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Al-Beltagi M, Saeed NK, Bediwy AS, Elbeltagi R. Unraveling the nutritional challenges in epilepsy: Risks, deficiencies, and management strategies: A systematic review. World J Exp Med 2025; 15:104328. [DOI: 10.5493/wjem.v15.i2.104328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/24/2025] [Accepted: 03/18/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Malnutrition and epilepsy share a complex bidirectional relationship, with malnutrition serving as a potential risk factor for epilepsy development, while epilepsy, in turn, often exerts profound effects on nutritional status. Nutritional interventions have emerged as a critical adjunctive approach in epilepsy management.
AIM To explore the multifaceted associations between malnutrition and epilepsy, structured into three primary sections: (1) Elucidating the impact of malnutrition as a risk factor for epilepsy onset; (2) Examining the reciprocal influence of epilepsy on nutritional status, and (3) Evaluating diverse nutritional interventions in the management of epilepsy.
METHODS A systematic search was conducted across PubMed, Scopus, and Web of Science databases utilizing defined keywords related to malnutrition, epilepsy, and nutritional interventions. Inclusion criteria encompassed various study types, including clinical trials, animal models, cohort studies, case reports, meta-analyses, systematic reviews, guidelines, editorials, and review articles. Four hundred sixteen pertinent references were identified, with 198 review articles, 153 research studies, 21 case reports, 24 meta-analyses, 14 systematic reviews, 4 guidelines, and 2 editorials meeting the predefined criteria.
RESULTS The review revealed the intricate interplay between malnutrition and epilepsy, highlighting malnutrition as a potential risk factor in epilepsy development and elucidating how epilepsy often leads to nutritional deficiencies. Findings underscored the importance of nutritional interventions in managing epilepsy, showing their impact on seizure frequency, neuronal function, and overall brain health.
CONCLUSION This systematic review emphasizes the bidirectional relationship between malnutrition and epilepsy while emphasizing the critical role of nutritional management in epilepsy treatment. The multifaceted insights underscore the need for a holistic approach to addressing nutritional aspects alongside conventional epilepsy management strategies.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatrics, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Governmental Hospitals, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, The Royal College of Surgeons in Ireland, Busaiteen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Reem Elbeltagi
- Medicine, Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Muharraq, Bahrain
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Yang MT, Chou IC, Wang HS. Role of vitamins in epilepsy. Epilepsy Behav 2023; 139:109062. [PMID: 36577336 DOI: 10.1016/j.yebeh.2022.109062] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/27/2022]
Abstract
Epilepsy is a chronic neurological disorder that presents as recurrent, unprovoked seizures. Pharmacotherapy is the main treatment for epilepsy, but at least 30% of patients with epilepsy have pharmacoresistant epilepsy. Therefore, non-pharmacological treatments are still required. In addition to electrophysiological aberrations contributing to epileptogenesis and pathophysiology in epilepsy, neuroinflammation, oxidative stress, and metabolic derangement have been investigated as drug targets in the treatment of epilepsy. Vitamins have antioxidant, anti-inflammatory, and immunomodulatory effects, which can be beneficial for the treatment of epilepsy. Herein, we comprehensively review the role of vitamins in epilepsy. Certain epilepsies are vitamin-dependent or vitamin-responsive. Most studies on vitamins in epilepsy are of low evidence level or limited to animal studies. Nevertheless, vitamin supplementation should be considered in epilepsy therapy. Additionally, certain anti-seizure medications may alter the serum levels of certain vitamins. Monitoring the serum levels of vitamins and supplementing vitamins when needed are suggested during the follow-up of patients with epilepsy.
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Affiliation(s)
- Ming-Tao Yang
- Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan.
| | - I-Ching Chou
- Division of Pediatrics Neurology, China Medical University Children's Hospital, Taichung, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Huei-Shyong Wang
- Division of Pediatric Neurology, Chang Gung Children's Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism. Int J Mol Sci 2020; 21:ijms21113847. [PMID: 32481712 PMCID: PMC7312377 DOI: 10.3390/ijms21113847] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/20/2020] [Accepted: 05/26/2020] [Indexed: 01/13/2023] Open
Abstract
As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.
