 system.
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Affiliation(s)
- Xiangyu Gao
- College of Energy Materials and Chemistry, Inner Mongolia University, Hohhot, 010070, Inner Mongolia, China
| | - Chunli Liu
- School of Life Sciences, Inner Mongolia University, Hohhot, 010070, Inner Mongolia, China
| | - Xue Zhao
- College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010070, Inner Mongolia, China.
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2
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Gao X, Zhao X. In-depth characterization of acylcarnitines: utilizing nitroxide radical-directed dissociation in tandem mass spectrometry. Anal Bioanal Chem 2025:10.1007/s00216-025-05868-2. [PMID: 40198344 DOI: 10.1007/s00216-025-05868-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/10/2025]
Abstract
Acylcarnitines (ACs) are metabolic intermediates of fatty acids playing important roles in regulating cellular energy and lipid metabolism. The large structural diversity of ACs arises from variations in acyl chain length and the presence of chemical modifications, such as methyl branching, desaturation, hydroxylation, and carboxylation. Numerous studies have demonstrated that these structural isomers of ACs function as biomarkers for a variety of diseases. However, conventional tandem mass spectrometry (MS/MS) via low-energy collision-induced dissociation (CID) faces challenges in distinguishing these isomers. In this study, we report a radical-directed dissociation (RDD) approach for characterization of the intrachain modifications within ACs. The method involves derivatizing ACs with O-benzylhydroxylamine (O-BHA), followed by MS2 CID to produce a nitroxide radical for subsequent RDD along the fatty acyl chain. The above RDD approach was employed on a cyclic ion mobility spectrometry (cIMS) and reversed-phase liquid chromatography (RPLC), enabling the identification and relative quantification of branched chain isomers of ACs. By derivatizing carboxylated ACs with O-BHA, their mass is shifted to a higher region, thereby facilitating their separation from the isobars of hydroxylated ACs. Furthermore, this RDD method effectively allows for the assignment and localization of C = C and hydroxylation positions. This RDD approach has been applied for in-depth profiling of ACs in mice plasma extracts.
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Affiliation(s)
- Xiangyu Gao
- College of Energy Materials and Chemistry, Inner Mongolia University, Hohhot, 010021, China
| | - Xue Zhao
- College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, China.
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3
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Mütze U, Stengel J, Gleich F, Keßler S, Grünert SC, Thimm E, Hennermann JB, Freisinger P, Krämer J, Schnabel-Besson E, Mengler K, Shtylla A, Morath M, Hoffmann GF, Garbade S, Kölker S. Long-Term Outcomes of Adolescents and Young Adults Identified by Metabolic Newborn Screening. Pediatrics 2025; 155:e2024068293. [PMID: 40101767 DOI: 10.1542/peds.2024-068293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/23/2024] [Indexed: 03/20/2025] Open
Abstract
OBJECTIVE Although newborn screening (NBS) programs were expanded with the implementation of tandem mass spectrometry in the late 1990s, the impact on long-term clinical and cognitive outcomes of adolescents and young adults with inherited metabolic diseases (IMDs) has remained fairly unknown for most IMDs. METHODS A prospective, multicenter, observational study is performed in Southwest Germany (NGS2025, DRKS-ID: DRKS00013329). For systematic follow-up from preschool up to adulthood, individuals with IMDs identified by NBS between 1999 and 2014 were included. RESULTS In total, 257 (124 boys, 133 girls) screened individuals with at least 1 study visit in adolescence were followed until median age of 13.7 years. During the observation period, most did not develop permanent disease-specific signs (70.1%) or metabolic decompensations (55.2% of those at risk), had normal cognitive outcome (81.4%; IQ mean [SD], 98 [15]), and attended regular primary (91.2%) and secondary schools (90.8%). Nonetheless, NBS and early start of treatment did not prevent metabolic decompensations in 69 (44.8%) individuals at risk, and in 33 of them, metabolic decompensation occurred already before the NBS result was available. Permanent disease-specific symptoms were more frequently observed in patients experiencing metabolic decompensations compared with those without decompensations (75% vs 12.8%). Reliable therapy adherence was associated with better long-term outcome. CONCLUSION NBS for IMDs is a highly successful program of secondary prevention for most early-diagnosed and early-treated individuals with an IMD, allowing the start in an independent life; however, therapeutic effectiveness and quality remain a relevant limitation in some diseases.
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Affiliation(s)
- Ulrike Mütze
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Julia Stengel
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Florian Gleich
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Svenja Keßler
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Sarah C Grünert
- University of Freiburg, Faculty of Medicine, Department of General Pediatrics, Adolescent Medicine and Neonatology, Freiburg, Germany
| | - Eva Thimm
- Heinrich Heine University Düsseldorf, Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Düsseldorf, Germany
| | - Julia B Hennermann
- Mainz University, Medical Center, Villa Metabolica, Center for Pediatric and Adolescent Medicine, Mainz, Germany
| | - Peter Freisinger
- Children's Hospital Reutlingen, Klinikum am Steinenberg, Reutlingen, Germany
| | - Johannes Krämer
- University of Ulm, Department of Pediatric and Adolescent Medicine, Division of Child Neurology and Metabolic Medicine, Ulm, Germany
| | - Elena Schnabel-Besson
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Katharina Mengler
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Alboren Shtylla
- Heidelberg University, Medical Faculty of Heidelberg, Center for Internal Medicine, Department I, Heidelberg, Germany
| | - Marina Morath
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Georg F Hoffmann
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Sven Garbade
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Stefan Kölker
- Heidelberg University, Medical Faculty of Heidelberg, Department of Pediatrics I, Division of Child Neurology and Metabolic Medicine, Heidelberg, Germany
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Schnabel‐Besson E, Garbade SF, Gleich F, Grünert SC, Krämer J, Thimm E, Hennermann JB, Freisinger P, Burgard P, Gramer G, Morath MA, Tuncel AT, Keßler S, Hoffmann GF, Kölker S, Mütze U. Parental and child's psychosocial and financial burden living with an inherited metabolic disease identified by newborn screening. J Inherit Metab Dis 2025; 48:e12784. [PMID: 39189622 PMCID: PMC11670445 DOI: 10.1002/jimd.12784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/28/2024]
Abstract
Newborn screening (NBS) is one of the most effective measures of secondary prevention. While the benefit of NBS on the clinical long-term outcomes of children with inherited metabolic diseases (IMD) has been demonstrated, the potential burden of families living with an early diagnosed and treated child with an IMD has not been thoroughly investigated. The aim of this longitudinal questionnaire-based study on 369 families living with a child with an IMD was to investigate the psychosocial and financial burden following a true-positive NBS. The reported psychosocial burden differed between children and their parents, and was associated with the child's age, diagnosis, and treatment. At younger ages, parent-reported burden was higher for the parents than for the individual child, while it increased for children and decreased for parents as the child grew older. Furthermore, psychosocial burden increased if the child required a strict dietary treatment and was at risk of metabolic decompensation. Regardless of diagnosis and treatment, the developmental delay of their child independently increased the parental psychosocial burden. Financial burden was reported by 24% of all families, and was higher in low-income families and in families whose children required dietary treatment. In conclusion, a substantial psychosocial and financial burden was revealed for children and their families after true-positive NBS. Since this burden is likely to have a negative impact on the long-term individual health benefits of NBS, this study underlines the importance of regularly assessing the psychosocial and financial needs of these families.
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Affiliation(s)
- Elena Schnabel‐Besson
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Sven F. Garbade
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Florian Gleich
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Sarah C. Grünert
- Department of General Pediatrics, Adolescent Medicine and NeonatologyMedical Center ‐ University of Freiburg, Faculty of MedicineFreiburgGermany
| | - Johannes Krämer
- Department of Pediatric and Adolescent MedicineUlm University Medical SchoolUlmGermany
| | - Eva Thimm
- Department of General Pediatrics, Neonatology, and Pediatric CardiologyUniversity Children's Hospital, Heinrich Heine University DüsseldorfDüsseldorfGermany
| | - Julia B. Hennermann
- Villa MetabolicaCenter for Pediatric and Adolescent Medicine, Mainz University Medical CenterMainzGermany
| | - Peter Freisinger
- Children's Hospital Reutlingen, Klinikum am SteinenbergReutlingenGermany
| | - Peter Burgard
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Gwendolyn Gramer
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
- Department for Inborn Metabolic DiseasesUniversity Children's Hospital, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Marina A. Morath
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - A. Tunç Tuncel
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Svenja Keßler
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Georg F. Hoffmann
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Stefan Kölker
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
| | - Ulrike Mütze
- Department of Pediatrics I, Division of Pediatric Neurology and Metabolic MedicineHeidelberg University, Medical Faculty HeidelbergHeidelbergGermany
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Wu J, Huang E, McMullen MR, Singh V, Mrdjen M, Bellar A, Wang L, Welch N, Dasarathy J, Dasarathy S, Streem D, Brown JM, Nagy LE. The pyruvate dehydrogenase kinase inhibitor dichloroacetate mitigates alcohol-induced hepatic inflammation and metabolic disturbances in mice. Hepatol Commun 2024; 8:e0547. [PMID: 39621302 PMCID: PMC11608733 DOI: 10.1097/hc9.0000000000000547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/07/2024] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND Dichloroacetate (DCA), a pan-pyruvate dehydrogenase kinase inhibitor, ameliorates multiple pathological conditions and tissue injury and shows strong potential for clinical applications. Here, we investigated the preventive effects of DCA in a murine model of alcohol-associated liver disease. METHODS C57BL/6J mice were subjected to the acute-on-chronic model of alcohol-associated liver disease and treated with DCA. Livers were assessed in liver histology, biochemistry, and gene expression. Mass spectrometry was used to compare protein expression and metabolite levels. RESULTS DCA inhibited hepatic expression of inflammatory genes but did not prevent steatosis and hepatocellular injury in ethanol-fed mice. Consistently, DCA repressed the expression of mRNAs for inflammatory genes in LPS-stimulated murine bone-marrow-derived macrophages and human monocytic THP-1 cells and inhibited both gene expression and protein release of interleukin-1 beta. DCA prevented hepatic accumulation of isovaleric acid in ethanol-fed mice, a short-chain fatty acid primarily produced by gut microbiota. In vitro, isovaleric acid potentiated LPS's effects, while DCA prevented this proinflammatory action. Ethanol feeding increased the expression of proteins involved in diverse metabolic pathways, including branched-chain amino acid (BCAA) degradation. In ethanol-fed mice, hepatic Fischer's ratio (the molar ratio of BCAAs to aromatic amino acids Phe and Tyr) and BTR (the molar ratio of BCAAs to Tyr) showed a decrease compared to pair-fed mice; however, this decrease was not observed in DCA-treated ethanol-fed mice. DCA blunted the ethanol-induced increase of BCKDHA, the rate-limiting enzyme in BCAA catabolism, and cytochrome P450 2E1. CONCLUSIONS Ethanol-induced hepatic inflammatory responses and metabolic disturbances were prevented by DCA in mice, indicating the potential to develop pyruvate dehydrogenase kinase inhibitors as an effective therapy to treat alcohol-associated liver disease.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Emily Huang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Megan R. McMullen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Vaibhav Singh
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Marko Mrdjen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Annette Bellar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Li Wang
- Independent Researcher, Tucson, Arizona, USA
| | - Nicole Welch
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jaividhya Dasarathy
- Department of Family Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
- Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - David Streem
- Department of Psychiatry and Psychology, Cleveland Clinic Lutheran Hospital, Cleveland, Ohio, USA
| | - J. Mark Brown
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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6
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Ravikumar A, Abdelgani A, Pawlak T, Raphael R, Abdalla A. Acute Metabolic Decompensation of Isovaleric Acidemia Presenting as Persistent Metabolic Acidosis in a Middle-Aged Man: A Case Report. Cureus 2024; 16:e67253. [PMID: 39301405 PMCID: PMC11412276 DOI: 10.7759/cureus.67253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2024] [Indexed: 09/22/2024] Open
Abstract
Isovaleric acidemia is a rare autosomal recessive inborn error of metabolism that affects the breakdown of the essential amino acid leucine. Acute metabolic decompensation is often triggered by stressors such as surgery, concurrent illness, excessive protein intake, or dehydration. This can lead to a catabolic state with increased endogenous protein turnover, posing a risk of potentially life-threatening crises due to the accumulation of toxic metabolites from incomplete leucine breakdown. Such episodes are rarely observed beyond childhood and adolescence, and the disease's rarity typically prevents single centers from gaining extensive experience with its full spectrum. This lack of familiarity can be challenging for adult physicians, who may not be well versed in the appropriate management strategies. This case report describes an acute metabolic crisis in a middle-aged man in his late 30s, triggered by an influenza virus infection and presenting as persistent and unresolved metabolic acidosis. We aim to emphasize the importance of early and prompt recognition of metabolic crises in metabolically stable adults with inborn errors of metabolism, particularly for intensivists and acute care physicians.
