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1
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Pan X, Yuan Y, Wu B, Zheng W, Tian M. Lipid-storage myopathy with glycogen storage disease gene mutations mimicking polymyositis: a case report and review of the literature. J Int Med Res 2022; 50:3000605221084873. [PMID: 35296144 PMCID: PMC8943314 DOI: 10.1177/03000605221084873] [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] [Indexed: 11/17/2022] Open
Abstract
A 26-year-old Asian woman with persistent muscle weakness was diagnosed with polymyositis based on biopsy findings at another hospital 11 years ago. However, her symptoms fluctuated repeatedly under treatment with prednisone and immunosuppressive agents, and worsened 2 months prior to the current presentation. A second muscle biopsy suggested metabolic myopathy, and genetic testing revealed a novel c.1074C > T variant in the glycogen synthase 1 gene (GYS1), which is implicated in muscle glycogen storage disease type 0. However, no abnormalities in glycogen deposition were found by biopsy; rather, muscle fibers exhibited large intracellular lipid droplets. Furthermore, muscle strength was greatly restored and circulating levels of creatine kinase indicative of muscle degeneration greatly reduced by vitamin B2 treatment. Therefore, the final diagnosis was lipid storage myopathy.
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Affiliation(s)
- Xiaoli Pan
- Department of Rheumatology and Immunology, 159358Affiliated Hospital of Zunyi Medical University, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P. R. China
| | - Yuan Yuan
- School of Foreign Languages of Zunyi Medical University, Zunyi, Guizhou 563003, P. R. China
| | - Bangcui Wu
- Department of Rheumatology and Immunology, 159358Affiliated Hospital of Zunyi Medical University, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P. R. China
| | - Wendan Zheng
- Department of Rheumatology and Immunology, 159358Affiliated Hospital of Zunyi Medical University, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P. R. China
| | - Mei Tian
- Department of Rheumatology and Immunology, 159358Affiliated Hospital of Zunyi Medical University, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P. R. China
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2
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Tang Z, Gao S, He M, Chen Q, Fang J, Luo Y, Yan W, Shi X, Huang H, Tang J. Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series. Front Neurol 2021; 12:747360. [PMID: 34819910 PMCID: PMC8606537 DOI: 10.3389/fneur.2021.747360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/05/2021] [Indexed: 01/24/2023] Open
Abstract
Background: Late-onset multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive genetic disease caused by ETFDH mutations that result in defects in ETF-ubiquinone oxidoreductase. Almost all patients are responsive to riboflavin. This study describes the clinical presentations and genetic characteristics of five LO-MADD patients. Methods: From 2018 to 2021, we collected clinical and genetic data on five patients diagnosed with LO-MADD at our hospital and retrospectively analyzed their clinical characteristics, laboratory examination, electromyography, muscle biopsy, genetic analysis, and outcome data. Results: This study included three males and two females with mean onset age of 37.8 years. Fluctuating exercise intolerance was the most common presentation. Serum creatine kinase (CK) levels were significantly elevated in all patients, and plasma acylcarnitine profiles revealed an increase in long-chain acylcarnitine species in three cases. The urinary organic acid study revealed a high level of hydroxyglutaric acid in all patients. Electrophysiology demonstrated myogenic impairment. Muscle biopsies revealed lipid storage myopathy. Molecular analysis identified nine mutations (three novels and six reported) in ETFDH. Exercise intolerance and muscle weakness were dramatically improved in all patients treated with riboflavin (100 mg) daily following diagnosis. Conclusions: LO-MADD is caused by ETFDH variants and responds well to riboflavin. Three novel ETFDH pathogenic variants were identified, expanding their spectrum in the Chinese population and facilitating future interpretation and analysis of ETFDH mutations.
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Affiliation(s)
- Zhenchu Tang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Shan Gao
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Miao He
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Qihua Chen
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jia Fang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yingying Luo
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Weiqian Yan
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoliu Shi
- Department of Medical Genetics, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hui Huang
- Department of Medical Genetics, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianguang Tang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
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3
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Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency. Genes (Basel) 2021; 12:genes12050703. [PMID: 34066864 PMCID: PMC8150808 DOI: 10.3390/genes12050703] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 04/29/2021] [Accepted: 05/05/2021] [Indexed: 12/20/2022] Open
Abstract
Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of ETFDH and PHGDH genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the ETFDH gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the PHGDH gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation.
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Tandon K, Tandon R, Patel M, Parikh C, Upadhyay H. Glutaric Aciduria Type II With Ketosis in a Male Infant. Cureus 2021; 13:e14407. [PMID: 33987057 PMCID: PMC8110299 DOI: 10.7759/cureus.14407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Glutaric aciduria type II (GA II) also known as multiple acyl-CoA dehydrogenase deficiency is an inborn metabolic disorder belonging to the family of organic acidurias. It is a disorder that interferes with the body's ability to break down proteins and fats to produce energy. Tandem mass spectrometry (TMS) acts as a screening tool, while the diagnosis of GA-II with ketosis is confirmed by a combination of tests like organic acids, quantitative random urine, and a full urine panel. Early diagnosis, compliance to specialized diet, affordability, and regular follow-ups are required to tackle this potentially life-threatening condition. Herein, we report a case of glutaric aciduria type-II with ketosis in a 4.5 months old male infant who was managed with a low-protein diet, which was free of tryptophan, lysine, and other specific dietary supplements.
