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Brage S Andresen - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial fatty acid oxidation defects remaining challenges
Journal of Inherited Metabolic Disease, 2008Co-Authors: Niels Gregersen, Thomas J Corydon, Rikke K. J. Olsen, Brage S Andresen, Christina Bak Pedersen, Peter BrossAbstract:Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3–4 ‘new’ disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the ‘old’ defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only ∼50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q10. With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.
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ETFDH mutations as a major cause of riboflavin responsive multiple acyl coa dehydrogenation deficiency
Brain, 2007Co-Authors: Rikke K. J. Olsen, Frank E. Frerman, Michael W Beresford, Morteza Pourfarzam, S E Olpin, Brage S Andresen, Zofia Miedzybrodzka, B Merinero, John Dean, Nanna CorneliusAbstract:Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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clear relationship between etf ETFDH genotype and phenotype in patients with multiple acyl coa dehydrogenation deficiency
Human Mutation, 2003Co-Authors: Rikke Katrine Jentoft Olsen, Peter Bross, Brage S Andresen, E Christensen, Flemming Skovby, Niels GregersenAbstract:Mutations in electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH) are the molecular basis of multiple acyl-CoA dehydrogenation deficiency (MADD), an autosomal recessively inherited and clinically heterogeneous disease that has been divided into three clinical forms: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). To examine whether these different clinical forms could be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, we have investigated the molecular genetic basis for disease development in nine patients representing the phenotypic spectrum of MADD. We report the genomic structures of the ETFA, ETFB, and ETFDH genes and the identification and characterization of seven novel and three previously reported disease-causing mutations. Our molecular genetic investigations of these nine patients are consistent with three clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of disease. Interestingly, our data suggest that homozygosity for two null mutations causes fetal development of congenital anomalies resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seem to be sufficient to prevent embryonic development of congenital anomalies giving rise to type II disease. Overexpression studies of an ETFB-D128N missense mutation identified in a patient with type III disease showed that the residual activity of the mutant enzyme could be rescued up to 59% of that of wild-type activity when ETFB-D128N-transformed E. coli cells were grown at low temperature. This indicates that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors like cellular temperature.
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late onset form of β electron transfer flavoprotein deficiency
Molecular Genetics and Metabolism, 2003Co-Authors: A Curcoy, Rikke K. J. Olsen, Brage S Andresen, Antonia Ribes, V Trenchs, M A Vilaseca, Jaume Campistol, Jose Henry Osorio, Niels GregersenAbstract:Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild beta-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis.
Chuanzhu Yan - One of the best experts on this subject based on the ideXlab platform.
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ETFDH mutations and flavin adenine dinucleotide homeostasis disturbance are essential for developing riboflavin responsive multiple acyl coenzyme a dehydrogenation deficiency
Annals of Neurology, 2018Co-Authors: Bing Wen, Yuying Zhao, Pengfei Lin, Fuchen Liu, Jingli Shan, Dandan Zhao, Joo Y Pok, Chuanzhu YanAbstract:OBJECTIVE Riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (RR-MADD) is an inherited fatty acid metabolism disorder mainly caused by genetic defects in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). The variant ETF:QO protein folding deficiency, which can be corrected by therapeutic dosage of riboflavin supplement, has been identified in HEK-293 cells and is believed to be the molecular mechanism of this disease. To verify this hypothesis in vivo, we generated ETFDH (h)A84T knockin (KI) mice. METHODS Tissues from these mice as well as muscle biopsies and fibroblasts from 7 RR-MADD patients were used to examine the flavin adenine dinucleotide (FAD) concentration and ETF:QO protein amount. RESULTS All of the homozygous KI mice (ETFDH (h)A84T/(h)A84T , KI/KI) were initially normal. After being given a high-fat and vitamin B2 -deficient (HF-B2 D) diet for 5 weeks, they developed weight loss, movement ability defects, lipid storage in muscle and liver, and elevated serum acyl-carnitine levels, which are clinically and biochemically similar to RR-MADD patients. Both ETF:QO protein and FAD concentrations were significantly decreased in tissues of HF-B2 D-KI/KI mice and in cultured fibroblasts from RR-MADD patients. After riboflavin treatment, ETF:QO protein increased in proportion to elevated FAD concentrations, but not related to mRNA levels. These results were further confirmed in cultured fibroblasts from RR-MADD patients. INTERPRETATION For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681.
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clinical features and ETFDH mutation spectrum in a cohort of 90 chinese patients with late onset multiple acyl coa dehydrogenase deficiency
Journal of Inherited Metabolic Disease, 2014Co-Authors: Bing Wen, Pengfei Lin, Jie Lin, Wenhua Zhu, Sushan Luo, Chongbo Zhao, Chuanzhu YanAbstract:The major cause of lipid storage myopathies (LSM) in China is multiple acyl-CoA dehydrogenase deficiency (MADD) caused by ETFDH mutations. We here present an analysis of the spectrum of ETFDH mutations in the largest cohort of patients with MADD (90 unrelated patients). We identified 61 ETFDH mutations, including 31 novel mutations, which were widely distributed within the coding sequence. Three frequent mutations were identified: c.250G > A (most common in South China), c.770A > G and c.1227A > C (most common in both South and North China). Regional differences of allele frequency and further haplotype analysis suggest the possibility of founder effects of c.250G > A and c.770A > G. These findings promise to provide the basis for implementing a rapid and economical strategy for diagnosing MADD.