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Affiliation(s)
- Aparna Ravikumar
- Internal Medicine, York and Scarborough Teaching Hospitals NHS Foundation Trust, Scarborough, GBR
| | - Abdelgani Abdelgani
- Cardiology, York and Scarborough Teaching Hospitals NHS Foundation Trust, Scarborough, GBR
| | - Tadeusz Pawlak
- Endocrinology and Diabetes, York and Scarborough Teaching Hospitals NHS Foundation Trust, Scarborough, GBR
| | - Riya Raphael
- Internal Medicine, York and Scarborough Teaching Hospitals NHS Foundation Trust, Scarborough, GBR
| | - Abdelgadir Abdalla
- Internal Medicine, York and Scarborough Teaching Hospitals NHS Foundation Trust, Scarborough, GBR
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7
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Xiao G, Feng Z, Xu C, Huang X, Chen M, Zhao M, Li Y, Gao Y, Wu S, Shen Y, Peng Y. 206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in Huaihua, China. Front Genet 2024; 15:1387423. [PMID: 38784038 PMCID: PMC11112075 DOI: 10.3389/fgene.2024.1387423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 04/15/2024] [Indexed: 05/25/2024] Open
Abstract
Background Inborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting. Currently, no studies have reported on the incidence of IEMs of multi-ethnic groups in Huaihua, China. Methods A total of 206,977 neonates with self-reported ethnicity who underwent IEM screening at Huaihua from 2015 to 2021 were selected for observation. Among them, 69 suspected IEM-positive neonates were referred for urine gas chromatography-mass spectrometry analysis, biochemical detection, next-generation sequencing, and Sanger sequencing. Results Sixty-nine newborns were diagnosed with IEMs, with an overall incidence of 1:3,000. The two most common disorders were 2-methylbutyryl glycinuria (1:7,137) and phenylalanine hydroxylase deficiency (1:22,997). Moreover, the incidence of IEMs in the minority ethnic group (Miao, Dong, Tujia and Yao) (1:1,852) was markedly higher than in the Han ethnic group (1:4,741). Some ethnic features variants were identified; NM_001609.4:c.1165A>G in the ACADSB gene for Miao and Dong ethnic groups, NM_014251.2:c.852_855del in the SLC25A13 gene for Miao ethnic groups. Conclusion This study revealed the IEM incidence within the minority ethnic groups is markedly higher than among the Han nationality and the gene variant spectrum is dramatically different in Huaihua, China. Hence, It serves as a theoretical reference for the screening and diagnosing of neonatal IEMs of multi-ethnic groups in the Huaihua area, and across China.
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Affiliation(s)
- Gang Xiao
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Zonghui Feng
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Chaochao Xu
- Technical Support Center, Zhejiang Biosan Biochemical Technologies Co., Ltd, Hangzhou, Zhejiang Province, China
| | - Xuzhen Huang
- Technical Support Center, Zhejiang Biosan Biochemical Technologies Co., Ltd, Hangzhou, Zhejiang Province, China
| | - Maosheng Chen
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Min Zhao
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Yanbin Li
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Yang Gao
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Shulin Wu
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Yuyan Shen
- Neonatal Disease Screening Center, Huaihua City Maternal and Child Health Care Hospital, Huaihua, Hunan Province, China
| | - Ying Peng
- Department of Medical Genetics, National Health Commission Key Laboratory of Birth Defects Research, Hunan Provincial Maternal and Child Healthcare Hospital, Changsha, China
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8
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Martelli F, Lin J, Mele S, Imlach W, Kanca O, Barlow CK, Paril J, Schittenhelm RB, Christodoulou J, Bellen HJ, Piper MDW, Johnson TK. Identifying potential dietary treatments for inherited metabolic disorders using Drosophila nutrigenomics. Cell Rep 2024; 43:113861. [PMID: 38416643 PMCID: PMC11037929 DOI: 10.1016/j.celrep.2024.113861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 12/09/2023] [Accepted: 02/08/2024] [Indexed: 03/01/2024] Open
Abstract
Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, behavior, and lifelong fly survival, thus providing a basis for further study into the pathogenic mechanisms involved in this disorder. Our work highlights the diet-sensitive nature of metabolic disorders and establishes Drosophila as a valuable tool for nutrigenomic studies for informing potential dietary therapies.
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Affiliation(s)
- Felipe Martelli
- School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia
| | - Jiayi Lin
- School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia
| | - Sarah Mele
- School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia
| | - Wendy Imlach
- Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Oguz Kanca
- Department of Molecular and Human Genetics and Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Christopher K Barlow
- Monash Proteomics & Metabolomics Facility, Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - Jefferson Paril
- School of BioSciences, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Ralf B Schittenhelm
- Monash Proteomics & Metabolomics Facility, Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - John Christodoulou
- Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Hugo J Bellen
- Department of Molecular and Human Genetics and Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Matthew D W Piper
- School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia.
| | - Travis K Johnson
- School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Chemistry and La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia.
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9
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Ivica J, Adam F, Wortel L, Kalika T, Pelly H, Gauthier J, Potter M. Development of a second-tier method for C4, C5 and C2 acylcarnitine analysis in plasma. Clin Biochem 2024; 123:110698. [PMID: 38048898 DOI: 10.1016/j.clinbiochem.2023.110698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/06/2023]
Abstract
INTRODUCTION Acylcarnitines are typically analyzed using either a flow injection analysis (FIA) method or liquid chromatography-mass spectrometry (LC-MS/MS) methods. The FIA method is a fast, efficient method, however it does not have the capability to separate compounds with the same molecular weight. These isobaric interferences can be removed by chromatographic separation with LC-MS/MS. In this study, we aimed to develop and optimize a qualitative LC-MS/MS method to separate the isobaric interferences for two-, four- and five-carbon acylcarnitines. METHODS The samples were first prepared by acylcarnitine derivatization with butanolic HCl. The developed LC-MS/MS method is a combination of isocratic and gradient elution used to separate acylcarnitines. Multiple reaction monitoring was used for determination of precursor and product ions for each acylcarnitine species as well as known interferences used in our study. We used this method to analyze quality assurance and patient samples with elevated two-, four- and five-carbon acylcarnitines. RESULTS Butyryl- and isobutyrylcarnitines as well as valeryl- and isovalerylcarnitines were successfully separated using the developed method. This method was able also to separate and distinguish acetylcarnitine from glutamate interference that has been causing overestimation of acetylcarnitine. In patients, the dominant five-carbon acylcarnitine was found to be isovalerylcarnitine. We confirmed that the majority of analyzed patient samples had additional carnitine adducts present but not valerylcarnitine. Butyryl- and isobutyrylcarnitines, in variable ratios, were present in every patient sample. CONCLUSION We developed a qualitative LC-MS/MS method for butyl-ester derivatized acylcarnitines, which can be used as a second-tier method for diagnosis and monitoring of various inborn errors of metabolism in our hospital network.
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Affiliation(s)
- Josko Ivica
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada.
| | - Faisal Adam
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Lyse Wortel
- Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Teresa Kalika
- Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Heather Pelly
- Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Jeannette Gauthier
- Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Murray Potter
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada.
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10
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Zhang Z, Tringides ML, Morgan CE, Miyagi M, Mears JA, Hoppel CL, Yu EW. High-Resolution Structural Proteomics of Mitochondria Using the 'Build and Retrieve' Methodology. Mol Cell Proteomics 2023; 22:100666. [PMID: 37839702 PMCID: PMC10709515 DOI: 10.1016/j.mcpro.2023.100666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/06/2023] [Accepted: 10/11/2023] [Indexed: 10/17/2023] Open
Abstract
The application of integrated systems biology to the field of structural biology is a promising new direction, although it is still in the infant stages of development. Here we report the use of single particle cryo-EM to identify multiple proteins from three enriched heterogeneous fractions prepared from human liver mitochondrial lysate. We simultaneously identify and solve high-resolution structures of nine essential mitochondrial enzymes with key metabolic functions, including fatty acid catabolism, reactive oxidative species clearance, and amino acid metabolism. Our methodology also identified multiple distinct members of the acyl-CoA dehydrogenase family. This work highlights the potential of cryo-EM to explore tissue proteomics at the atomic level.
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Affiliation(s)
- Zhemin Zhang
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Marios L Tringides
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Christopher E Morgan
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Masaru Miyagi
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Jason A Mears
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Charles L Hoppel
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Edward W Yu
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
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11
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Skvorak K, Liu J, Kruse N, Mehmood R, Das S, Jenne S, Chng C, Lao UL, Duan D, Asfaha J, Du F, Teadt L, Sero A, Ching C, Riggins J, Pope L, Yan P, Mashiana H, Ismaili MHA, McCluskie K, Huisman G, Silverman AP. Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates. J Inherit Metab Dis 2023; 46:1089-1103. [PMID: 37494004 DOI: 10.1002/jimd.12662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/06/2023] [Accepted: 07/25/2023] [Indexed: 07/27/2023]
Abstract
Maple syrup urine disease (MSUD) is an inborn error of branched-chain amino acid metabolism affecting several thousand individuals worldwide. MSUD patients have elevated levels of plasma leucine and its metabolic product α-ketoisocaproate (KIC), which can lead to severe neurotoxicity, coma, and death. Patients must maintain a strict diet of protein restriction and medical formula, and periods of noncompliance or illness can lead to acute metabolic decompensation or cumulative neurological impairment. Given the lack of therapeutic options for MSUD patients, we sought to develop an oral enzyme therapy that can degrade leucine within the gastrointestinal tract prior to its systemic absorption and thus enable patients to maintain acceptable plasma leucine levels while broadening their access to natural protein. We identified a highly active leucine decarboxylase enzyme from Planctomycetaceae bacterium and used directed evolution to engineer the enzyme for stability to gastric and intestinal conditions. Following high-throughput screening of over 12 000 enzyme variants over 9 iterative rounds of evolution, we identified a lead variant, LDCv10, which retains activity following simulated gastric or intestinal conditions in vitro. In intermediate MSUD mice or healthy nonhuman primates given a whey protein meal, oral treatment with LDCv10 suppressed the spike in plasma leucine and KIC and reduced the leucine area under the curve in a dose-dependent manner. Reduction in plasma leucine correlated with decreased brain leucine levels following oral LDCv10 treatment. Collectively, these data support further development of LDCv10 as a potential new therapy for MSUD patients.
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Affiliation(s)
| | - Joyce Liu
- Codexis, Inc., Redwood City, California, USA
| | - Nikki Kruse
- Codexis, Inc., Redwood City, California, USA
| | | | | | | | | | - U Loi Lao
- Codexis, Inc., Redwood City, California, USA
| | - Da Duan
- Codexis, Inc., Redwood City, California, USA
| | | | - Faye Du
- Codexis, Inc., Redwood City, California, USA
| | - Leann Teadt
- Codexis, Inc., Redwood City, California, USA
| | | | | | | | - Lianne Pope
- Codexis, Inc., Redwood City, California, USA
| | - Ping Yan
- Codexis, Inc., Redwood City, California, USA
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12
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Mütze U, Henze L, Schröter J, Gleich F, Lindner M, Grünert SC, Spiekerkoetter U, Santer R, Thimm E, Ensenauer R, Weigel J, Beblo S, Arélin M, Hennermann JB, Marquardt I, Freisinger P, Krämer J, Dieckmann A, Weinhold N, Schiergens KA, Maier EM, Hoffmann GF, Garbade SF, Kölker S. Isovaleric aciduria identified by newborn screening: Strategies to predict disease severity and stratify treatment. J Inherit Metab Dis 2023; 46:1063-1077. [PMID: 37429829 DOI: 10.1002/jimd.12653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/12/2023]
Abstract
Newborn screening (NBS) allows early identification of individuals with rare disease, such as isovaleric aciduria (IVA). Reliable early prediction of disease severity of positively screened individuals with IVA is needed to guide therapeutic decision, prevent life-threatening neonatal disease manifestation in classic IVA and over-medicalization in attenuated IVA that may remain asymptomatic. We analyzed 84 individuals (median age at last study visit 8.5 years) with confirmed IVA identified by NBS between 1998 and 2018 who participated in the national, observational, multicenter study. Screening results, additional metabolic parameters, genotypes, and clinical phenotypic data were included. Individuals with metabolic decompensation showed a higher median isovalerylcarnitine (C5) concentration in the first NBS sample (10.6 vs. 2.7 μmol/L; p < 0.0001) and initial urinary isovalerylglycine concentration (1750 vs. 180 mmol/mol creatinine; p = 0.0003) than those who remained asymptomatic. C5 was in trend inversely correlated with full IQ (R = -0.255; slope = -0.869; p = 0.0870) and was lower for the "attenuated" variants compared to classic genotypes [median (IQR; range): 2.6 μmol/L (2.1-4.0; 0.7-6.4) versus 10.3 μmol/L (7.4-13.1; 4.3-21.7); N = 73]. In-silico prediction scores (M-CAP, MetaSVM, and MetaLR) correlated highly with isovalerylglycine and ratios of C5 to free carnitine and acetylcarnitine, but not sufficiently with clinical endpoints. The results of the first NBS sample and biochemical confirmatory testing are reliable early predictors of the clinical course of IVA, facilitating case definition (attenuated versus classic IVA). Prediction of attenuated IVA is supported by the genotype. On this basis, a reasonable algorithm has been established for neonates with a positive NBS result for IVA, with the aim of providing the necessary treatment immediately, but whenever possible, adjusting the treatment to the individual severity of the disease.