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Affiliation(s)
| | - Rahul Tandon
- Pediatrics, Pramukhswami Medical College, Anand, IND
| | - Meet Patel
- Pediatrics, Pramukhswami Medical College, Anand, IND
| | - Charmy Parikh
- Pediatrics, Pramukhswami Medical College, Anand, IND
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Missaglia S, Tavian D, Angelini C. ETF dehydrogenase advances in molecular genetics and impact on treatment. Crit Rev Biochem Mol Biol 2021; 56:360-372. [PMID: 33823724 DOI: 10.1080/10409238.2021.1908952] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Electron transfer flavoprotein dehydrogenase, also called ETF-ubiquinone oxidoreductase (ETF-QO), is a protein localized in the inner membrane of mitochondria, playing a central role in the electron-transfer system. Indeed, ETF-QO mediates electron transport from flavoprotein dehydrogenases to the ubiquinone pool. ETF-QO mutations are often associated with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD, OMIM#231680), a multisystem genetic disease characterized by various clinical manifestations with different degrees of severity. In this review, we outline the clinical features correlated with ETF-QO deficiency and the benefits obtained from different treatments, such as riboflavin, L-carnitine and/or coenzyme Q10 supplementation, and a diet poor in fat and protein. Moreover, we provide a detailed summary of molecular and bioinformatic investigations, describing the mutations identified in ETFDH gene and highlighting their predicted impact on enzymatic structure and activity. In addition, we report biochemical and functional analysis, performed in HEK293 cells and patient fibroblasts and muscle cells, to show the relationship between the nature of ETFDH mutations, the variable impairment of enzyme function, and the different degrees of RR-MADD severity. Finally, we describe in detail 5 RR-MADD patients carrying different ETFDH mutations and presenting variable degrees of clinical symptom severity.
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Affiliation(s)
- Sara Missaglia
- Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Università Cattolica del Sacro Cuore, Milan, Italy.,Psychology Department, Università Cattolica del Sacro Cuore, Milan, Italy
| | - Daniela Tavian
- Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Università Cattolica del Sacro Cuore, Milan, Italy.,Psychology Department, Università Cattolica del Sacro Cuore, Milan, Italy
| | - Corrado Angelini
- Neuromuscular Laboratory, Department of Neurosciences, University of Padova, Padova, Italy
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6
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Ding M, Liu R, Qiubo L, Zhang Y, Kong Q. Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD) in the ETFDH gene: A case report and a literature review. Medicine (Baltimore) 2020; 99:e21944. [PMID: 32925727 PMCID: PMC7489629 DOI: 10.1097/md.0000000000021944] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
RATIONALE Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid, amino acid, and choline metabolism. The clinical manifestation of MADD is heterogeneous, from severe neonatal forms to mild late-onset forms. PATIENT CONCERNS Here, we report a patient who presented with severe hypoglycemia and exercise intolerance suggestive of MADD. Serum tandem mass spectrometry analysis indicated elevated levels of various acyl carnitines at 25 days of age. Exome sequencing of the proband revealed compound heterozygous mutations, c. 413T>G (p.Leu138Arg) and c.1667C > G (p.Pro556Arg), in the ETFDH gene as the probable causative mutations. DIAGNOSES Based on the patient's clinical presentation and test results, the patient was diagnosed with MADD. INTERVENTIONS A high-calorie and reduced-fat diet was given together with oral supplements of L-carnitine (150 mg/day). OUTCOMES He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness. LESSONS He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD and may not only prevent the need for invasive testing but also allow for timely initiation of treatment.
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Affiliation(s)
| | - Ruihua Liu
- Department of Pediatric, Affiliated Hospital of Jining Medical University
| | - Li Qiubo
- Department of Pediatric, Affiliated Hospital of Jining Medical University
| | - Yanke Zhang
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, P.R. China
| | - Qingxia Kong
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, P.R. China
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7
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Ou M, Zhu L, Zhang Y, Zhang Y, Zhou J, Zhang Y, Chen X, Yang L, Li T, Su X, Hu Q, Wang W. A novel electron transfer flavoprotein dehydrogenase (ETFDH) gene mutation identified in a newborn with glutaric acidemia type II: a case report of a Chinese family. BMC MEDICAL GENETICS 2020; 21:98. [PMID: 32393189 PMCID: PMC7212588 DOI: 10.1186/s12881-020-00995-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 03/10/2020] [Indexed: 12/04/2022]
Abstract
Background Glutaric acidemia type II (GA II) or multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) is an inherited autosomal recessive disease affecting fatty acid, amino acid and choline metabolism, due to mutations in one of three genes namely, electron transfer flavoprotein alpha-subunit, ETFA, electron transfer flavoprotein β-subunit, ETFB and electron transfer flavoprotein dehydrogenase, ETFDH. Currently, few studies have reported genetic profiling of neonatal-onset GA II. This study aimed to identify the genetic mutations in a Chinese family with GA II. Case presentation We reported a case of GA II with purulent meningitis and septicemia and identified a novel ETFDH gene mutation in a female infant. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acylcarnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two mutations in the ETFDH gene (c.623_626 del / c. 1399G > C), which were considered to be the etiology for the disease. The novel mutation c.623_626 del was identified in the proband infant and her father, her mother was carriers of the mutation c.1399G > C. Conclusions A novel variant (c.623_626 del) and a previously reported missense (c.1399G > C) in the ETFDH gene have been identified in the family. The two variants of ETFDH gene identified probably underlie the pathogenesis of Glutaric acidemia type II in this family, and also enlarge ETFDH genotype-phenotype correlations spectrum.
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Affiliation(s)
- Mingcai Ou
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Lin Zhu
- Hangzhou Genuine Clinical Laboratory Co. Ltd, 859 Shixiang West Road, Hangzhou, 310007, Zhejiang Province, China
| | - Yong Zhang
- Neonatal unit, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Yaguo Zhang
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Jingyao Zhou
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Yu Zhang
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Xuelian Chen
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Lijuan Yang
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Ting Li
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Xingyue Su
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China
| | - Qi Hu
- Department of Neonatal screen, Sichuan Provincial Hospital for Women and Children, Chengdu, 610000, Sichuan Province, China.
| | - Wenjun Wang
- Hangzhou Genuine Clinical Laboratory Co. Ltd, 859 Shixiang West Road, Hangzhou, 310007, Zhejiang Province, China.