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Nochi Z, Olsen RKJ, Gregersen N. Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms. J Inherit Metab Dis 2017; 40:641-655. [PMID: 28516284 DOI: 10.1007/s10545-017-0047-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 03/31/2017] [Accepted: 04/05/2017] [Indexed: 12/15/2022]
Abstract
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inherited disorder of mitochondrial fatty acid oxidation that is characterized by the presence of increased butyrylcarnitine and ethylmalonic acid (EMA) concentrations in plasma and urine. Individuals with symptomatic SCADD may show relatively severe phenotype, while the majority of those who are diagnosed through newborn screening by tandem mass spectrometry may remain asymptomatic. As such, the associated clinical symptoms are very diverse, ranging from severe metabolic or neuromuscular disabilities to asymptomatic. Molecular analysis of affected individuals has identified rare gene variants along with two common gene variants, c.511C > T and c.625G > A. In vitro studies have demonstrated that the common variants as well as the great majority of rare variants, which are missense variants, impair folding, that may lead to toxic accumulation of the encoded protein, and/or metabolites, and initiate excessive production of ROS and chronic oxidative stress. It has been suggested that this cell toxicity in combination with yet unknown factors can trigger disease development. This association and the full implications of SCADD are not commonly appreciated. Accordingly, there is a worldwide discussion of the relationship of clinical manifestation to SCADD, and whether SCAD gene variants are disease associated at all. Therefore, SCADD is not part of the newborn screening programs in most countries, and consequently many patients with SCAD gene variants do not get a diagnosis and the possibilities to be followed up during development.
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Affiliation(s)
- Zahra Nochi
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital and Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark.
| | - Rikke Katrine Jentoft Olsen
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital and Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark
| | - Niels Gregersen
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital and Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark
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McCammon KM, Panda SP, Xia C, Kim JJP, Moutinho D, Kranendonk M, Auchus RJ, Lafer EM, Ghosh D, Martasek P, Kar R, Masters BS, Roman LJ. Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype. J Biol Chem 2016; 291:20487-502. [PMID: 27496950 PMCID: PMC5034044 DOI: 10.1074/jbc.m116.716019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 07/18/2016] [Indexed: 11/06/2022] Open
Abstract
Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of cytochrome P450 17A1, 19A1, and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing cytochromes P450, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo Differential scanning calorimetry and limited trypsinolysis studies revealed a relatively unstable A287P compared with WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability. The crystal structures of the soluble domains of WT and A287P reveal only subtle differences between them, but these differences are consistent with the differential scanning calorimetry results as well as the differential susceptibility of A287P and WT observed with trypsinolysis. The relative in vivo stabilities of WT and A287P proteins were also examined in an osteoblast cell line by treatment with cycloheximide, a protein synthesis inhibitor, showing that the level of A287P protein post-inhibition is lower than WT and suggesting that A287P may be degraded at a higher rate. Current studies demonstrate that, unlike previously described mutations, A287P causes POR deficiency disorder due to conformational instability leading to proteolytic susceptibility in vivo, rather than through an inherent flavin-binding defect.
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Affiliation(s)
- Karen M McCammon
- From the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Satya P Panda
- From the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Chuanwu Xia
- the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Jung-Ja P Kim
- the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Daniela Moutinho
- the Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School/FCM, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal
| | - Michel Kranendonk
- the Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School/FCM, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal
| | - Richard J Auchus
- the Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109
| | - Eileen M Lafer
- From the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Debashis Ghosh
- the Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, and
| | - Pavel Martasek
- the Department of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital, 116 36 Prague 1, Czech Republic
| | - Rekha Kar
- From the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Bettie Sue Masters
- From the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229,
| | - Linda J Roman
- From the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229,
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van Maldegem BT, Wanders RJA, Wijburg FA. Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2010; 33:507-11. [PMID: 20429031 PMCID: PMC2946545 DOI: 10.1007/s10545-010-9080-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Revised: 03/08/2010] [Accepted: 03/12/2010] [Indexed: 10/26/2022]
Abstract
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing SCAD gene mutations and/or variants. SCAD gene variants are present in homozygous form in approximately 6% of the general population and considered to confer susceptibility to development of clinical disease. Clinically, SCADD generally appears to present early in life and to be most frequently associated with developmental delay, hypotonia, epilepsy, behavioral disorders, and hypoglycemia. However, these symptoms often ameliorate and even disappear spontaneously during follow-up and were found to be unrelated to the SCAD genotype. In addition, in some cases, symptoms initially attributed to SCADD could later be explained by other causes. Finally, SCADD relatives of SCADD patients as well as almost all SCADD individuals diagnosed by neonatal screening remained asymptomatic during follow-up. This potential lack of clinical consequences of SCADD has several implications. First, the diagnosis of SCADD should never preclude extension of the diagnostic workup for other potential causes of the observed symptoms. Second, patients and parents should be clearly informed about the potential lack of relevance of the disorder to avoid unfounded anxiety. Furthermore, to date, SCADD is not an optimal candidate for inclusion in newborn screening programs. More studies are needed to fully establish the relevance of SCADD and solve the question as to whether SCADD is involved in a multifactorial disease or represents a nondisease.