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Affiliation(s)
- Ulrike Mütze
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Lucy Henze
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Julian Schröter
- Division of Pediatric Epileptology, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Florian Gleich
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Lindner
- Division of Pediatric Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany
| | - Sarah C Grünert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - René Santer
- Department of Pediatrics, University Medical Centre Eppendorf, Hamburg, Germany
| | - Eva Thimm
- Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Regina Ensenauer
- Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Institute of Child Nutrition, Max-Rubner-Institut, Karlsruhe, Germany
| | - Johannes Weigel
- Praxis für Kinder- und Jugendmedizin, Endokrinologie und Stoffwechsel, Augsburg, Germany
| | - Skadi Beblo
- Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany
| | - Maria Arélin
- Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany
| | - Julia B Hennermann
- Villa Metabolica, Center for Pediatric and Adolescent Medicine, Mainz University Medical Center, Mainz, Germany
| | - Iris Marquardt
- Department of Child Neurology, Children's Hospital Oldenburg, Oldenburg, Germany
| | - Peter Freisinger
- Children's Hospital Reutlingen, Klinikum am Steinenberg, Reutlingen, Germany
| | - Johannes Krämer
- Department of Pediatric and Adolescent Medicine, University of Ulm, Ulm, Germany
| | - Andrea Dieckmann
- Center for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany
| | - Natalie Weinhold
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Center of Chronically Sick Children, Berlin, Germany
| | | | - Esther M Maier
- Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
| | - Georg F Hoffmann
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Sven F Garbade
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Kölker
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
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13
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Zegarra Buitron E, Vidal Panduro DA, Guillén Ramírez NS, González Arteaga M. Isovaleric Acidemia: A Case Report. Cureus 2023; 15:e49362. [PMID: 38146578 PMCID: PMC10749218 DOI: 10.7759/cureus.49362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2023] [Indexed: 12/27/2023] Open
Abstract
Isovaleric acidemia is an autosomal recessive disease of leucine metabolism. The clinical presentation is variable and three phenotypes are described, asymptomatic, acute neonatal, and chronic intermittent. Infections are the most important trigger for catabolic crises. Diagnosis is based on the detection of isovalerylglycine CoA in urine and elevated levels of isovaleryl (C5) carnitine in blood. Long-term treatment consists of prevention of catabolic state, dietary restriction, and supplementation with L-carnitine and/or L-glycine. We present the case of a three-year-old female patient with multiple episodes of decompensation since the age of two years. The episode in which she was diagnosed had encephalopathy, with no neurological sequelae. Currently, the patient continues with dietary restrictions and supplementation with good nutritional and growth results for her age.
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Affiliation(s)
| | - Daniel A Vidal Panduro
- Internal Medicine, School of Medicine, Universidad Peruana de Ciencias Aplicadas, Lima, PER
| | | | - María González Arteaga
- Paediatrics and Child Health, Hospital Nacional Docente Madre Niño San Bartolomé, LIMA, PER
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14
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Di Cicco F, Evans RL, James AG, Weddell I, Chopra A, Smeets MAM. Intrinsic and extrinsic factors affecting axillary odor variation. A comprehensive review. Physiol Behav 2023; 270:114307. [PMID: 37516230 DOI: 10.1016/j.physbeh.2023.114307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/14/2023] [Accepted: 07/27/2023] [Indexed: 07/31/2023]
Abstract
Humans produce odorous secretions from multiple body sites according to the microbiomic profile of each area and the types of secretory glands present. Because the axilla is an active, odor-producing region that mediates social communication via the sense of smell, this article focuses on the biological mechanisms underlying the creation of axillary odor, as well as the intrinsic and extrinsic factors likely to impact the odor and determine individual differences. The list of intrinsic factors discussed includes sex, age, ethnicity, emotions, and personality, and extrinsic factors include dietary choices, diseases, climate, and hygienic habits. In addition, we also draw attention to gaps in our understanding of each factor, including, for example, topical areas such as the effect of climate on body odor variation. Fundamental challenges and emerging research opportunities are further outlined in the discussion. Finally, we suggest guidelines and best practices based on the factors reviewed herein for preparatory protocols of sweat collection, data analysis, and interpretation.
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Affiliation(s)
- Francesca Di Cicco
- Faculty of Social and Behavioural Sciences, Utrecht University, Heidelberglaan 1, Utrecht, CS 3584, the Netherlands.
| | - Richard L Evans
- Unilever Research & Development, Port Sunlight Laboratory, Bebington, UK
| | - A Gordon James
- Unilever Research & Development, Colworth House, Sharnbrook, UK
| | - Iain Weddell
- Unilever Research & Development, Port Sunlight Laboratory, Bebington, UK
| | - Anita Chopra
- Unilever Research & Development, Port Sunlight Laboratory, Bebington, UK
| | - Monique A M Smeets
- Faculty of Social and Behavioural Sciences, Utrecht University, Heidelberglaan 1, Utrecht, CS 3584, the Netherlands; Unilever Research & Development, Rotterdam, the Netherlands
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15
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Wen X, Wan F, Wu Y, Liu L, Liu Y, Zhong R, Chen L, Zhang H. Caffeic acid supplementation ameliorates intestinal injury by modulating intestinal microbiota in LPS-challenged piglets. Food Funct 2023; 14:7705-7717. [PMID: 37547959 DOI: 10.1039/d3fo02286b] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
During weaning, piglets are susceptible to intestinal injuries caused by a range of infections, which result in serious economic losses for pig producers. Caffeic acid (CA) is a plant-derived phenolic acid that exhibits potential as a dietary supplement for enhancing intestinal health. There is, however, limited information available about the potential benefits of CA supplementation on intestinal injury and growth performance in piglets. A 28-day study was conducted to examine the effectiveness of CA supplementation in protecting against intestinal injury induced by intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) in piglets. Twenty-four piglets (7.43 ± 0.79 kg body weight; Duroc × Landrace × Large White; barrows) were randomly divided into 4 groups: the control group, the LPS group, the LPS + CA group, and the CA group. Piglets were administered with LPS or saline on d21 and d28 of the experiment. Supplementation with CA improved intestinal barrier function in LPS-challenged piglets by enhancing intestinal morphology and integrity, as well as increasing the expression of Claudin-1 and ZO-1. Meanwhile, CA supplementation improved the systemic and colonic inflammation responses, oxidative stress, and apoptosis induced by LPS. CA supplementation improved the alpha diversity and structure of the intestinal microbiota by increasing the abundance of beneficial microbiota. Additionally, it was found that it improves metabolic disorders of colonic bile acids (BAs) and short-chain fatty acids (SCFAs) in LPS-challenged piglets, including an increase in primary BAs and isovalerate. In conclusion, CA supplementation could enhance intestinal integrity and barrier function by modifying intestinal microbiota and its metabolites, which could lead to a reduction in inflammatory responses and oxidative stress and ultimately enhanced growth performance in piglets.
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Affiliation(s)
- Xiaobin Wen
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Fan Wan
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
- State Key Laboratory of Grassland Agro-Ecosystem, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - You Wu
- College of Biological Science and Engineering, Beijing University of Agriculture, Beijing 102206, China
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Lei Liu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Yueping Liu
- College of Biological Science and Engineering, Beijing University of Agriculture, Beijing 102206, China
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Liang Chen
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
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16
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Masschelin PM, Saha P, Ochsner SA, Cox AR, Kim KH, Felix JB, Sharp R, Li X, Tan L, Park JH, Wang L, Putluri V, Lorenzi PL, Nuotio-Antar AM, Sun Z, Kaipparettu BA, Putluri N, Moore DD, Summers SA, McKenna NJ, Hartig SM. Vitamin B2 enables regulation of fasting glucose availability. eLife 2023; 12:e84077. [PMID: 37417957 PMCID: PMC10328530 DOI: 10.7554/elife.84077] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 06/24/2023] [Indexed: 07/08/2023] Open
Abstract
Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.
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Affiliation(s)
- Peter M Masschelin
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Pradip Saha
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
| | - Scott A Ochsner
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Aaron R Cox
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
| | - Kang Ho Kim
- Department of Anesthesiology, University of Texas Health Sciences CenterHoustonUnited States
| | - Jessica B Felix
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Robert Sharp
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
| | - Xin Li
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
| | - Lin Tan
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterHoustonUnited States
| | - Jun Hyoung Park
- Department of Molecular and Human Genetics, Baylor College of MedicineHoustonUnited States
| | - Liping Wang
- Department of Nutrition and Integrative Physiology, University of UtahSalt Lake CityUnited States
| | - Vasanta Putluri
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Philip L Lorenzi
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterHoustonUnited States
| | | | - Zheng Sun
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
| | | | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - David D Moore
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
- Department of Nutritional Sciences and Toxicology, University of California, BerkeleyBerkeleyUnited States
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of UtahSalt Lake CityUnited States
| | - Neil J McKenna
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Sean M Hartig
- Department of Diabetes, Endocrinology, and Metabolism, Baylor College of MedicineHoustonUnited States
- Department of Medicine, Baylor College of MedicineHoustonUnited States
- Department of Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
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17
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Sharma A, Kumar R, Varadwaj P. Smelling the Disease: Diagnostic Potential of Breath Analysis. Mol Diagn Ther 2023; 27:321-347. [PMID: 36729362 PMCID: PMC9893210 DOI: 10.1007/s40291-023-00640-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2023] [Indexed: 02/03/2023]
Abstract
Breath analysis is a relatively recent field of research with much promise in scientific and clinical studies. Breath contains endogenously produced volatile organic components (VOCs) resulting from metabolites of ingested precursors, gut and air-passage bacteria, environmental contacts, etc. Numerous recent studies have suggested changes in breath composition during the course of many diseases, and breath analysis may lead to the diagnosis of such diseases. Therefore, it is important to identify the disease-specific variations in the concentration of breath to diagnose the diseases. In this review, we explore methods that are used to detect VOCs in laboratory settings, VOC constituents in exhaled air and other body fluids (e.g., sweat, saliva, skin, urine, blood, fecal matter, vaginal secretions, etc.), VOC identification in various diseases, and recently developed electronic (E)-nose-based sensors to detect VOCs. Identifying such VOCs and applying them as disease-specific biomarkers to obtain accurate, reproducible, and fast disease diagnosis could serve as an alternative to traditional invasive diagnosis methods. However, the success of VOC-based identification of diseases is limited to laboratory settings. Large-scale clinical data are warranted for establishing the robustness of disease diagnosis. Also, to identify specific VOCs associated with illness states, extensive clinical trials must be performed using both analytical instruments and electronic noses equipped with stable and precise sensors.
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Affiliation(s)
- Anju Sharma
- Systems Biology Lab, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India
| | - Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Uttar Pradesh, Lucknow Campus, Lucknow, India
| | - Pritish Varadwaj
- Systems Biology Lab, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India.