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8
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Lucas TG, Henriques BJ, Gomes CM. Conformational analysis of the riboflavin-responsive ETF:QO-p.Pro456Leu variant associated with mild multiple acyl-CoA dehydrogenase deficiency. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140393. [PMID: 32087359 DOI: 10.1016/j.bbapap.2020.140393] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 02/09/2020] [Accepted: 02/17/2020] [Indexed: 01/07/2023]
Abstract
Multiple-CoA dehydrogenase deficiency (MADD) is an inborn disorder of fatty acid and amino acid metabolism caused by mutations in the genes encoding for human electron transfer flavoprotein (ETF) and its partner electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO). Albeit a rare disease, extensive newborn screening programs contributed to a wider coverage of MADD genotypes. However, the impact of non-lethal mutations on ETF:QO function remains scarcely understood from a structural perspective. To this end, we here revisit the relatively common MADD mutation ETF:QO-p.Pro456Leu, in order to clarify how it affects enzyme structure and folding. Given the limitation in recombinant expression of human ETF:QO, we resort to its bacterial homologue from Rhodobacter sphaeroides (Rs), in which the corresponding mutation (p.Pro389Leu) was inserted. The in vitro biochemical and biophysical investigations of the Rs ETF:QO-p.Pro389Leu variant showed that, while the mutation does not significantly affect the protein α/β fold, it introduces some plasticity on the tertiary structure and within flavin interactions. Indeed, in the p.Pro389Leu variant, FAD exhibits a higher thermolability during thermal denaturation and a faster rate of release in temperature-induced dissociation experiments, in comparison to the wild type. Therefore, although this clinical mutation occurs in the ubiquinone domain, its effect likely propagates to the nearby FAD binding domain, probably influencing electron transfer and redox potentials. Overall, our results provide a molecular rational for the decreased enzyme activity observed in patients and suggest that compromised FAD interactions in ETF:QO might account for the known riboflavin responsiveness of this mutation.
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Affiliation(s)
- Tânia G Lucas
- Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Bárbara J Henriques
- Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Cláudio M Gomes
- Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
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10
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Saral NY, Aksungar FB, Aktuglu-Zeybek C, Coskun J, Demirelce O, Serteser M. Glutaric acidemia type II patient with thalassemia minor and novel electron transfer flavoprotein-A gene mutations: A case report and review of literature. World J Clin Cases 2018; 6:786-790. [PMID: 30510944 PMCID: PMC6264994 DOI: 10.12998/wjcc.v6.i14.786] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/10/2018] [Accepted: 10/11/2018] [Indexed: 02/05/2023] Open
Abstract
Glutaric acidemia type II (GAII), also known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAII with novel electron transfer flavoprotein (ETF)-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, riboflavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor development was normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.
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Affiliation(s)
- Neslihan Yildirim Saral
- Department of Clinical Biochemistry and Metabolism, Acibadem Labmed Clinical Laboratories, Istanbul 34752, Turkey
| | - Fehime Benli Aksungar
- Department of Clinical Biochemistry and Metabolism, Acibadem Labmed Clinical Laboratories, Istanbul 34752, Turkey
- Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul 34752, Turkey
| | - Cigdem Aktuglu-Zeybek
- Department of Pediatric Metabolic Diseases, Cerrahpasa School of Medicine, Istanbul University, Istanbul 34098, Turkey
| | - Julide Coskun
- Department of Clinical Biochemistry and Metabolism, Acibadem Labmed Clinical Laboratories, Istanbul 34752, Turkey
| | - Ozlem Demirelce
- Department of Clinical Biochemistry and Metabolism, Acibadem Labmed Clinical Laboratories, Istanbul 34752, Turkey
| | - Mustafa Serteser
- Department of Clinical Biochemistry and Metabolism, Acibadem Labmed Clinical Laboratories, Istanbul 34752, Turkey
- Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul 34752, Turkey
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11
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Fan X, Xie B, Zou J, Luo J, Qin Z, D'Gama AM, Shi J, Yi S, Yang Q, Wang J, Luo S, Chen S, Agrawal PB, Li Q, Shen Y. Novel ETFDH mutations in four cases of riboflavin responsive multiple acyl-CoA dehydrogenase deficiency. Mol Genet Metab Rep 2018; 16:15-19. [PMID: 29988809 PMCID: PMC6031868 DOI: 10.1016/j.ymgmr.2018.05.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 02/01/2023] Open
Abstract
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships.
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Affiliation(s)
- Xin Fan
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Bobo Xie
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Jun Zou
- Department of Gastroenterology, The Second Affiliated Hospital, Guangxi Medical University, Nanning 530000, People's Republic of China
| | - Jingsi Luo
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Zailong Qin
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Alissa M D'Gama
- Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.,The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Jiahai Shi
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region
| | - Shang Yi
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Qi Yang
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Jin Wang
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Shiyu Luo
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Shaoke Chen
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China
| | - Pankaj B Agrawal
- Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.,The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.,Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Qifei Li
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China.,Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.,The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.,Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Yiping Shen
- Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China.,Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
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12
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Chen M, Peng J, Wei W, Wang R, Xu H, Liu H. A novel ETFDH mutation in an adult patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Int J Neurosci 2017; 128:291-294. [PMID: 28914566 DOI: 10.1080/00207454.2017.1380641] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
AIM OF THE STUDY To report a novel mutation in the electron transfer flavoprotein dehydrogenase (ETFDH) gene in an adult patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. MATERIALS AND METHODS The genomic DNAs from a patient whose main clinical presentations are muscles weakness and hypoglycemia was analysed. RESULTS The patient was identified to carry compound heterozygous mutations in ETFDH gene. Two missense mutations c.814 G > A and c.389 A > T were found. CONCLUSION This is the first report of c.814G > A mutation in ETFDH in adult patient with MADD.