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Affiliation(s)
- Bianca T van Maldegem
- Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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van Maldegem BT, Duran M, Wanders RJA, Waterham HR, Wijburg FA. Flavin adenine dinucleotide status and the effects of high-dose riboflavin treatment in short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 2010; 67:304-8. [PMID: 19952864 DOI: 10.1203/pdr.0b013e3181cbd57b] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inborn error, biochemically characterized by increased plasma butyrylcarnitine (C4-C) concentration and increased ethylmalonic acid (EMA) excretion and caused by rare mutations and/or common gene variants in the SCAD encoding gene. Although its clinical relevance is not clear, SCADD is included in most US newborn screening programs. Riboflavin, the precursor of flavin adenine dinucleotide (FAD, cofactor), might be effective for treating SCADD. We assessed the FAD status and evaluated the effects of riboflavin treatment in a prospective open-label cohort study involving 16 patients with SCADD, subdivided into mutation/mutation (mut/mut), mutation/variant (mut/var), and variant/variant (var/var) genotype groups. Blood FAD levels were normal in all patients before therapy, but significantly lower in the mut/var and var/var groups compared with the mut/mut group. Riboflavin treatment resulted in a decrease in EMA excretion in the mut/var group and in a subjective clinical improvement in four patients from this group. However, this improvement persisted after stopping treatment. These results indicate that high-dose riboflavin treatment may improve the biochemical features of SCADD, at least in patients with a mut/var genotype and low FAD levels. As our study could not demonstrate a clinically relevant effect of riboflavin, general use of riboflavin cannot be recommended.
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8
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Marohnic CC, Panda SP, McCammon K, Rueff J, Masters BSS, Kranendonk M. Human cytochrome P450 oxidoreductase deficiency caused by the Y181D mutation: molecular consequences and rescue of defect. Drug Metab Dispos 2010; 38:332-40. [PMID: 19884324 PMCID: PMC2812058 DOI: 10.1124/dmd.109.030445] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Accepted: 10/29/2009] [Indexed: 02/01/2023] Open
Abstract
Patients with congenital adrenal hyperplasia, exhibiting combined CYP17 and CYP21 deficiency, were shown by Arlt et al. (2004) to harbor a 541T-->G mutation in exon 5 of POR (encoding NADPH-cytochrome P450 reductase, CYPOR), which resulted in a Y181D substitution that obliterated electron transfer capacity. Using bacterial expression models, we examined catalytic and physical properties of the human CYPOR Y181D variant. As purified, Y181D lacked flavin mononucleotide (FMN) and NADPH-cytochrome c reductase (NCR) activity but retained normal flavin adenine dinucleotide binding and NADPH utilization. Titration of the purified protein with FMN restored 64 of wild-type (WT) NCR activity in Y181D with an activation constant of approximately 2 microM. As determined by FMN fluorescence quenching, Y181D had K(d)(FMN) = 7.3 microM. Biplasmid coexpression of CYPOR and CYP1A2, at the physiological ratio of approximately 1:10 in the engineered MK_1A2_POR Escherichia coli strain, showed the compromised capacity of Y181D to support CYP1A2-catalyzed metabolism of the procarcinogens 2-aminoanthracene, 2-amino-3-methylimidazo(4,5-f)quinoline, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Isolated MK1A2_POR membranes confirmed FMN stimulation of Y181D NCR activity with a 1.6 microM activation constant. CYP1A2 ethoxyresorufin-O-dealkylase activity of the MK1A2_POR(Y181D) membranes, undetectable in the absence of added FMN, increased to 37% of MK1A2_POR(WT) membranes with a 1.2 microM FMN activation constant. Therefore, we conclude that compromised FMN binding is the specific molecular defect causing POR deficiency in patients with Y181D mutation and that this defect, in large part, can be overcome in vitro by FMN addition.