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18
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Cai A, Portengen L, Ertaylan G, Legler J, Vermeulen R, Lenters V, Remy S. Prenatal Exposure to Metabolism-Disrupting Chemicals, Cord Blood Transcriptome Perturbations, and Birth Weight in a Belgian Birth Cohort. Int J Mol Sci 2023; 24:ijms24087607. [PMID: 37108768 PMCID: PMC10141364 DOI: 10.3390/ijms24087607] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/10/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023] Open
Abstract
Prenatal exposure to metabolism-disrupting chemicals (MDCs) has been linked to birth weight, but the molecular mechanisms remain largely unknown. In this study, we investigated gene expressions and biological pathways underlying the associations between MDCs and birth weight, using microarray transcriptomics, in a Belgian birth cohort. Whole cord blood measurements of dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyls 153 (PCB-153), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and transcriptome profiling were conducted in 192 mother-child pairs. A workflow including a transcriptome-wide association study, pathway enrichment analysis with a meet-in-the-middle approach, and mediation analysis was performed to characterize the biological pathways and intermediate gene expressions of the MDC-birth weight relationship. Among 26,170 transcriptomic features, we successfully annotated five overlapping metabolism-related gene expressions associated with both an MDC and birth weight, comprising BCAT2, IVD, SLC25a16, HAS3, and MBOAT2. We found 11 overlapping pathways, and they are mostly related to genetic information processing. We found no evidence of any significant mediating effect. In conclusion, this exploratory study provides insights into transcriptome perturbations that may be involved in MDC-induced altered birth weight.
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Affiliation(s)
- Anran Cai
- Department of Population Health Sciences, Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
- VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
| | - Lützen Portengen
- Department of Population Health Sciences, Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Gökhan Ertaylan
- VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
| | - Juliette Legler
- Department of Population Health Sciences, Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Roel Vermeulen
- Department of Population Health Sciences, Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
| | - Virissa Lenters
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
| | - Sylvie Remy
- VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
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19
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Kühn S, Williams ME, Dercksen M, Sass JO, van der Sluis R. The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA - an in-silico and in vitro validation. Comput Struct Biotechnol J 2023; 21:1236-1248. [PMID: 36817957 PMCID: PMC9932296 DOI: 10.1016/j.csbj.2023.01.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/01/2023] Open
Abstract
Isovaleric acidemia (IVA), due to isovaleryl-CoA dehydrogenase (IVD) deficiency, results in the accumulation of isovaleryl-CoA, isovaleric acid and secondary metabolites. The increase in these metabolites decreases mitochondrial energy production and increases oxidative stress. This contributes to the neuropathological features of IVA. A general assumption in the literature exists that glycine N-acyltransferase (GLYAT) plays a role in alleviating the symptoms experienced by IVA patients through the formation of N-isovalerylglycine. GLYAT forms part of the phase II glycine conjugation pathway in the liver and detoxifies excess acyl-CoA's namely benzoyl-CoA. However, very few studies support GLYAT as the enzyme that conjugates isovaleryl-CoA to glycine. Furthermore, GLYATL1, a paralogue of GLYAT, conjugates phenylacetyl-CoA to glutamine. Therefore, GLYATL1 might also be a candidate for the formation of N-isovalerylglycine. Based on the findings from the literature review, we proposed that GLYAT or GLYATL1 can form N-isovalerylglycine in IVA patients. To test this hypothesis, we performed an in-silico analysis to determine which enzyme is more likely to conjugate isovaleryl-CoA with glycine using AutoDock Vina. Thereafter, we performed in vitro validation using purified enzyme preparations. The in-silico and in vitro findings suggested that both enzymes could form N-isovaleryglycine albeit at lower affinities than their preferred substrates. Furthermore, an increase in glycine concentration does not result in an increase in N-isovalerylglycine formation. The results from the critical literature appraisal, in-silico, and in vitro validation, suggest the importance of further investigating the reaction kinetics and binding behaviors between these substrates and enzymes in understanding the pathophysiology of IVA.
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Affiliation(s)
- Stefan Kühn
- Focus Area for Human Metabolomics, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Monray E. Williams
- Focus Area for Human Metabolomics, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Marli Dercksen
- Focus Area for Human Metabolomics, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Jörn Oliver Sass
- Research Group Inborn Errors of Metabolism, Institute for Functional Gene Analytics, Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig-Str. 20, 53359 Rheinbach, Germany
| | - Rencia van der Sluis
- Focus Area for Human Metabolomics, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa,Corresponding author.
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20
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Li Q, Hoppe T. Role of amino acid metabolism in mitochondrial homeostasis. Front Cell Dev Biol 2023; 11:1127618. [PMID: 36923249 PMCID: PMC10008872 DOI: 10.3389/fcell.2023.1127618] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/16/2023] [Indexed: 03/03/2023] Open
Abstract
Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic processes that provide energy in the cell is amino acid metabolism. Almost all of the 20 amino acids that serve as the building blocks of proteins are produced or degraded in the mitochondria. The synthesis of the amino acids aspartate and arginine depends on the activity of the respiratory chain, which is essential for cell proliferation. The degradation of branched-chain amino acids mainly occurs in the mitochondrial matrix, contributing to energy metabolism, mitochondrial biogenesis, as well as protein quality control in both mitochondria and cytosol. Dietary supplementation or restriction of amino acids in worms, flies and mice modulates lifespan and health, which has been associated with changes in mitochondrial biogenesis, antioxidant response, as well as the activity of tricarboxylic acid cycle and respiratory chain. Consequently, impaired amino acid metabolism has been associated with both primary mitochondrial diseases and diseases with mitochondrial dysfunction such as cancer. Here, we present recent observations on the crosstalk between amino acid metabolism and mitochondrial homeostasis, summarise the underlying molecular mechanisms to date, and discuss their role in cellular functions and organismal physiology.
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Affiliation(s)
- Qiaochu Li
- Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Thorsten Hoppe
- Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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21
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Xiong W, Ge H, Shen C, Li C, Zhang X, Tang L, Shen Y, Lu S, Zhang H, Wang Z. PRSS37 deficiency leads to impaired energy metabolism in testis and sperm revealed by DIA-based quantitative proteomic analysis. Reprod Sci 2023; 30:145-168. [PMID: 35471551 DOI: 10.1007/s43032-022-00918-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/12/2022] [Indexed: 01/11/2023]
Abstract
Our previous studies have reported that a putative trypsin-like serine protease, PRSS37, is exclusively expressed in testicular germ cells during late spermatogenesis and essential for sperm migration from the uterus into the oviduct and sperm-egg recognition via mediating the interaction between PDILT and ADAM3. In the present study, the global proteome profiles of wild-type (wt) and Prss37-/- mice in testis and sperm were compared employing data independent acquisition (DIA) technology. Overall, 2506 and 459 differentially expressed proteins (DEPs) were identified in Prss37-null testis and sperm, respectively, when compared to control groups. Bioinformatic analyses revealed that most of DEPs were related to energy metabolism. Of note, the DEPs associated with pathways for the catabolism such as glucose via glycolysis, fatty acids via β-oxidation, and amino acids via oxidative deamination were significantly down-regulated. Meanwhile, the DEPs involved in the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation (OXPHOS) were remarkably decreased. The DIA data were further confirmed by a markedly reduction of intermediate metabolites (citrate and fumarate) in TCA cycle and terminal metabolite (ATP) in OXPHOS system after disruption of PRSS37. These outcomes not only provide a more comprehensive understanding of the male fertility of energy metabolism modulated by PRSS37 but also furnish a dynamic proteomic resource for further reproductive biology studies.
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Affiliation(s)
- Wenfeng Xiong
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Haoyang Ge
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Chunling Shen
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Chaojie Li
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Xiaohong Zhang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Lingyun Tang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Yan Shen
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Shunyuan Lu
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Hongxin Zhang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Zhugang Wang
- State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China.
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22
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Smith-Byrne K, Cerani A, Guida F, Zhou S, Agudo A, Aleksandrova K, Barricarte A, Barranco MR, Bochers CH, Gram IT, Han J, Amos CI, Hung RJ, Grankvist K, Nøst TH, Imaz L, Chirlaque-López MD, Johansson M, Kaaks R, Kühn T, Martin RM, McKay JD, Pala V, Robbins HA, Sandanger TM, Schibli D, Schulze MB, Travis RC, Vineis P, Weiderpass E, Brennan P, Johansson M, Richards JB. Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements. Cancer Epidemiol Biomarkers Prev 2022; 31:1966-1974. [PMID: 35839461 PMCID: PMC9530646 DOI: 10.1158/1055-9965.epi-21-1033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/09/2021] [Accepted: 07/13/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. MATERIALS AND METHODS We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). RESULTS An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. CONCLUSIONS Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. IMPACT Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.
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Affiliation(s)
- Karl Smith-Byrne
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Agustin Cerani
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada/Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
| | - Florence Guida
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Sirui Zhou
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada/Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
| | - Antonio Agudo
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia, Spain
| | - Krasimira Aleksandrova
- Nutrition, Immunity and Metabolism Senior Scientist Group, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
- University of Potsdam, Institute of Nutritional Science, Potsdam, Germany
| | - Aurelio Barricarte
- Navarra Institute for Health Research (IdiSNA) Pamplona, Spain
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Miguel Rodríguez Barranco
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Escuela Andaluza de Salud Pública (EASP), Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
| | - Christoph H. Bochers
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada/Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
- University of Victoria–Genome British Columbia Proteomics Centre, Victoria, BC, Canada/Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Inger Torhild Gram
- Faculty of Health Sciences, Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Norway
| | - Jun Han
- University of Victoria–Genome British Columbia Proteomics Centre, Victoria, BC, Canada/Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Christopher I. Amos
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Rayjean J. Hung
- Prosserman Centre for Health Research, Mount Sinai Hospital, Toronto, Canada
| | - Kjell Grankvist
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Therese Haugdhal Nøst
- Faculty of Health Sciences, Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Norway
| | - Liher Imaz
- Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, Donostia-San Sebastian, Spain
- Biodonostia Health Research Institute, Donostia-San Sebastian, Spain
| | - María Dolores Chirlaque-López
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain
| | | | - Rudolf Kaaks
- German Cancer Research Center (DKFZ), Heidelberg, Department of Cancer Epidemiology
- Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany
| | - Tilman Kühn
- German Cancer Research Center (DKFZ), Heidelberg, Department of Cancer Epidemiology
| | - Richard M. Martin
- Clinical Epidemiology & Public Health, University of Bristol, Bristol, United Kingdom
| | - James D. McKay
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Valeria Pala
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
| | - Hilary A. Robbins
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Torkjel M. Sandanger
- Faculty of Health Sciences, Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Norway
| | - David Schibli
- University of Victoria–Genome British Columbia Proteomics Centre, Victoria, BC, Canada/Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Matthias B. Schulze
- Nutrition, Immunity and Metabolism Senior Scientist Group, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
- University of Potsdam, Institute of Nutritional Science, Potsdam, Germany
| | - Ruth C. Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Elisabete Weiderpass
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Paul Brennan
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - J. Brent Richards
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada/Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
- Division of Endocrinology, Department of Medicine & Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Twin Research and Genetic Epidemiology, King's College London, Strand, London, United Kingdom
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23
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Miyamoto S, Ntege EH, Chinen Y, Goto T, Shirakawa J, Goto S, Kawano T, Shimizu Y, Nakanishi K, Nakamura H. An unusual case of oral surgical management in a patient with isovaleric acidemia and schizophrenia: A case report. Biomed Rep 2022; 17:64. [PMID: 35815189 PMCID: PMC9260163 DOI: 10.3892/br.2022.1547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/09/2022] [Indexed: 11/06/2022] Open
Abstract
Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. In addition to technical complications, different comorbidities also present a complex range of concerning factors/challenges, which can increase the incidence of morbidity and mortality associated with surgery. IVA, a congenital error of metabolism, is a rare organic acidemia with a predisposition towards acute acidosis and life-threatening metabolic decompensation during stressful conditions, such as prolonged fasting and surgery. In addition, schizophrenia, a major neurological disorder, can result in manifestation of severe dental or periodontal conditions, including pericoronitis. The condition is associated with significant risk factors of postoperative complications, such as dangerous behaviors and adverse interactions between antipsychotic drugs and anesthetic agents. A case of comorbid dental disease with two coexisting chronic and life-threatening medical conditions, one of which is rare, is an unusual encounter in oral/dental surgery that is seldomly published. Moreover, implementing a safe and effective surgical intervention in such patients requires several informed considerations. However, only a few reported experiences or guidelines exist, reporting appropriate perioperative management strategies to minimize risks. Hence, in this case report, our experience of managing one of these rare encounters of a 20-year-old man who suffered from bilaterally partially erupted third molars, associated with chronic pericoronitis and dental caries of both the maxilla wisdom teeth with coexisting IVA and schizophrenia comorbidities is described. Additionally, the presentation and anticipated complications of the comorbid disorders of the patient are briefly reviewed. In this case, the pericoronitis and dental caries were treated by surgically removing the impacted third molars and the antagonist maxilla wisdom teeth under regional anesthesia and application of antibiotics for 3 days. The patient recovered without any postoperative complications after 1 year of follow-up.