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Affiliation(s)
- Min Chen
- a Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Jing Peng
- a Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Wei Wei
- a Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Rui Wang
- a Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Hongliang Xu
- a Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Hongbo Liu
- a Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , P.R. China
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Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency. Neurol Sci 2016; 37:1099-105. [PMID: 27000805 DOI: 10.1007/s10072-016-2549-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 03/04/2016] [Indexed: 10/22/2022]
Abstract
Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) with electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations is the most common lipid storage myopathy (LSM) in China. Its clinical features vary widely and pose a challenge for diagnosis. We presented the significant clinical heterogeneity among three Chinese late-onset MADD patients with similar ETFDH genotype by collecting clinical information, muscle histology, and genetic analysis. Three novel compound heterozygous variants of ETFDH gene were identified: c.892C > T (p.Pro298Ser), c.453delA (p.Glu152ArgfsTer15), and c.449_453delTAACA (p.Leu150Ter). Moreover, all patients carried a hotspot mutation c.250G > A (p.Ala84Thr). Western blot analysis of the patients' muscular tissue showed a significantly reduced ETFDH expression, and normal electron transfer flavoprotein A (ETFA) and electron transfer flavoprotein B (ETFB) expression. Two patients with similar genotypes (c.453delA and c.449_453delTAACA) presented a significant clinical heterogeneity. Among them, one exhibited muscle weakness and exercise intolerance as initial and major symptoms, and the other showed episodic recurrent gastrointestinal symptoms before a serious muscle weakness appeared in later life. The novel variants in ETFDH and the corresponding clinical features enrich the variant spectrum of late-onset MADD and provide a new insight into the genotype-phenotype relationship. Late-onset MADD should be included in differential diagnosis for adult myopathy along with chronic digestive disease.
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Ersoy EO, Rama D, Ünal Ö, Sivri S, Topeli A. Glutaric aciduria type 2 presenting with acute respiratory failure in an adult. Respir Med Case Rep 2015; 15:92-4. [PMID: 26236614 PMCID: PMC4501457 DOI: 10.1016/j.rmcr.2015.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Glutaric aciduria (GTA) type II can be seen as late onset form with myopathic phenotype. We present a case of a 19-year old female with progressive muscle weakness was admitted in intensive care unit (ICU) with respiratory failure and acute renal failure. Patient was unconscious. Pupils were anisocoric and light reflex was absent. She had hepatomegaly. The laboratory results showed a glucose level of 70 mg/dl and the liver enzymes were high. The patient also had hyponatremia (117 mEq/L) and lactate level of 3.9 mmol/L. Tandem MS and organic acid analysis were compatible with GTA type II. Carnitine 1gr, riboflavin 100 mg and co-enzymeQ10 100 mg was arranged. After four months from beginning of treatment tandem MS results are improved. Respiratory failure, acute renal failure due to profound proximal myopathy can be due to glutaric aciduria type II that responded rapidly to appropriate therapy.
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Affiliation(s)
- Ebru Ortac Ersoy
- Department of Internal Intensive Care Medicine, Hacettepe University Medicine Faculty Hospital, Ankara, Turkey
| | - Dorina Rama
- Department of Internal Intensive Care Medicine, Hacettepe University Medicine Faculty Hospital, Ankara, Turkey
| | - Özlem Ünal
- Department of Internal Intensive Care Medicine, Hacettepe University Medicine Faculty Hospital, Ankara, Turkey
| | - Serap Sivri
- Department of Internal Intensive Care Medicine, Hacettepe University Medicine Faculty Hospital, Ankara, Turkey
| | - Arzu Topeli
- Department of Internal Intensive Care Medicine, Hacettepe University Medicine Faculty Hospital, Ankara, Turkey
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15
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A case of late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (MADD) with a novel mutation in ETFDH gene. J Neurol Sci 2015; 353:84-6. [PMID: 25913573 DOI: 10.1016/j.jns.2015.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 04/07/2015] [Accepted: 04/10/2015] [Indexed: 11/21/2022]
Abstract
We report a novel mutation in the electron transfer flavoprotein dehydrogenase (EFTDH) gene in an adolescent Chinese patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by muscle weakness as early symptom. At the age of 9 years, the patient experienced progressive muscle weakness. Blood creatine kinase level and aminotransferase were higher than normal. The muscle biopsy revealed lipid storage myopathy. Serum acylcarnitine and urine organic acid analyses were consistent with MADD. Genetic mutation analysis revealed a compound heterozygous mutation in EFTDH gene. The patients showed good response to riboflavin and l-carnitine treatment.
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16
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Abstract
Late-onset glutaric aciduria type II has been described recently as a rare but treatable cause of proximal myopathy in teenagers and adults. It is an autosomal recessive disease affecting fatty acid, amino acid, and choline metabolism. This is usually a result of 2 defective flavoproteins: either electron transfer flavoprotein (ETF) or electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). We present a 14-year-old boy with a background of autistic spectrum disorder who presented with severe muscle weakness and significant rhabdomyolysis. Before the onset of muscle weakness, he was very active but was completely bedridden at presentation. Diagnosis was established quickly by urine organic acid and plasma acylcarnitine analysis. He has shown significant improvement after starting oral riboflavin supplementation and is now fully mobile. This case highlights that late-onset glutaric aciduria type II is an important differential diagnosis to consider in teenagers presenting with proximal myopathy and rhabdomyolysis and it may not be associated with hypoglycemia.