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Affiliation(s)
- Christopher C Marohnic
- Department of Biochemistry, 7760, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
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Gonzalez-Cabo P, Ros S, Palau F. Flavin adenine dinucleotide rescues the phenotype of frataxin deficiency. PLoS One 2010; 5:e8872. [PMID: 20111601 PMCID: PMC2810331 DOI: 10.1371/journal.pone.0008872] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2009] [Accepted: 12/29/2009] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Friedreich ataxia is a neurodegenerative disease caused by the lack of frataxin, a mitochondrial protein. We previously demonstrated that frataxin interacts with complex II subunits of the electronic transport chain (ETC) and putative electronic transfer flavoproteins, suggesting that frataxin could participate in the oxidative phosphorylation. METHODS AND FINDINGS Here we have investigated the effect of riboflavin and its cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in Saccharomyces cerevisiae and Caenorhabditis elegans models of frataxin deficiency. We used a S. cerevisiae strain deleted for the yfh1 gene obtained by homologous recombination and we assessed growth in fermentable and non-fermentable cultures supplemented with either riboflavin or its derivates. Experiments with C. elegans were performed in transient knock-down worms (frh-1[RNAi]) generated by microinjection of dsRNA frh-1 into the gonads of young worms. We observed that FAD rescues the phenotype of both defective organisms. We show that cell growth and enzymatic activities of the ETC complexes and ATP production of yfh1Delta cells were improved by FAD supplementation. Moreover, FAD also improved lifespan and other physiological parameters in the C. elegans knock-down model for frataxin. CONCLUSIONS/SIGNIFICANCE We propose that rescue of frataxin deficiency by FAD supplementation could be explained by an improvement in mitochondrial respiration. We suggest that riboflavin may be useful in the treatment of Friedreich ataxia.
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Affiliation(s)
- Pilar Gonzalez-Cabo
- Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain
- CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Sheila Ros
- Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain
- CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Francesc Palau
- Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain
- CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
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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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Jethva R, Bennett MJ, Vockley J. Short-chain acyl-coenzyme A dehydrogenase deficiency. Mol Genet Metab 2008; 95:195-200. [PMID: 18977676 PMCID: PMC2720545 DOI: 10.1016/j.ymgme.2008.09.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Revised: 09/23/2008] [Accepted: 09/24/2008] [Indexed: 10/21/2022]
Abstract
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a disorder of mitochondrial fatty acid oxidation that leads to the accumulation of butyrylcarnitine and ethylmalonic acid in blood and urine. Originally described with a relatively severe phenotype, most patients are now diagnosed through newborn screening by tandem mass spectrometry and remain asymptomatic. Molecular analysis of affected individuals has identified a preponderance of private inactivating point mutations and one common one present in high frequency in individuals of Ashkenazi Jewish ancestry. In addition, two polymorphic variants have been identified that have little affect on enzyme kinetics but impair folding and stability. Individuals homozygous for one of these variants or compound heterozygous for one of each often show an increased level of ethylmalonic acid excretion that appears not to be clinically significant. The combination of asymptomatic affected newborns and the frequent variants can cause much confusion in evaluating and treating individuals with SCADD. The long-term consequences and the need for chronic therapy remain current topics of contention and investigation.
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Affiliation(s)
- Reena Jethva
- Children’s Hospital of Philadelphia, Division of Human and Molecular Genetics, The Children’s Hospital of Philadelphia, Abramson Research Center, Room 1002, 3615 Civic Center Boulevard, Philadelphia, PA 19104
| | - Michael J. Bennett
- University of Pennsylvania School of Medicine, The Children’s Hospital of Philadelphia, Department of Pathology, 34th Street and Civic Center Blvd., Philadelphia, PA 19104
| | - Jerry Vockley
- University of Pittsburgh, School of Medicine, Department of Pediatrics, Graduate School of Public Health, Department of Human Genetics, Children’s Hospital of Pittsburgh, Division of Medical Genetics, 3705 5th Avenue, Pittsburgh, PA 15213
- To whom correspondence should be addressed
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Tein I, Elpeleg O, Ben-Zeev B, Korman SH, Lossos A, Lev D, Lerman-Sagie T, Leshinsky-Silver E, Vockley J, Berry GT, Lamhonwah AM, Matern D, Roe CR, Gregersen N. Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin. Mol Genet Metab 2008; 93:179-89. [PMID: 18054510 DOI: 10.1016/j.ymgme.2007.09.021] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Accepted: 09/22/2007] [Indexed: 11/28/2022]
Abstract
We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.
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Affiliation(s)
- Ingrid Tein
- Division of Neurology, Department of Pediatrics, Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Canada M5G 1X8.