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Affiliation(s)
- Sho Miyamoto
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Edward Hose Ntege
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Yasutsugu Chinen
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Takahiro Goto
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Jumpei Shirakawa
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Shimpei Goto
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Toshihiro Kawano
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Yusuke Shimizu
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Koichi Nakanishi
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Hiroyuki Nakamura
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
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24
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Liu X, Liu X, Fan W, Zhang Z, Zhang P, Liu X, Lei M, Li Q, Yu X, Li D. Analysis of the genotype–phenotype correlation in isovaleric acidaemia: A case report of long-term follow-up of a chinese patient and literature review. Front Neurol 2022; 13:928334. [PMID: 35968299 PMCID: PMC9366085 DOI: 10.3389/fneur.2022.928334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/06/2022] [Indexed: 12/01/2022] Open
Abstract
Background Isovaleric acidaemia (IVA), characterized by an acute metabolic crisis and psychomotor delay, is a rare inherited metabolic disease caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD). Methods We report the case of a Chinese patient with IVA who was admitted to Tianjin Children's Hospital and followed up for 8 years. Genetic analysis of the patient and his parents was conducted using the whole-exome sequencing and Sanger sequencing. We searched for similar reported cases in the PubMed and Wanfang databases using the term “isovaleric acidaemia,” reviewed the related literature to obtain a summary of the clinical and genetic characteristics, and analyzed the genotype–phenotype correlations. Results The patient presented with encephalopathic symptoms, such as vomiting, lethargy, and somnolence. We identified compound heterozygous variants of the IVD gene, including the unreported variant c.224A>G (p.Asn75Ser) and the reported variant c.1195G>C (p.Asp399His). The child was prescribed a low-protein diet supplemented with L-carnitine. During the 8-year follow-up, no metabolic disorder or encephalopathic symptoms recurred. At present, the child is 11 years of age and has normal mental and motor performance. Another 154 cases identified in 25 relevant references were combined with this case, resulting in a sample of 155 patients, including 52 asymptomatic patients, 64 with neonatal onset, and 39 with the chronic intermittent disease with onset from ages of 1 month to 10 years (median age, 2 years). Among articles that reported sex, the male-to-female ratio was 1:1.06. The cardinal symptoms included vomiting, lethargy, “sweaty foot” odor, poor feeding, developmental delay, and epilepsy. The proportion of variants in regions 123–159 and 356–403 of the IVD protein was greater in symptomatic patients than in asymptomatic patients. Conversely, in asymptomatic patients, the proportion of variants in the 282–318 region was greater than in symptomatic patients. Conclusion This case report describes an unreported variant c.224A>G (p.Asn75Ser) of the IVD gene, and summarizes previously reported cases. Furthermore, the correlation between the genotype and clinical phenotype of IVA is analyzed to improve the understanding of this disease.
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Affiliation(s)
- Xingmiao Liu
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Xinquan Liu
- School of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin, China
| | - Wenxuan Fan
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Zhongbin Zhang
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Peiyuan Zhang
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Xiaojun Liu
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Meifang Lei
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Qing Li
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
| | - Xiaoli Yu
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
- Xiaoli Yu
| | - Dong Li
- Department of Pediatric Neurology, Tianjin Children's Hospital/Tianjin University Children's Hospital, Tianjin, China
- *Correspondence: Dong Li
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25
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Ding S, Liang L, Qiu W, Zhang H, Xiao B, Dong L, Ji W, Xu F, Gong Z, Gu X, Wang L, Han L. Prenatal Diagnosis of Isovaleric Acidemia From Amniotic Fluid Using Genetic and Biochemical Approaches. Front Genet 2022; 13:898860. [PMID: 35846131 PMCID: PMC9280075 DOI: 10.3389/fgene.2022.898860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and different approaches have been applied to its prenatal diagnosis. However, systemic application of a biochemical strategy is rare. To evaluate its reliability and validity, we conducted a retrospective study of our experience with metabolite measurement together with genetic analysis in IVA prenatal diagnosis at a single center. Methods: A total of eight pregnancies whose probands were diagnosed as IVA were referred to our center for prenatal diagnosis. Prenatal data of genetic analysis and metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) in amniotic fluid (AF) samples were retrospectively reviewed. Results: Genetic and biochemical results were both available in these eight at-risk fetuses. Among them, two fetuses had higher levels of isovalerylcarnitine (C5) and C5/acetylcarnitine (C2) in AF compared with normal reference range and, thus, were determined to be affected, both of whom were found to carry compound heterogeneous mutations according to genetic analysis. The remaining six fetuses were determined to be unaffected based on a normal AF metabolite profile, except one showed slightly elevated C5 and they were found to be carriers according to genetic analysis. However, the level of isovalerylglycine (IVG) could not be detected at all in both groups. Conclusion: The biochemical analysis, as a quick and convenient method, could be an additional reliable option for the prenatal diagnosis of IVA, especially in families with inconclusive genetic results, and can achieve a more precise diagnosis in conjunction with mutation analysis.
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Affiliation(s)
- Si Ding
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lili Liang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjuan Qiu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huiwen Zhang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Xiao
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liping Dong
- Neonatal Disease Screening Center, Zibo Maternal and Child Health Hospital, Zibo, China
| | - Wenjun Ji
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Xu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuwen Gong
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuefan Gu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Wang
- Center for Prenatal Diagnosis, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Lei Wang, ; Lianshu Han,
| | - Lianshu Han
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Lei Wang, ; Lianshu Han,
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26
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Kazlauskaite R, Cheaib B, Humble J, Heys C, Ijaz UZ, Connelly S, Sloan WT, Russell J, Martinez-Rubio L, Sweetman J, Kitts A, McGinnity P, Lyons P, Llewellyn MS. Deploying an In Vitro Gut Model to Assay the Impact of the Mannan-Oligosaccharide Prebiotic Bio-Mos on the Atlantic Salmon ( Salmo salar) Gut Microbiome. Microbiol Spectr 2022; 10:e0195321. [PMID: 35532227 PMCID: PMC9241627 DOI: 10.1128/spectrum.01953-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/09/2022] [Indexed: 11/20/2022] Open
Abstract
Alpha mannose-oligosaccharide (MOS) prebiotics are widely deployed in animal agriculture as immunomodulators as well as to enhance growth and gut health. Their mode of action is thought to be mediated through their impact on host microbial communities and their associated metabolism. Bio-Mos is a commercially available prebiotic currently used in the agri-feed industry, but studies show contrasting results of its effect on fish performance and feed efficiency. Thus, detailed studies are needed to investigate the effect of MOS supplements on the fish microbiome to enhance our understanding of the link between MOS and gut health. To assess Bio-Mos for potential use as a prebiotic growth promoter in salmonid aquaculture, we have modified an established Atlantic salmon in vitro gut model, SalmoSim, to evaluate its impact on the host microbial communities. The microbial communities obtained from ceca compartments from four adult farmed salmon were inoculated in biological triplicate reactors in SalmoSim. Prebiotic treatment was supplemented for 20 days, followed by a 6-day washout period. Inclusion of Bio-Mos in the media resulted in a significant increase in formate (P = 0.001), propionate (P = 0.037) and 3-methyl butanoic acid (P = 0.024) levels, correlated with increased abundances of several, principally, anaerobic microbial genera (Fusobacterium, Agarivorans, Pseudoalteromonas). DNA metabarcoding with the 16S rDNA marker confirmed a significant shift in microbial community composition in response to Bio-Mos supplementation with observed increase in lactic acid producing Carnobacterium. In conjunction with previous in vivo studies linking enhanced volatile fatty acid production alongside MOS supplementation to host growth and performance, our data suggest that Bio-Mos may be of value in salmonid production. Furthermore, our data highlights the potential role of in vitro gut models to complementin vivo trials of microbiome modulators. IMPORTANCE In this paper we report the results of the impact of a prebiotic (alpha-MOS supplementation) on microbial communities, using an in vitro simulator of the gut microbial environment of the Atlantic salmon. Our data suggest that Bio-Mos may be of value in salmonid production as it enhances volatile fatty acid production by the microbiota from salmon pyloric ceca and correlates with a significant shift in microbial community composition with observed increase in lactic acid producing Carnobacterium. In conjunction with previous in vivo studies linking enhanced volatile fatty acid production alongside MOS supplementation to host growth and performance, our data suggest that Bio-Mos may be of value in salmonid production. Furthermore, our data highlights the potential role of in vitro gut models to augment in vivo trials of microbiome modulators.
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Affiliation(s)
- Raminta Kazlauskaite
- Institute of Behaviour, Animal Health and Comparative Medicine, Graham Kerr Building, University of Glasgow, Glasgow, Scotland
| | - Bachar Cheaib
- Institute of Behaviour, Animal Health and Comparative Medicine, Graham Kerr Building, University of Glasgow, Glasgow, Scotland
| | - Joseph Humble
- Institute of Behaviour, Animal Health and Comparative Medicine, Graham Kerr Building, University of Glasgow, Glasgow, Scotland
| | - Chloe Heys
- Institute of Behaviour, Animal Health and Comparative Medicine, Graham Kerr Building, University of Glasgow, Glasgow, Scotland
| | | | | | | | - Julie Russell
- School of Engineering, University of Glasgow, Glasgow, Scotland
| | | | | | - Alex Kitts
- Institute of Behaviour, Animal Health and Comparative Medicine, Graham Kerr Building, University of Glasgow, Glasgow, Scotland
| | - Philip McGinnity
- School of Biological, Earth and Environmental Sciences, University College Cork, Cork, Ireland
- Marine Institute, Foras na Mara, Newport, Ireland
| | | | - Martin S. Llewellyn
- Institute of Behaviour, Animal Health and Comparative Medicine, Graham Kerr Building, University of Glasgow, Glasgow, Scotland
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A Simple Flow Injection Analysis-Tandem Mass Spectrometry Method to Reduce False Positives of C5-Acylcarnitines Due to Pivaloylcarnitine Using Reference Ions. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9050694. [PMID: 35626871 PMCID: PMC9139860 DOI: 10.3390/children9050694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/12/2022] [Accepted: 05/06/2022] [Indexed: 11/21/2022]
Abstract
Flow injection analysis−tandem mass spectrometry (FIA-TMS) has been applied in a first-tier test of newborn screening (NBS). Although isovalerylcarnitine (i-C5), which is a diagnostic indicator of isovaleric acidemia (IVA), is isobaric with pivaloylcarnitine (p-C5), 2-methylbutyrylcarnitine, and n-valerylcarnitine, these isomers cannot be distinguished by the FIA-TMS. There are many reports of false positives derived from p-C5 due to the use of pivalate-conjugated antibiotics. In this study, we developed a new FIA-TMS method to distinguish i-C5 and p-C5. We found that the intensity ratio of product ions for i-C5 and p-C5 was different in a certain range even under the same analytical conditions. The product ions with the most distinct differences in ionic intensity between the isomers and the collision energies that produce them were determined to be m/z 246.2 > 187.1 and −15 V, respectively. In addition to the quantification ion, a reference ion was defined, and the similarity of the i-C5 and p-C5 reference ion ratios (i-C5 score and p-C5 score, respectively) were used to estimate which isomer (i-C5 and p-C5) was responsible for elevated C5 acylcarnitine in dried blood spots (DBSs). As a result of analyses of 11 DBS samples derived from pivalate-conjugated antibiotics and four DBS samples from IVA patients using our method, it was found that our method was able to correctly determine the type of C5-acylcarnitine (i-C5 or p-C5) in the DBS samples. Implementation of this new FIA-TMS method into the current NBS protocol will allow for a reduction in false positives in IVA.