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Affiliation(s)
- Manish Prasad
- Department of Paediatric Neurology and Neurodisability, Dewsbury Hospital, Wakefield, United Kingdom
| | - Shanawaz Hussain
- Department of Paediatric Neurology, Sheffield Children's Hospital, Wakefield, United Kingdom
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17
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Scheicht D, Werthmann ML, Zeglam S, Holtmeier J, Holtmeier W, Strunk J. [Muscle weakness and early stages of liver failure in a 22-year-old man]. Internist (Berl) 2014; 54:1016-22. [PMID: 23900454 DOI: 10.1007/s00108-013-3329-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
A 22-year-old man without pre-existing medical conditions presented to our hospital with a progressive reduction of his physical overall performance, muscle weakness of the extremities, and diarrhea for the last 2 months concomitant with elevated liver enzymes and creatine kinase activity. After ruling out infectious diseases, neoplasia, and autoimmune disorders as a cause of these symptoms, the histology of liver and muscle samples led us to suspect a diagnosis of a rare lipid metabolism disorder. Molecular biologic testing provided the diagnosis of multiple acyl-coA dehydrogenase deficiency with ubiquinone deficiency and late onset. The course of disease was complicated by liver failure and severe pneumonia requiring ventilatory assistance. With the substitution of riboflavin and ubiquinone, the patient showed a gradual recovery of his clinical presentation and an improvement of his laboratory tests. A congenital lipid metabolic disorder might be a rare cause of severe myopathy and hepatopathy in a young adult.
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Affiliation(s)
- D Scheicht
- Klinik für Rheumatologie, Krankenhaus Porz am Rhein, Akademisches Lehrkrankenhaus der Universitätsklinik Köln, Urbacher Weg 19, 51149, Köln, Deutschland.
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18
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Meng X, Mao W, Sun W, Li L, Zhan S, Wu X, Huang Z, Zhang X, Ma Y, Wang Y. Sleep induced abnormal motor behaviors caused by medium-chain acyl-CoA dehydrogenase deficiency: a case report. Sleep Med 2011; 13:115-7. [PMID: 22137110 DOI: 10.1016/j.sleep.2011.04.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Revised: 04/09/2011] [Accepted: 04/22/2011] [Indexed: 11/27/2022]
Affiliation(s)
- Xianghong Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, No. 45 Changchunjie Road, Beijing 100053, China
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19
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Swanson MA, Kathirvelu V, Majtan T, Frerman FE, Eaton GR, Eaton SS. Electron transfer flavoprotein domain II orientation monitored using double electron-electron resonance between an enzymatically reduced, native FAD cofactor, and spin labels. Protein Sci 2011; 20:610-20. [PMID: 21308847 DOI: 10.1002/pro.595] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Human electron transfer flavoprotein (ETF) is a soluble mitochondrial heterodimeric flavoprotein that links fatty acid β-oxidation to the main respiratory chain. The crystal structure of human ETF bound to medium chain acyl-CoA dehydrogenase indicates that the flavin adenine dinucleotide (FAD) domain (αII) is mobile, which permits more rapid electron transfer with donors and acceptors by providing closer access to the flavin and allows ETF to accept electrons from at least 10 different flavoprotein dehydrogenases. Sequence homology is high and low-angle X-ray scattering is identical for Paracoccus denitrificans (P. denitrificans) and human ETF. To characterize the orientations of the αII domain of P. denitrificans ETF, distances between enzymatically reduced FAD and spin labels in the three structural domains were measured by double electron-electron resonance (DEER) at X- and Q-bands. An FAD to spin label distance of 2.8 ± 0.15 nm for the label in the FAD-containing αII domain (A210C) agreed with estimates from the crystal structure (3.0 nm), molecular dynamics simulations (2.7 nm), and rotamer library analysis (2.8 nm). Distances between the reduced FAD and labels in αI (A43C) were between 4.0 and 4.5 ± 0.35 nm and for βIII (A111C) the distance was 4.3 ± 0.15 nm. These values were intermediate between estimates from the crystal structure of P. denitrificans ETF and a homology model based on substrate-bound human ETF. These distances suggest that the αII domain adopts orientations in solution that are intermediate between those which are observed in the crystal structures of free ETF (closed) and ETF bound to a dehydrogenase (open).
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Affiliation(s)
- Michael A Swanson
- Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, USA
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20
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Kaminsky P, Acquaviva-Bourdain C, Jonas J, Pruna L, Chaloub GE, Rigal O, Grignon Y, Vianey-Saban C. Subacute myopathy in a mature patient due to multiple acyl-coenzyme A dehydrogenase deficiency. Muscle Nerve 2011; 43:444-6. [PMID: 21321959 DOI: 10.1002/mus.21881] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), also called glutaric aciduria type II, is an inherited metabolic disorder resulting from a deficiency in electron transfer flavoprotein (ETF) or of its ubiquinone oxidoreductase (ETF-QO). It usually occurs in the neonatal period or in early infancy and, very rarely, in adolescents and young adult patients. METHODS We report the case of a 55-year-old woman who developed a painful subacute myopathy. RESULTS Lipid accumulation was found at biopsy. MADD was confirmed by plasma acylcarnitine profile and by assessment of ETF-QO activity in muscle. CONCLUSIONS This study demonstrates that metabolic myopathies usually found in infancy may be also diagnosed in older patients. MADD may be easily treated by riboflavin and coenzyme Q10 and therefore should be included in the differential diagnosis of adult-onset painful myopathy.
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Affiliation(s)
- Pierre Kaminsky
- Service de Médecine Interne orientée vers les Maladies Orphelines et Systémiques, Centre de Référence des Maladies Héréditaires du Métabolisme, CHU de Nancy-Hôpitaux de Brabois, Vandoeuvre-lès-Nancy, France.