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Marohnic CC, Panda SP, Martásek P, Masters BS. Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. J Biol Chem 2006; 281:35975-82. [PMID: 16998238 DOI: 10.1074/jbc.m607095200] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Numerous mutations/polymorphisms of the POR gene, encoding NADPH:cytochrome P450 oxidoreductase (CYPOR), have been described in patients with Antley-Bixler syndrome (ABS), presenting with craniofacial dysmorphogenesis, and/or disordered steroidogenesis, exhibiting ambiguous genitalia. CYPOR is the obligate electron donor to 51 microsomal cytochromes P450 that catalyze critical steroidogenic and xenobiotic reactions, and to two heme oxygenase isoforms, among other redox partners. To address the molecular basis of CYPOR dysfunction in ABS patients, the soluble catalytic domain of human CYPOR was bacterially expressed. WT enzyme was green, due to air-stable FMN semiquinone (blue) and oxidized FAD (yellow). The ABS mutant V492E was blue-gray. Flavin analysis indicated that WT had a protein:FAD:FMN ratio of approximately 1:1:1, whereas approximately 1:0.1:0.9 was observed for V492E, which retained 9% of the WT k(cat)/K(m) in NADPH:cytochrome c reductase assays. V492E was reconstituted upon addition of FAD, post-purification, as shown by flavin analysis, activity assay, and near UV-visible CD. Both Y459H and V492E were expressed as membrane anchor-containing proteins, which also exhibited FAD deficiency. CYP4A4-catalyzed omega-hydroxylation of prostaglandin E1 was supported by WT CYPOR but not by either of the ABS mutants. Hydroxylation activity was rescued for both Y459H and V492E upon addition of FAD to the reaction. Based on these findings, decreased FAD-binding affinity is proposed as the basis of the observed loss of CYPOR function in the Y459H and V492E POR mutations in ABS.
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Affiliation(s)
- Christopher C Marohnic
- Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78229, USA
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Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr 2002; 75:616-58. [PMID: 11916749 DOI: 10.1093/ajcn/75.4.616] [Citation(s) in RCA: 175] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Michaelis constant, or K(m), (decreased binding affinity) for a coenzyme, resulting in a lower rate of reaction. About 50 human genetic dis-eases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity. Several single-nucleotide polymorphisms, in which the variant amino acid reduces coenzyme binding and thus enzymatic activity, are likely to be remediable by raising cellular concentrations of the cofactor through high-dose vitamin therapy. Some examples include the alanine-to-valine substitution at codon 222 (Ala222-->Val) [DNA: C-to-T substitution at nucleo-tide 677 (677C-->T)] in methylenetetrahydrofolate reductase (NADPH) and the cofactor FAD (in relation to cardiovascular disease, migraines, and rages), the Pro187-->Ser (DNA: 609C-->T) mutation in NAD(P):quinone oxidoreductase 1 [NAD(P)H dehy-drogenase (quinone)] and FAD (in relation to cancer), the Ala44-->Gly (DNA: 131C-->G) mutation in glucose-6-phosphate 1-dehydrogenase and NADP (in relation to favism and hemolytic anemia), and the Glu487-->Lys mutation (present in one-half of Asians) in aldehyde dehydrogenase (NAD + ) and NAD (in relation to alcohol intolerance, Alzheimer disease, and cancer).
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Affiliation(s)
- Bruce N Ames
- Department of Molecular and Cellular Biology, University of California, Berkeley, USA.
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Vergani L, Barile M, Angelini C, Burlina AB, Nijtmans L, Freda MP, Brizio C, Zerbetto E, Dabbeni-Sala F. Riboflavin therapy. Biochemical heterogeneity in two adult lipid storage myopathies. Brain 1999; 122 ( Pt 12):2401-11. [PMID: 10581232 DOI: 10.1093/brain/122.12.2401] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Two unrelated adult males, aged 36 (patient 1) and 25 (patient 2) years, presented with subacute carnitine-deficient lipid storage myopathy that was totally and partly responsive to riboflavin supplementation in the two patients, respectively. Plasma acyl-carnitine and urinary organic acid profiles indicated multiple acyl coenzyme A dehydrogenase deficiency, which was mild in patient 1 and severe in patient 2. The activities of short-chain and medium-chain acyl coenzyme A dehydrogenases in mitochondrial fractions were decreased, especially in patient 2. This was in agreement with Western blotting results. Flavin-dependent complexes I and II were studied by immunoblotting and densitometric quantification of two-dimensional electrophoresis with comparable results. Complex I was present in normal amounts in both patients, whereas complex II was decreased only in the pretherapy muscle of patient 2. Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) concentrations in muscle and isolated mitochondria, and the activity of mitochondrial FAD pyrophosphatase, showed that patient 1 had low levels of FAD (46%) and FMN (49%) in mitochondria, with a significant increase (P < 0.01) in mitochondrial FAD pyrophosphatase (273%) compared with controls. Patient 2 had similar low levels of FAD and FMN in both total muscle (FAD and FMN 22% of controls) and mitochondria (FAD 26%; FMN 16%) and normal activity of mitochondrial FAD pyrophosphatase. All of these biochemical parameters were either totally or partly corrected after riboflavin therapy.
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Affiliation(s)
- L Vergani
- Neuromuscular Center, Department of Neurological Science, University of Padova, Padova, Italy.
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