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28
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Spiekerkoetter U, Krude H. Target Diseases for Neonatal Screening in Germany. DEUTSCHES ARZTEBLATT INTERNATIONAL 2022; 119:306-316. [PMID: 35140012 PMCID: PMC9450505 DOI: 10.3238/arztebl.m2022.0075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/12/2021] [Accepted: 11/11/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Neonatal screening in Germany currently comprises 19 congenital diseases, 13 of which are metabolic diseases. Approximately one in 1300 newborns suffers from one of these target diseases. Early diagnosis and treatment enable the affected children to undergo better development and even, in many cases, to have a normal life. METHODS This review is based on pertinent publications retrieved by a selective search in the PubMed and Embase databases. RESULTS Positive screening findings are confirmed in approximately one out of five newborns. The prompt evaluation of suspected diagnoses is essential, as treatment for some of these diseases must be initiated immediately after birth to prevent longterm sequelae. The most commonly identified diseases are primary hypothyroidism (1:3338), phenylketonuria/hyperphenylalaninemia (1 : 5262), cystic fibrosis (1 : 5400), and medium-chain acyl-CoA dehydrogenase deficiency (1 : 10 086). Patient numbers are rising as new variants of the target diseases are being identified, and treatments must be adapted to their heterogeneous manifestations. Precise diagnosis and the planning of treatment, which is generally lifelong, are best carried out in a specialized center. CONCLUSION Improved diagnosis and treatment now prolong the lives of many patients with congenital diseases. The provision of appropriate long-term treatment extending into adulthood will be a central structural task for screening medicine in the future.
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Affiliation(s)
- Ute Spiekerkoetter
- General Pediatrics, Adolescent Medicine and Neonatology, University Medical Center, Medical Faculty, University of Freiburg
| | - Heiko Krude
- Institute of Experimental Pediatric Endocrinology, Charité—University Medical Center Berlin
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29
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Fully Automated Quantitative Measurement of Serum Organic Acids via LC-MS/MS for the Diagnosis of Organic Acidemias: Establishment of an Automation System and a Proof-of-Concept Validation. Diagnostics (Basel) 2021; 11:diagnostics11122195. [PMID: 34943431 PMCID: PMC8700112 DOI: 10.3390/diagnostics11122195] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 11/20/2022] Open
Abstract
Gas chromatography-mass spectrometry has been widely used to analyze hundreds of organic acids in urine to provide a diagnostic basis for organic acidemia. However, it is difficult to operate in clinical laboratories on a daily basis due to sample pretreatment processing. Therefore, we aimed to develop a fully automated system for quantifying serum organic acids using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pretreatment CLAM-2030 device was connected to an LC-MS/MS system for processing serum under optimized conditions, which included derivatizing serum organic acids using 3-Nitrophenylhydrazine. The derivatized organic acids were separated on a reverse-phase Sceptor HD-C column and detected using negative-ion electrospray ionization multiple reaction monitoring MS. The automated pretreatment-LC-MS/MS system processed serum in less than 1 h and analyzed 19 serum organic acids, which are used to detect organic acidemias. The system exhibited high quantitative sensitivity ranging from approximately 2 to 100 µM with a measurement reproducibility of 10.4% CV. Moreover, a proof-of-concept validation of the system was performed using sera from patients with propionic acidemia (n = 5), methylmalonic acidemia (n = 2), and 3-methylcrotonylglycinuria (n = 1). The levels of marker organic acids specific to each disease were significantly elevated in the sera of the patients compared to those in control samples. The automated pretreatment-LC-MS/MS system can be used as a rapid in-hospital system to measure organic acid levels in serum for the diagnosis of organic acidemias.
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30
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D'Annibale OM, Koppes EA, Alodaib AN, Kochersperger C, Karunanidhi A, Mohsen AW, Vockley J. Characterization of variants of uncertain significance in isovaleryl-CoA dehydrogenase identified through newborn screening: An approach for faster analysis. Mol Genet Metab 2021; 134:29-36. [PMID: 34535384 PMCID: PMC8578405 DOI: 10.1016/j.ymgme.2021.08.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Clinical standard of care for newborn screening (NBS) is acylcarnitine metabolites quantitation by tandem mass spectrometry (MS/MS) from dried blood spots. Follow up sequencing often results in identification of one or more variants of uncertain significance (VUS). Isovaleric acidemia (IVA) is an autosomal recessive inborn error of metabolism caused by deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the Leu catabolism pathway. Many IVD mutations are characterized as VUS complicating IVA clinical diagnoses and treatment. We present a testing platform approach to confirm the functional implication of VUS identified in newborns with IVA applicable to multiple inborn errors of metabolism identified by NBS. METHODS An IVD null HEK293T cell culture model was generated by using a dual sgRNA CRISPR/Cas9 genome-editing strategy targeting IVD exons 2-3. Clonal cell lines were confirmed by a combination of genomic breakpoint sequencing and droplet digital PCR. The IVD null model had no IVDH antigen signal and 96% reduction in IVDH enzyme activity. The IVD null model was transfected with vectors containing control or variant IVD and functional assays were performed to determine variant pathogenicity. RESULTS c.149G > C (p.Arg50Pro; precursor numbering), c.986T > C (p.Met329Thr), and c.1010G > A (p.Arg337Gln), c.1179del394 f. mutant proteins had reduced IVDH protein and activity. c.932C > T (p.Ala311Val), c.707C > T (p.Thr236Ile), and c.1232G > A (p.Arg411Gln) had stable IVDH protein, but no enzyme activity. c.521T > G (p.Val174Gly) had normal IVDH protein and activity. IVD variant transfection results confirmed results from IVA fibroblasts containing the same variants. CONCLUSIONS We have developed an IVD null HEK293T cell line to rapidly allow determination of VUS pathogenicity following identification of novel alleles by clinical sequencing following positive NBS results for suspected IVA. We suggest similar models can be generated via genome-editing for high throughput assessment of VUS function for a multitude of inborn errors of metabolism and can ideally supplement NBS programs.
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Affiliation(s)
- Olivia M D'Annibale
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA
| | - Erik A Koppes
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Ahmad N Alodaib
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Catherine Kochersperger
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Anuradha Karunanidhi
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Al-Walid Mohsen
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA
| | - Jerry Vockley
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
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31
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Tan J, Chen D, Chang R, Pan L, Yang J, Yuan D, Huang L, Yan T, Ning H, Wei J, Cai R. Tandem Mass Spectrometry Screening for Inborn Errors of Metabolism in Newborns and High-Risk Infants in Southern China: Disease Spectrum and Genetic Characteristics in a Chinese Population. Front Genet 2021; 12:631688. [PMID: 34394177 PMCID: PMC8355895 DOI: 10.3389/fgene.2021.631688] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 07/12/2021] [Indexed: 12/28/2022] Open
Abstract
Inborn errors of metabolism (IEMs) often causing progressive and irreversible neurological damage, physical and intellectual development lag or even death, and serious harm to the family and society. The screening of neonatal IEMs by tandem mass spectrometry (MS/MS) is an effective method for early diagnosis and presymptomatic treatment to prevent severe permanent sequelae and death. A total of 111,986 healthy newborns and 7,461 hospitalized high-risk infants were screened for IEMs using MS/MS to understand the characteristics of IEMs and related gene mutations in newborns and high-risk infants in Liuzhou. Positive samples were analyzed by Sanger sequencing or next-generation sequencing. The results showed that the incidence of IEMs in newborns in the Liuzhou area was 1/3,733, and the incidence of IEMs in high-risk infants was 1/393. Primary carnitine deficiency (1/9,332), phenylketonuria (1/18,664), and isovaleric acidemia (1/37,329) ranked the highest in neonates, while citrullinemia type II ranked the highest in high-risk infants (1/1,865). Further, 56 mutations of 17 IEMs-related genes were found in 49 diagnosed children. Among these, HPD c.941T > C, CBS c.1465C > T, ACADS c.337G > A, c.1195C > T, ETFA c.737G > T, MMACHC 1076bp deletion, PCCB c.132-134delGACinsAT, IVD c.548C > T, c.757A > G, GCDH c.1060G > T, and HMGCL c.501C > G were all unreported variants. Some related hotspot mutations were found, including SLC22A5 c.51C > G, PAH c.1223G > A, IVD c.1208A > G, ACADS c.625G > A, and GCDH c.532G > A. These results show that the overall incidence of IEMs in the Liuzhou area is high. Hence, the scope of IEMs screening and publicity and education should be expanded for a clear diagnosis in the early stage of the disease.
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Affiliation(s)
- Jianqiang Tan
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Dayu Chen
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Rongni Chang
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Lizhen Pan
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Jinling Yang
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Dejian Yuan
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Lihua Huang
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Tizhen Yan
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Haiping Ning
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Jiangyan Wei
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
| | - Ren Cai
- Key Laboratory of Prevention and Control of Birth Defects, Department of Medical Genetics, Newborn Screening Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou Institute for Reproduction and Genetics, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, China
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32
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Mütze U, Henze L, Gleich F, Lindner M, Grünert SC, Spiekerkoetter U, Santer R, Blessing H, Thimm E, Ensenauer R, Weigel J, Beblo S, Arélin M, Hennermann JB, Marquardt T, Marquardt I, Freisinger P, Krämer J, Dieckmann A, Weinhold N, Keller M, Walter M, Schiergens KA, Maier EM, Hoffmann GF, Garbade SF, Kölker S. Newborn screening and disease variants predict neurological outcome in isovaleric aciduria. J Inherit Metab Dis 2021; 44:857-870. [PMID: 33496032 DOI: 10.1002/jimd.12364] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/14/2021] [Accepted: 01/20/2021] [Indexed: 12/16/2022]
Abstract
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.
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Affiliation(s)
- Ulrike Mütze
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Lucy Henze
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Florian Gleich
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Lindner
- Division of Pediatric Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany
| | - Sarah C Grünert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - René Santer
- Department of Pediatrics, University Medical Centre Eppendorf, Hamburg, Germany
| | - Holger Blessing
- Kinder- und Jugendklinik, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Eva Thimm
- Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Regina Ensenauer
- Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Institute of Child Nutrition, Max-Rubner-Institut, Karlsruhe, Germany
| | - Johannes Weigel
- Praxis für Kinder- und Jugendmedizin, Endokrinologie und Stoffwechsel, Augsburg, Germany
| | - Skadi Beblo
- Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany
| | - Maria Arélin
- Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany
| | - Julia B Hennermann
- Villa Metabolica, Department for Pediatric and Adolescent Medicine, Mainz University Medical Center, Mainz, Germany
| | - Thorsten Marquardt
- Department of General Pediatrics, Metabolic Diseases, University Children's Hospital Muenster, Muenster, Germany
| | - Iris Marquardt
- Department of Child Neurology, Children's Hospital Oldenburg, Oldenburg, Germany
| | - Peter Freisinger
- Children's Hospital Reutlingen, Klinikum am Steinenberg, Reutlingen, Germany
| | - Johannes Krämer
- University of Ulm, Department of Pediatric and Adolescent Medicine, Ulm, Germany
| | - Andrea Dieckmann
- Center for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany
| | - Natalie Weinhold
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Chronically Sick Children, Berlin, Germany
| | - Mareike Keller
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Magdalena Walter
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Esther M Maier
- Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
| | - Georg F Hoffmann
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Sven F Garbade
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Kölker
- Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine and Dietmar Hopp Metabolic Center, University Hospital Heidelberg, Heidelberg, Germany
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Shepard BD. The Sniffing Kidney: Roles for Renal Olfactory Receptors in Health and Disease. KIDNEY360 2021; 2:1056-1062. [PMID: 35373087 PMCID: PMC8791376 DOI: 10.34067/kid.0000712021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/19/2021] [Indexed: 12/17/2022]
Abstract
AbstractOlfactory receptors (ORs) represent the largest gene family in the human genome. Despite their name, functions exist for these receptors outside of the nose. Among the tissues known to take advantage of OR signaling is the kidney. From mouse to man, the list of renal ORs continues to expand, and they have now been linked to a variety of processes involved in the maintenance of renal homeostasis, including the modulation of blood pressure, response to acidemia, and the development of diabetes. In this review, we highlight the recent progress made on the growing appreciation for renal ORs in physiology and pathophysiology.
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Ezhuthachan AS, Holman JLN. Case 3: What's That Smell? The Significance of Infant Body Odors in the Evaluation of Metabolic Acidosis. Neoreviews 2021; 22:e266-e268. [PMID: 33795403 DOI: 10.1542/neo.22-4-e266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Alok S Ezhuthachan
- Division of Neonatology, Department of Pediatrics, Lenox Hill Hospital, Northwell Health, New York, NY
| | - Jennifer L N Holman
- Division of Neonatology, Department of Pediatrics, Brenner Children's Hospital, Wake Forest Baptist Medical Center, Winston-Salem, NC
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Wu F, Fan SJ, Zhou XH. Neonatal isovaleric acidemia in China: A case report and review of literature. World J Clin Cases 2021; 9:436-444. [PMID: 33521113 PMCID: PMC7812894 DOI: 10.12998/wjcc.v9.i2.436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/07/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Isovaleric acidemia (IVA) is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD). Its morbidity is low, but mortality is high. There is no effective cure for this disease. Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality. Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease.