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Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM. Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle. J Inherit Metab Dis 2010; 33 Suppl 3:S481-7. [PMID: 21088898 PMCID: PMC3970109 DOI: 10.1007/s10545-010-9246-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 10/05/2010] [Accepted: 10/29/2010] [Indexed: 10/18/2022]
Abstract
We describe a 22-year-old male who developed severe hypoglycemia and lethargy during an acute illness at 4 months of age and subsequently grew and developed normally. At age 4 years he developed recurrent vomiting with mild hyperammonemia and dehydration requiring frequent hospitalizations. Glutaric aciduria Type II was suspected based upon biochemical findings and managed with cornstarch, carnitine and riboflavin supplements. He did not experience metabolic crises between ages 4-12 years. He experienced recurrent vomiting, mild hyperammonemia, and generalized weakness associated with acute illnesses and growth spurts. At age 18 years, he developed exercise intolerance and proximal muscle weakness leading to the identification of multiple acyl-CoA dehydrogenase and complex II/III deficiencies in both skeletal muscle and liver. Subsequent molecular characterization of the ETFDH gene revealed novel heterozygous mutations, p.G274X:c.820 G > T (exon 7) and p.P534L: c.1601 C > T (exon 12), the latter within the iron sulfur-cluster and predicted to affect ubiquinone reductase activity of ETFDH and the docking of ETF to ETFDH. Our case supports the concept of a structural interaction between ETFDH and other enzyme partners, and suggests that the conformational change upon ETF binding to ETFDH may play a key role in linking ETFDH to II/III super-complex formation.
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Affiliation(s)
- Lynne A Wolfe
- Division of Medical Genetics, Department of Pediatrics, Children's Hospital of UPMC, Pittsburgh, PA, USA
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Glutaric aciduria type 2, late onset type in Thai siblings with myopathy. Pediatr Neurol 2010; 43:279-82. [PMID: 20837308 DOI: 10.1016/j.pediatrneurol.2010.05.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 05/11/2010] [Accepted: 05/19/2010] [Indexed: 11/20/2022]
Abstract
Reported here is a novel presentation of late onset glutaric aciduria type 2 in two Thai siblings. A 9-year-old boy presented with gradual onset of proximal muscle weakness for 6 weeks. The initial diagnosis was postviral myositis, and then polymyositis. Electromyography and nerve conduction velocity testing indicated a myopathic pattern. Muscle biopsy revealed excessive accumulation of fat. Acylcarnitine profiling led to the diagnosis of glutaric aciduria type 2. Immunoblot analysis of electron-transferring-flavoprotein and its dehydrogenase electron-transferring-flavoprotein dehydrogenase led to mutation analysis of the ETFDH gene, which revealed two different pathogenic mutations in both alleles and confirmed the diagnosis of glutaric aciduria type 2 caused by electron-transferring-flavoprotein dehydrogenase deficiency. The boy recovered completely after treatment. Later, his younger sibling became symptomatic; the same diagnosis was confirmed, and treatment was similarly effective. Acylcarnitine profiling was a crucial investigation in making this diagnosis in the presence of normal urine organic acid findings. Late onset glutaric aciduria type 2, a rare cause of muscle weakness in children, should be included in the differential diagnosis of myopathy.
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23
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Ishii K, Komaki H, Ohkuma A, Nishino I, Nonaka I, Sasaki M. Central nervous system and muscle involvement in an adolescent patient with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Brain Dev 2010; 32:669-72. [PMID: 19783111 DOI: 10.1016/j.braindev.2009.08.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2009] [Revised: 08/24/2009] [Accepted: 08/24/2009] [Indexed: 10/20/2022]
Abstract
We report an adolescent case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by intermittent nausea and depressive state as early symptoms. At the age of 12 years and 11 months, the patient experienced intermittent nausea and vomiting, and depressive state. She was on medication for depression for 5 months but it was ineffective. Brain magnetic resonance imaging showed disseminated high-intensity areas in the periventricular white matter and in the splenium of the corpus callosum on T2-weighted images and fluid-attenuated inversion-recovery images. Progressive muscle weakness occurred and blood creatine kinase level was found to be elevated. The muscle biopsy revealed lipid storage myopathy. Urine organic acid analysis and mutation analysis of the ETFDH gene confirmed the diagnosis of MADD. With oral supplements of riboflavin and l-carnitine, in addition to a high-calorie and reduced-fat diet, her clinical symptoms improved dramatically. Early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD.
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Affiliation(s)
- Kiyoko Ishii
- Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan
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24
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Chew DS, Mah AK, Baillie DL. Characterizing the transcriptional regulation of let-721, a Caenorhabditis elegans homolog of human electron flavoprotein dehydrogenase. Mol Genet Genomics 2009; 282:555-70. [PMID: 19774399 DOI: 10.1007/s00438-009-0485-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Accepted: 09/07/2009] [Indexed: 11/28/2022]
Abstract
LET-721 is the Caenorhabditis elegans ortholog of electron-transferring flavoprotein dehydrogenase (ETFDH). We are studying this protein in C. elegans in order to establish a tractable model system for further exploration of ETFDH structure and function. ETFDH is an inner mitochondrial membrane localized enzyme that plays a key role in the beta-oxidation of fatty acids and catabolism of amino acids and choline. ETFDH accepts electrons from at least twelve mitochondrial matrix flavoprotein dehydrogenases via an intermediate dimer protein and transfers the electrons to ubiquinone. In humans, ETFDH mutations result in the autosomal recessive metabolic disorder, multiple acyl-CoA dehydrogenase deficiency. Mutants of let-721 in C. elegans are either maternal effect lethals or semi-sterile. let-721 is transcribed in the pharynx, body wall muscle, hypoderm, intestine and somatic gonad. In addition, the subcellular localization of LET-721 agrees with predictions that it is localized to mitochondria. We identified and confirmed three cis-regulatory sequences (pha-site, rep-site, and act-site). Phylogenetic footprinting of each site indicates that they are conserved between four Caenorhabditis species. The pha-site mapped roughly 1,300 bp upstream of let-721's translational start site and is necessary for expression in pharyngeal tissues. The rep-site mapped roughly 830 bp upstream of the translational start site and represses expression of LET-721 within pharyngeal tissues. The act-site mapped roughly 800 bp upstream of the translational start site and is required for expression within spermatheca, body wall muscle, pharynx, and intestine. Taken together, we find that LET-721 is a mitochondrially expressed protein that is under complex transcriptional controls.