CASE SUMMARY A 12-day-old male neonate with “poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h” was hospitalized. The patient was the first child of nonconsanguineous ethnic Chinese parents. He was delivered by cesarean section due to breech position at 39 + 1 wk of gestation with a birth weight of 3.27 kg. Initially, he suffered from dyspnea and rhinobyon, and at 10 d after birth the patient suddenly developed poor feeding, low response, lethargy and seizures. Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine. The patient had an acute episode of IVA causing severe metabolic stress and eventually died.
CONCLUSION A new case of an IVA patient carrying c.1193G>A (p.Arg398Gln) and c.1208A>G (p.Try403Cys) mutations is reported in China.
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Affiliation(s)
- Fang Wu
- Department of Neonatalogy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Shu-Juan Fan
- Department of Neonatalogy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xi-Hui Zhou
- Department of Neonatalogy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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Leyrolle Q, Cserjesi R, Mulders MDGH, Zamariola G, Hiel S, Gianfrancesco MA, Rodriguez J, Portheault D, Amadieu C, Leclercq S, Bindels LB, Neyrinck AM, Cani PD, Karkkainen O, Hanhineva K, Lanthier N, Trefois P, Paquot N, Cnop M, Thissen JP, Klein O, Luminet O, Delzenne NM. Specific gut microbial, biological, and psychiatric profiling related to binge eating disorders: A cross-sectional study in obese patients. Clin Nutr 2020; 40:2035-2044. [PMID: 33023763 DOI: 10.1016/j.clnu.2020.09.025] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Binge eating disorder (BED) is a frequent eating disorder associated with obesity and co-morbidities including psychiatric pathologies, which represent a big health burden on the society. The biological processes related to BED remain unknown. Based on psychological testing, anthropometry, clinical biology, gut microbiota analysis and metabolomic assessment, we aimed to examine the complex biological and psychiatric profile of obese patients with and without BED. METHODS Psychological and biological characteristics (anthropometry, plasma biology, gut microbiota, blood pressure) of 101 obese subjects from the Food4Gut cohort were analysed to decipher the differences between BED and Non BED patients, classified based on the Questionnaire for Eating Disorder Diagnosis (Q-EDD). Microbial 16S rDNA sequencing and plasma non-targeted metabolomics (liquid chromatography-mass spectrometry) were performed in a subcohort of 91 and 39 patients respectively. RESULTS BED subjects exhibited an impaired affect balance, deficits in inhibition and self-regulation together with marked alterations of eating behaviour (increased emotional and external eating). BED subjects displayed a lower blood pressure and hip circumference. A decrease in Akkermansia and Intestimonas as well as an increase in Bifidobacterium and Anaerostipes characterized BED subjects. Interestingly, metabolomics analysis revealed that BED subjects displayed a higher level of one food contaminants, Bisphenol A bis(2,3-dihydroxypropyl) ether (BADGE.2H(2)O) and a food derived-metabolite the Isovalerylcarnitine. CONCLUSIONS Non-targeted omics approaches allow to select specific microbial genera and two plasma metabolites that characterize BED obese patients. Further studies are needed to confirm their potential role as drivers or biomarkers of binge eating disorder. Food4gut, clinicaltrial.gov:NCT03852069, https://clinicaltrials.gov/ct2/show/NCT03852069.
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Affiliation(s)
- Quentin Leyrolle
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Renata Cserjesi
- Center for Social and Cultural Psychology, Université libre de Bruxelles, Belgium
| | - Maria D G H Mulders
- Center for Social and Cultural Psychology, Université libre de Bruxelles, Belgium
| | - Giorgia Zamariola
- Research Institute for Psychological Sciences, UCLouvain, Louvain-La-Neuve, Belgium
| | - Sophie Hiel
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Marco A Gianfrancesco
- Laboratory of Immunometabolism and Nutrition, GIGA-Inflammation, Infection & Immunity, University of Liège, Liège, Belgium
| | - Julie Rodriguez
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Daphnée Portheault
- ULB Center for Diabetes Research, Université Libre de Bruxelles, and Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Camille Amadieu
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium; Institute of Neuroscience, UClouvain, Brussels, Belgium
| | - Sophie Leclercq
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium; Institute of Neuroscience, UClouvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium; WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, UCLouvain, Brussels, Belgium
| | - Olli Karkkainen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Kati Hanhineva
- Food Chemistry and Food Development Unit, Department of Biochemistry, University of Turku, Turku, Finland; Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Nicolas Lanthier
- Laboratory of Hepatogastroenterology, Institut de recherche expérimentale et Clinique, UCLouvain, Brussels, Belgium; Service d'Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Pierre Trefois
- Medical Imaging Department, Cliniques Universitaires St-Luc, Brussels, Belgium
| | - Nicolas Paquot
- Laboratory of Immunometabolism and Nutrition, GIGA-Inflammation, Infection & Immunity, University of Liège, Liège, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, and Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Paul Thissen
- Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, UCLouvain, Brussels, Belgium
| | - Olivier Klein
- Center for Social and Cultural Psychology, Université libre de Bruxelles, Belgium
| | - Olivier Luminet
- Research Institute for Psychological Sciences, UCLouvain, Louvain-La-Neuve, Belgium
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Brussels, Belgium.
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Long Term Follow-Up of Polish Patients with Isovaleric Aciduria. Clinical and Molecular Delineation of Isovaleric Aciduria. Diagnostics (Basel) 2020; 10:diagnostics10100738. [PMID: 32977617 PMCID: PMC7598207 DOI: 10.3390/diagnostics10100738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/19/2020] [Accepted: 09/21/2020] [Indexed: 11/16/2022] Open
Abstract
Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children's Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients' medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1-Q2) was 2.5 years (1.5-9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0-20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one-severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients.
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Huang Z, Pan Z, Yang R, Bi Y, Xiong X. The canine gastrointestinal microbiota: early studies and research frontiers. Gut Microbes 2020; 11:635-654. [PMID: 31992112 PMCID: PMC7524387 DOI: 10.1080/19490976.2019.1704142] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The canine gut microbiota is a complex microbial population that is potentially related to metabolism, immunologic activity and gastrointestinal (GI) diseases. Early studies revealed that the canine gut microbiota was dynamic, and bacterial populations in the adjacent gut segments were similar, with anaerobes predominating. Metagenomics analysis revealed that nutrient contents in the diet modulated bacterial populations and metabolites in the canine gut. Further research revealed significant correlations between dietary factors and canine gut core microbiomes. Canine GI diseases are closely correlated with gut microbiota dysbiosis and metabolic disorders. Probiotic-related therapies can effectively treat canine GI diseases. Recent studies have revealed that the canine gut microbiota is similar to the human gut microbiota, and dietary factors affect both. Studying canine intestinal microorganisms enables clarifying changes in the canine intestinal bacteria under different conditions, simulating human diseases in dog models, and conducting in-depth studies of the interactions between intestinal bacteria and disease.
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Affiliation(s)
- Zongyu Huang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, China,State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Zhiyuan Pan
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Ruifu Yang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Yujing Bi
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China,CONTACT Yujing Bi State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Xiaohui Xiong
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, China,Xiaohui Xiong Nanjing Tech University, Nanjing, China
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Lin Y, Chen D, Peng W, Wang K, Lin W, Zhuang J, Zheng Z, Li M, Fu Q. Newborn screening for isovaleric acidemia in Quanzhou, China. Clin Chim Acta 2020; 509:25-29. [PMID: 32505769 DOI: 10.1016/j.cca.2020.06.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/05/2020] [Accepted: 06/03/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND Isovaleric acidemia (IVA) is a rare autosomal recessive disorder of leucine metabolism caused by a defective isovaleryl-CoA dehydrogenase (IVD) gene. Reports of IVA diagnoses following newborn screening (NBS) in the Chinese population are few. METHODS We investigated the biochemical, clinical, and molecular profiles of 5 patients with IVA in China. The estimated incidence of IVA in Quanzhou, China is 1 in 1:84,469. RESULTS Initial NBS revealed mild to markedly increased isovalerylcarnitine (C5) concentrations in all 5 patients, and differential diagnosis revealed increased urinary isovaleryglycine concentrations in 2 patients. One patient presented with acute neonatal symptoms, whereas the other 4 remained asymptomatic. Eight distinct IVD gene variants were identified. The most common variant was c.1208A > G (p.Y403C), with an allele frequency of 30%. Five variants were previously unreported, namely, c.499A > G (p.M167V), c.640A > G (p.T214A), c.740G > A (p.G247E), c.832G > C (p.V278L), and c.1195G > C (p.D399H). Different in silico prediction analyses suggested that these previously unreported missense variants are pathogenic. Protein modelling analyses also showed that these missense variants may cause structural damage and dysfunction in IVD. CONCLUSIONS Patients with IVA may have C5 concentrations approaching the cut-off values, highlighting the need for stringent recall criteria and second-tier tests to improve screening performance.
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Affiliation(s)
- Yiming Lin
- Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China
| | - Dongmei Chen
- Department of Neonatal Intensive Care Unit, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China
| | - Weilin Peng
- Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China
| | - Kunyi Wang
- Integrated Technical Service Center, Quanzhou Customs, Quanzhou, Fujian Province 362000, China
| | - Weihua Lin
- Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China
| | - Jianlong Zhuang
- Prenatal Diagnosis Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China
| | - Zhenzhu Zheng
- Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China
| | - Min Li
- Hangzhou Genuine Clinical Laboratory Co. Ltd, Hangzhou, Zhejiang Province 310007, China.
| | - Qingliu Fu
- Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China.
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Dobrowolski SF, Alodaib A, Karunanidhi A, Basu S, Holecko M, Lichter-Konecki U, Pappan KL, Vockley J. Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case. Mol Genet Metab 2020; 129:272-277. [PMID: 32151545 DOI: 10.1016/j.ymgme.2020.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/15/2022]
Abstract
Methylmalonate semialdehyde dehydrogenase deficiency (MMSDD; MIM 614105) is a rare autosomal recessive defect of valine and pyrimidine catabolism. Four prior MMSDD cases are published. We present a fifth case, along with functional and metabolomic analysis. The patient, born to non-consanguineous parents of East African origin, was admitted at two weeks of age for failure to thrive. She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia. Gastroesophageal reflux occurred with feeding. Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate, while urine amino acid analysis identified elevated concentrations of β-aminoisobutyrate and β-alanine. Plasma amino acids showed an elevated concentration of β-aminoisobutyrate with undetectable β-alanine. ALDH6A1 gene sequencing identified a homozygous variant of uncertain significance, c.1261C > T (p.Pro421Ser). Management with valine restriction led to reduced concentration of abnormal analytes in blood and urine, improved growth, and reduced gastroesophageal reflux. Western blotting of patient fibroblast extracts demonstrated a large reduction of methylmalonate semialdehyde dehydrogenase (MMSD) protein. Patient cells displayed compromised mitochondrial function with increased superoxide production, reduced oxygen consumption, and reduced ATP production. Metabolomic profiles from patient fibroblasts demonstrated over-representation of fatty acids and fatty acylcarnitines, presumably due to methylmalonate semialdehyde shunting to β-alanine and subsequently to malonyl-CoA with ensuing increase of fatty acid synthesis. Previously reported cases of MMSDD have shown variable clinical presentation. Our case continues the trend as clinical phenotypes diverge from prior cases. Recognition of mitochondrial dysfunction and novel metabolites in this patient provide the opportunity to assess future patients for secondary changes that may influence clinical outcome.