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Affiliation(s)
- Derek S Chew
- Department Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada
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25
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Liang WC, Ohkuma A, Hayashi YK, López LC, Hirano M, Nonaka I, Noguchi S, Chen LH, Jong YJ, Nishino I. ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord 2009; 19:212-6. [PMID: 19249206 PMCID: PMC10409523 DOI: 10.1016/j.nmd.2009.01.008] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2008] [Revised: 01/07/2009] [Accepted: 01/13/2009] [Indexed: 10/21/2022]
Abstract
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a metabolic disorder due to dysfunction of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO). Mutations in ETFDH, encoding ETF-QO have been associated with both riboflavin-responsive and non-responsive MADD as well as a myopathic form of CoQ(10) deficiency, although pathomechanisms responsible for these different phenotypes are not well-defined. We performed mutation analysis in four Taiwanese MADD patients. Three novel ETFDH mutations were identified in four patients and all harbored the p.A84T mutation. Muscle CoQ(10) levels and respiratory chain activities measured in two patients were normal. Three patients improved on riboflavin together with carnitine. Our results show that not all MADD patients have CoQ(10) deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD.
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Affiliation(s)
- Wen-Chen Liang
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan
- Departments of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Aya Ohkuma
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan
| | - Yukiko K. Hayashi
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan
| | - Luis Carlos López
- Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Michio Hirano
- Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Ikuya Nonaka
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan
| | - Satoru Noguchi
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan
| | - Liang-Hui Chen
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yuh-Jyh Jong
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Departments of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Departments of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ichizo Nishino
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan
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Henriques BJ, Rodrigues JV, Olsen RK, Bross P, Gomes CM. Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency: a molecular rationale for the effects of riboflavin supplementation. J Biol Chem 2008; 284:4222-9. [PMID: 19088074 DOI: 10.1074/jbc.m805719200] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Mutations in the genes encoding the alpha-subunit and beta-subunit of the mitochondrial electron transfer flavoprotein (ETF) and the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) cause multiple acyl-CoA dehydrogenation deficiency (MADD), a disorder of fatty acid and amino acid metabolism. Point mutations in ETF, which may compromise folding, and/or activity, are associated with both mild and severe forms of MADD. Here we report the investigation on the conformational and stability properties of the disease-causing variant ETFbeta-D128N, and our findings on the effect of flavinylation in modulating protein conformational stability and activity. A combination of biochemical and biophysical methods including circular dichroism, visible absorption, flavin, and tryptophan fluorescence emission allowed the analysis of structural changes and of the FAD moiety. The ETFbeta-D128N variant retains the overall fold of the wild type, but under stress conditions its flavin becomes less tightly bound. Flavinylation is shown to improve the conformational stability and biological activity of a destabilized D128N variant protein. Moreover, the presence of flavin prevented proteolytic digestion by avoiding protein destabilization. A patient homozygous for the ETFbeta-D128N mutation developed severe disease symptoms in association with a viral infection and fever. In agreement, our results suggest that heat inactivation of the mutant may be more relevant at temperatures above 37 degrees C. To mimic a situation of fever in vitro, the flavinylation status was tested at 39 degrees C. FAD exerts the effect of a pharmacological chaperone, improving ETF conformation, and yielding a more stable and active enzyme. Our results provide a structural and functional framework that could help to elucidate the role that an increased cellular FAD content obtained from riboflavin supplementation may play in the molecular pathogenesis of not only MADD, but genetic disorders of flavoproteins in general.
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Affiliation(s)
- Bárbara J Henriques
- Instituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2780-756 Oeiras, Portugal
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27
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Swanson MA, Usselman RJ, Frerman FE, Eaton GR, Eaton SS. The iron-sulfur cluster of electron transfer flavoprotein-ubiquinone oxidoreductase is the electron acceptor for electron transfer flavoprotein. Biochemistry 2008; 47:8894-901. [PMID: 18672901 DOI: 10.1021/bi800507p] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) accepts electrons from electron transfer flavoprotein (ETF) and reduces ubiquinone from the ubiquinone pool. It contains one [4Fe-4S] (2+,1+) and one FAD, which are diamagnetic in the isolated oxidized enzyme and can be reduced to paramagnetic forms by enzymatic donors or dithionite. In the porcine protein, threonine 367 is hydrogen bonded to N1 and O2 of the flavin ring of the FAD. The analogous site in Rhodobacter sphaeroides ETF-QO is asparagine 338. Mutations N338T and N338A were introduced into the R. sphaeroides protein by site-directed mutagenesis to determine the impact of hydrogen bonding at this site on redox potentials and activity. The mutations did not alter the optical spectra, EPR g-values, spin-lattice relaxation rates, or the [4Fe-4S] (2+,1+) to FAD point-dipole interspin distances. The mutations had no impact on the reduction potential for the iron-sulfur cluster, which was monitored by changes in the continuous wave EPR signals of the [4Fe-4S] (+) at 15 K. For the FAD semiquinone, significantly different potentials were obtained by monitoring the titration at 100 or 293 K. Based on spectra at 293 K the N338T mutation shifted the first and second midpoint potentials for the FAD from +47 and -30 mV for wild type to -11 and -19 mV, respectively. The N338A mutation decreased the potentials to -37 and -49 mV. Lowering the midpoint potentials resulted in a decrease in the quinone reductase activity and negligible impact on disproportionation of ETF 1e (-) catalyzed by ETF-QO. These observations indicate that the FAD is involved in electron transfer to ubiquinone but not in electron transfer from ETF to ETF-QO. Therefore, the iron-sulfur cluster is the immediate acceptor from ETF.
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Affiliation(s)
- Michael A Swanson
- Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, USA
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Chiong MA, Sim KG, Carpenter K, Rhead W, Ho G, Olsen RKJ, Christodoulou J. Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. Mol Genet Metab 2007; 92:109-14. [PMID: 17689999 DOI: 10.1016/j.ymgme.2007.06.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2007] [Revised: 06/11/2007] [Accepted: 06/11/2007] [Indexed: 12/18/2022]
Abstract
A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant's birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother's defect in riboflavin metabolism remains to be established.
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Affiliation(s)
- M A Chiong
- Western Sydney Genetics Program, Children's Hospital at Westmead, and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
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Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BGH, Hans VH, Pálmafy B, Kale G, Tokatli A, Quinzii C, Hirano M, Naini A, DiMauro S, Prokisch H, Lochmüller H, Horvath R. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. ACTA ACUST UNITED AC 2007; 130:2037-44. [PMID: 17412732 PMCID: PMC4345103 DOI: 10.1093/brain/awm054] [Citation(s) in RCA: 229] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with heterogenous phenotypic manifestations and genetic background. We describe seven patients from five independent families with an isolated myopathic phenotype of CoQ10 deficiency. The clinical, histological and biochemical presentation of our patients was very homogenous. All patients presented with exercise intolerance, fatigue, proximal myopathy and high serum CK. Muscle histology showed lipid accumulation and subtle signs of mitochondrial myopathy. Biochemical measurement of muscle homogenates showed severely decreased activities of respiratory chain complexes I and II + III, while complex IV (COX) was moderately decreased. CoQ10 was significantly decreased in the skeletal muscle of all patients. Tandem mass spectrometry detected multiple acyl-CoA deficiency, leading to the analysis of the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII). All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. Our results indicate that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Since this condition is treatable, correct diagnosis is of the utmost importance and should be considered both in children and in adults. We suggest to give patients both CoQ10 and riboflavin supplementation, especially for long-term treatment.
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Affiliation(s)
- Klaus Gempel
- Metabolic Disease Center Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics; Academic Hospital Schwabing, Munich, Germany
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Beresford MW, Pourfarzam M, Davidson JE. “So doctor, what exactly is wrong with my muscles? Glutaric aciduria type II presenting in a teenager”. Neuromuscul Disord 2006; 16:613. [PMID: 16919953 DOI: 10.1016/j.nmd.2006.07.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Brereton PS, Verhagen MF, Zhou ZH, Adams MW. Effect of iron-sulfur cluster environment in modulating the thermodynamic properties and biological function of ferredoxin from Pyrococcus furiosus. Biochemistry 1998; 37:7351-62. [PMID: 9585549 PMCID: PMC2731698 DOI: 10.1021/bi972864b] [Citation(s) in RCA: 75] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The ferredoxin (7.5 kDa) of the hyperthermophilic archaeon, Pyrococcus furiosus, contains a single [4Fe-4S]1+,2+ cluster that is coordinated by three Cys and one Asp residue rather than the expected four Cys. The role of this Asp residue was investigated using a series of mutants, D14X, where X = C, S, H, N, V, and Y, prepared by heterologous gene expression in Escherichia coli. While the recombinant form of the wild-type and the D14S and D14C mutants contained a [4Fe-4S]1+,2+ cluster, the D14V, D14H, D14Y, and D14N proteins contained a [3Fe-4S]0,+ center, as determined by visible spectroscopy and electrochemistry. The redox potentials (at pH 7.0, 23 degrees C) of the D14C and D14S mutants were decreased by 58 and 133 mV, respectively, compared to those of the wild-type 4Fe-ferredoxin (Em -368 mV), while those of the 3Fe-protein mutants (including the 3Fe-form of the D14S, generated by chemical oxidation) were between 15 and 118 mV more positive than that of wild-type 3Fe-form (obtained by chemical oxidation, Em -203 mV). The reduction potentials of all of the 3Fe-forms, except the D14S mutant, showed a pH response over the range 3.0-10.0 with a pK of 3.3-4.7, and this was assigned to cluster protonation. The D14H mutant and the wild-type 3Fe-proteins showed an additional pK (both at 5.9) assumed to arise from protonation of the amino acid side chain. With the 4Fe-proteins, there was no dramatic change in the potentials of the wild-type or D14C form, while the pH response of the D14S mutant (pK 4.75) was ascribed to protonation of the serinate. While the ferredoxin variants exhibited a range of thermal stabilities (measured at 80 degrees C, pH 2.5), none of them showed any temperature-dependent transitions (0-80 degrees C) in their reduction potentials, and there was no correlation between the calculated DeltaS degrees' values and the absorbance maximum, reduction potential, or hydrophobicity of residue 14. In contrast, there was a linear correlation between the DeltaH degrees' value and reduction potential. Kinetic analyses were carried out at 80 degrees C using the ferredoxin as either an electron acceptor to pyruvate oxidoreductase (POR) or as an electron donor to ferredoxin:NADP oxidoreductase (FNOR, both from P. furiosus). The data showed that the reduction potential of the ferredoxin, rather than cluster type or the nature of the residue at position 14, appears to be the predominant factor in determining efficiency of electron transfer in both systems. However, compared to all the variants, the reduction potential of WT Fd makes it the most appropriate protein to both accept electrons from POR and donate them to FNOR.
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Affiliation(s)
- P S Brereton
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens 30602-7229, USA
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