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Affiliation(s)
- Steven F Dobrowolski
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Ahmad Alodaib
- Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Anuradha Karunanidhi
- Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Shrabini Basu
- Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Meghan Holecko
- Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Uta Lichter-Konecki
- Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | | | - Jerry Vockley
- Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
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Ibarra-González I, Fernández-Lainez C, Guillén-López S, López-Mejía L, Belmont-Matínez L, Sokolsky TD, Amin VR, Kitchener RL, Vela-Amieva M, Naylor EW, Bhattacharjee A. Molecular analysis using targeted next generation DNA sequencing and clinical spectrum of Mexican patients with isovaleric acidemia. Clin Chim Acta 2020; 501:216-221. [DOI: 10.1016/j.cca.2019.10.041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 10/07/2019] [Accepted: 10/28/2019] [Indexed: 10/25/2022]
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De Biase I, Pasquali M, Asamoah A. Unusual Metabolites in a Patient with Isovaleric Acidemia. Clin Chem 2020; 65:595-597. [PMID: 30923063 DOI: 10.1373/clinchem.2018.300558] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 01/22/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Irene De Biase
- Department of Pathology, University of Utah, Salt Lake City, UT; .,ARUP Laboratories, Salt Lake City, UT
| | - Marzia Pasquali
- Department of Pathology, University of Utah, Salt Lake City, UT.,ARUP Laboratories, Salt Lake City, UT.,Department of Pediatrics, University of Utah, Salt Lake City, UT
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Peripheral biomarkers allow differential diagnosis between schizophrenia and bipolar disorder. J Psychiatr Res 2019; 119:67-75. [PMID: 31568986 DOI: 10.1016/j.jpsychires.2019.09.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/02/2019] [Accepted: 09/19/2019] [Indexed: 01/03/2023]
Abstract
Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders that pose important challenges for diagnosis by sharing common symptoms, such as delusions and hallucinations. The underlying pathophysiology of both disorders remains largely unknown, and the identification of biomarkers with potential to support diagnosis is highly desirable. In a previous study, we successfully discriminated SCZ and BD patients from healthy control (HC) individuals by employing proton magnetic resonance spectroscopy (1H-NMR). In this study, 1H-NMR data treated by chemometrics, principal component analysis (PCA) and supervised partial least-squares discriminant analysis (PLS-DA), provided the identification of metabolites present only in BD (as for instance the 2,3-diphospho-D-glyceric acid, N-acetyl aspartyl-glutamic acid, monoethyl malonate) or only in SCZ (as isovaleryl carnitine, pantothenate, mannitol, glycine, GABA). This may represent a set of potential biomarkers to support the diagnosis of these mental disorders, enabling the discrimination between SCZ and BD, and among these psychiatric patients and HC (as 6-hydroxydopamine was present in BD and SCZ but not in HC). The presence or absence of these metabolites in blood allowed the categorization of 182 independent subjects into one of these three groups. In addition, the presented data suggest disturbances in metabolic pathways in SCZ and BD, which may provide new and important information to support the elucidation and/or new insights into the neurobiology underlying these mental disorders.
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Li Y, Shen M, Jin Y, Liu Y, Kang L, He R, Song J, Luo L, Yang Y. Eight novel mutations detected from eight Chinese patients with isovaleric acidemia. Clin Chim Acta 2019; 498:116-121. [DOI: 10.1016/j.cca.2019.08.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 08/03/2019] [Accepted: 08/20/2019] [Indexed: 12/23/2022]
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McCalley S, Pirman D, Clasquin M, Johnson K, Jin S, Vockley J. Metabolic analysis reveals evidence for branched chain amino acid catabolism crosstalk and the potential for improved treatment of organic acidurias. Mol Genet Metab 2019; 128:57-61. [PMID: 31133529 PMCID: PMC6864255 DOI: 10.1016/j.ymgme.2019.05.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/14/2019] [Accepted: 05/17/2019] [Indexed: 01/07/2023]
Abstract
Branched chain amino acid (BCAA) metabolism occurs within the mitochondrial matrix and is comprised of multiple enzymes, some shared, organized into three pathways for the catabolism of leucine, isoleucine, and valine (LEU, ILE, and VAL respectively). Three different acyl-CoA dehydrogenases (ACADs) are active in each catabolic pathway and genetic deficiencies in each have been identified. While characteristic metabolites related to the enzymatic block accumulate in each deficiency, for reasons that are not clear, clinical symptoms are only seen in the context of deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the leucine pathway. Metabolism of fibroblasts derived from patients with mutations in each of the BCAA ACADs were characterized using metabolomics to better understand the flux of BCAA through their respective pathways. Stable isotope labeled LEU, ILE, and VAL in patient and control cell lines revealed that mutations in isobutyryl-CoA dehydrogenase (IBDH in the valine pathway) lead to a significant increase in isobutyrylcarnitine (a surrogate for the enzyme substrate isobutyryl-CoA) leading to metabolism by short-branched chain acyl-CoA dehydrogenase (SBCADH in the isoleucine pathway) and production of the pathway end product propionylcarnitine (a surrogate for propionyl-CoA). Similar cross activity was observed for SBCADH deficient patient cells, leading to a significant increase in propionylcarnitine, presumably by metabolism of 2 methylbutyryl-CoA via IBDH activity. Labeled BCAA studies identified that the majority of the intracellular propionyl-CoA pool in fibroblasts is generated from isoleucine, but heptanoic acid (a surrogate for odd-chain fatty acids) is also efficiently converted to propionate.
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Affiliation(s)
- Stephen McCalley
- University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - David Pirman
- Agios Pharmaceuticals, 88 Sydney St, Cambridge, MA 02139, USA
| | | | - Kendall Johnson
- Agios Pharmaceuticals, 88 Sydney St, Cambridge, MA 02139, USA
| | - Shengfang Jin
- Agios Pharmaceuticals, 88 Sydney St, Cambridge, MA 02139, USA
| | - Jerry Vockley
- University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA.
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Yang H, Zhao C, Tang MC, Wang Y, Wang SP, Allard P, Furtos A, Mitchell GA. Inborn errors of mitochondrial acyl-coenzyme a metabolism: acyl-CoA biology meets the clinic. Mol Genet Metab 2019; 128:30-44. [PMID: 31186158 DOI: 10.1016/j.ymgme.2019.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 03/30/2019] [Accepted: 05/05/2019] [Indexed: 12/18/2022]
Abstract
The last decade saw major advances in understanding the metabolism of Coenzyme A (CoA) thioesters (acyl-CoAs) and related inborn errors (CoA metabolic diseases, CAMDs). For diagnosis, acylcarnitines and organic acids, both derived from acyl-CoAs, are excellent markers of most CAMDs. Clinically, each CAMD is unique but strikingly, three main patterns emerge: first, systemic decompensations with combinations of acidosis, ketosis, hypoglycemia, hyperammonemia and fatty liver; second, neurological episodes, particularly acute "stroke-like" episodes, often involving the basal ganglia but sometimes cerebral cortex, brainstem or optic nerves and third, especially in CAMDs of long chain fatty acyl-CoA metabolism, lipid myopathy, cardiomyopathy and arrhythmia. Some patients develop signs from more than one category. The pathophysiology of CAMDs is not precisely understood. Available data suggest that signs may result from CoA sequestration, toxicity and redistribution (CASTOR) in the mitochondrial matrix has been suggested to play a role. This predicts that most CAMDs cause deficiency of CoA, limiting mitochondrial energy production, and that toxic effects from the abnormal accumulation of acyl-CoAs and from extramitochondrial functions of acetyl-CoA may also contribute. Recent progress includes the following. (1) Direct measurements of tissue acyl-CoAs in mammalian models of CAMDs have been related to clinical features. (2) Inborn errors of CoA biosynthesis were shown to cause clinical changes similar to those of inborn errors of acyl-CoA degradation. (3) CoA levels in cells can be influenced pharmacologically. (4) Roles for acetyl-CoA are increasingly identified in all cell compartments. (5) Nonenzymatic acyl-CoA-mediated acylation of intracellular proteins occurs in mammalian tissues and is increased in CAMDs.
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Affiliation(s)
- Hao Yang
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada
| | - Chen Zhao
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada; College of Animal Science and Technology, Northwest A&F University, China
| | | | - Youlin Wang
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada
| | - Shu Pei Wang
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada
| | - Pierre Allard
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada
| | | | - Grant A Mitchell
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Canada.
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Erban T, Sopko B, Kadlikova K, Talacko P, Harant K. Varroa destructor parasitism has a greater effect on proteome changes than the deformed wing virus and activates TGF-β signaling pathways. Sci Rep 2019; 9:9400. [PMID: 31253851 PMCID: PMC6599063 DOI: 10.1038/s41598-019-45764-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 06/10/2019] [Indexed: 02/07/2023] Open
Abstract
Honeybee workers undergo metamorphosis in capped cells for approximately 13 days before adult emergence. During the same period, Varroa mites prick the defenseless host many times. We sought to identify proteome differences between emerging Varroa-parasitized and parasite-free honeybees showing the presence or absence of clinical signs of deformed wing virus (DWV) in the capped cells. A label-free proteomic analysis utilizing nanoLC coupled with an Orbitrap Fusion Tribrid mass spectrometer provided a quantitative comparison of 2316 protein hits. Redundancy analysis (RDA) showed that the combination of Varroa parasitism and DWV clinical signs caused proteome changes that occurred in the same direction as those of Varroa alone and were approximately two-fold higher. Furthermore, proteome changes associated with DWV signs alone were positioned above Varroa in the RDA. Multiple markers indicate that Varroa activates TGF-β-induced pathways to suppress wound healing and the immune response and that the collective action of stressors intensifies these effects. Furthermore, we indicate JAK/STAT hyperactivation, p53-BCL-6 feedback loop disruption, Wnt pathway activation, Wnt/Hippo crosstalk disruption, and NF-κB and JAK/STAT signaling conflict in the Varroa–honeybee–DWV interaction. These results illustrate the higher effect of Varroa than of DWV at the time of emergence. Markers for future research are provided.
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Affiliation(s)
- Tomas Erban
- Crop Research Institute, Drnovska 507/73, Prague 6-Ruzyne, CZ-161 06, Czechia.
| | - Bruno Sopko
- Crop Research Institute, Drnovska 507/73, Prague 6-Ruzyne, CZ-161 06, Czechia
| | - Klara Kadlikova
- Crop Research Institute, Drnovska 507/73, Prague 6-Ruzyne, CZ-161 06, Czechia.,Department of Plant Protection, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Prague 6-Suchdol, CZ-165 00, Czechia
| | - Pavel Talacko
- Proteomics Core Facility, Faculty of Science, Charles University, BIOCEV, Prumyslova 595, Vestec, CZ-25242, Czechia
| | - Karel Harant
- Proteomics Core Facility, Faculty of Science, Charles University, BIOCEV, Prumyslova 595, Vestec, CZ-25242, Czechia
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Sarker SK, Islam MT, Hasib SH, Sultana N, Hossain SR, Biswas A, Sultana R, Bhuyan GS, Begum MN, Konica FA, Qadri SK, Qadri SS, Saha N, Qadri F, Mannoor K. A novel missense mutation of Isovaleryl-CoA dehydrogenase gene associated with chronic intermittent Isovaleric acidemia in a Bangladeshi patient. Meta Gene 2019. [DOI: 10.1016/j.mgene.2019.100557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway. Dig Dis Sci 2019; 64:1171-1181. [PMID: 30560338 PMCID: PMC6499669 DOI: 10.1007/s10620-018-5417-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 12/06/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Isovaleric acid (IVA) is a 5-carbon branched-chain fatty acid present in fermented foods and produced in the colon by bacterial fermentation of leucine. We previously reported that the shorter, straight-chain fatty acids acetate, propionate and butyrate differentially affect colonic motility; however, the effect of branched-chain fatty acids on gut smooth muscle and motility is unknown. AIMS To determine the effect of IVA on contractility of colonic smooth muscle. METHODS Murine colonic segments were placed in a longitudinal orientation in organ baths in Krebs buffer and fastened to force transducers. Segments were contracted with acetylcholine (ACh), and the effects of IVA on ACh-induced contraction were measured in the absence and presence of tetrodotoxin (TTx) or inhibitors of nitric oxide synthase [L-N-nitroarginine (L-NNA)] or adenylate cyclase (SQ22536). The effect of IVA on ACh-induced contraction was also measured in isolated muscle cells in the presence or absence of SQ22536 or protein kinase A (PKA) inhibitor (H-89). Direct activation of PKA was measured in isolated muscle cells. RESULTS In colonic segments, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion; the IVA response was not affected by TTx or L-NNA but inhibited by SQ22536. Similarly, in isolated colonic muscle cells, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion and the effect blocked by SQ22536 and H-89. IVA also increased PKA activity in isolated smooth muscle cells. CONCLUSIONS The branched-chain fatty acid IVA acts directly on colonic smooth muscle and causes muscle relaxation via the PKA pathway.
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