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increased muscle coenzyme q10 in riboflavin responsive madd with ETFDH gene mutations due to secondary mitochondrial proliferation
Molecular Genetics and Metabolism, 2013Co-Authors: Bing Wen, Yuying Zhao, Pengfei Lin, Jingli Shan, Shuping Liu, Jinfan Zheng, Yaoqin Gong, Chuanzhu YanAbstract:Multiple acyl-coenzyme A dehydrogenation deficiency (MADD) has a wide range of phenotypic variation ranging from a neonatal lethal form to a mild late-onset form. Our previous data showed that in a group of Chinese patients, a mild type of MADD characterized by myopathy with clinically no other systemic involvement was caused by mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, which encodes electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO). Coenzyme Q10 (CoQ10), a downstream electron receptor of ETF:QO was first reported deficient in muscle of MADD patients with ETFDH gene mutations. Nevertheless, this result was not confirmed in a recently published study. Therefore to elucidate muscle CoQ10 level in a large group of MADD patients may provide further insight into the pathomechanism and therapeutic strategies. In this study, we found that 34 riboflavin responsive patients with ETFDH gene mutations had an elevated CoQ10 pool in muscle by high performance liquid chromatography (HPLC). However, when CoQ10 levels were normalized to citrate synthase, a marker of mitochondrial mass, there was no significant difference between patients and normal controls. Meanwhile, the increased mitochondrial DNA copy number in muscle also supported that the elevated CoQ10 pool was mainly due to mitochondrial mass proliferation. The expression of CoQ10 biosynthesis genes showed no significant changes whereas genes involved in lipid metabolism, such as PPARα, were marked up regulated. Our results suggested that CoQ10 seems not to be a primary factor in riboflavin responsive MADD and the apparent increase in CoQ10 may be secondary to mitochondrial proliferation.
Niels Gregersen - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial fatty acid oxidation defects remaining challenges
Journal of Inherited Metabolic Disease, 2008Co-Authors: Niels Gregersen, Thomas J Corydon, Rikke K. J. Olsen, Brage S Andresen, Christina Bak Pedersen, Peter BrossAbstract:Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3–4 ‘new’ disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the ‘old’ defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only ∼50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q10. With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.
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clear relationship between etf ETFDH genotype and phenotype in patients with multiple acyl coa dehydrogenation deficiency
Human Mutation, 2003Co-Authors: Rikke Katrine Jentoft Olsen, Peter Bross, Brage S Andresen, E Christensen, Flemming Skovby, Niels GregersenAbstract:Mutations in electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH) are the molecular basis of multiple acyl-CoA dehydrogenation deficiency (MADD), an autosomal recessively inherited and clinically heterogeneous disease that has been divided into three clinical forms: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). To examine whether these different clinical forms could be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, we have investigated the molecular genetic basis for disease development in nine patients representing the phenotypic spectrum of MADD. We report the genomic structures of the ETFA, ETFB, and ETFDH genes and the identification and characterization of seven novel and three previously reported disease-causing mutations. Our molecular genetic investigations of these nine patients are consistent with three clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of disease. Interestingly, our data suggest that homozygosity for two null mutations causes fetal development of congenital anomalies resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seem to be sufficient to prevent embryonic development of congenital anomalies giving rise to type II disease. Overexpression studies of an ETFB-D128N missense mutation identified in a patient with type III disease showed that the residual activity of the mutant enzyme could be rescued up to 59% of that of wild-type activity when ETFB-D128N-transformed E. coli cells were grown at low temperature. This indicates that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors like cellular temperature.
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late onset form of β electron transfer flavoprotein deficiency
Molecular Genetics and Metabolism, 2003Co-Authors: A Curcoy, Rikke K. J. Olsen, Brage S Andresen, Antonia Ribes, V Trenchs, M A Vilaseca, Jaume Campistol, Jose Henry Osorio, Niels GregersenAbstract:Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild beta-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis.
Wenchen Liang - One of the best experts on this subject based on the ideXlab platform.
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neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors
Muscle & Nerve, 2017Co-Authors: Wenchen Liang, Yenfong Lin, Tingyuan Liu, Shincheng Chang, Baihsiun Chen, Ichizo Nishino, Yuhjyh JongAbstract:INTRODUCTION c.250G>A (p.Ala84Thr) in ETFDH is the most common mutation that causes later-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) in the southern Chinese population. No functional study has targeted this mutation. METHODS Using cells expressing ETFDH-wild-type (WT) or ETFDH-mutant (p.Ala84Thr), reactive oxygen species (ROS) production and neurite length were analyzed, followed by pathomechanism exploration and drug screening. RESULTS Increased ROS production and marked neurite shortening were observed in the cells expressing the ETFDH-mutant, compared with WT. Further studies demonstrated that suberic acid, an accumulated intermediate metabolite in MADD, could significantly impair neurite outgrowth of NSC34 cells, but neurite shortening could be restored by supplementation with carnitine, riboflavin, or Coenzyme Q10. CONCLUSIONS Neurite shortening caused by the c.250G>A mutation in ETFDH suggests that neural defects could be underdiagnosed in human patients with MADD. This impairment might be treatable with mitochondrial cofactor supplementation. Muscle Nerve 56: 479-485, 2017.
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p 17 11 c 250g a in ETFDH a common sequence variant in southern chinese population is a pathogenic mutation to cause multiple acyl coa dehydrogenase deficiency
Neuromuscular Disorders, 2013Co-Authors: Wenchen Liang, Ichizo Nishino, Y F Lin, D Y Liu, Yuhjyh JongAbstract:Multiple acyl-CoA deyhydrogenase deficiency (MADD) is caused by defects in electron transfer flavoprotein and ETF-ubiquinone oxidoreductase (ETF-QO). Recently, a common sequence variant in ETFDH, encoding ETF-QO, was initially identified in Taiwanese MADD patients with carrier frequency about 1%. Several subsequent reports supported that this probable founder mutation, c.250G > A (p.Ala84Thr), is the most common cause of MADD in southern Chinese population. Later-onset MADD clinically present with episodic muscle weakness under acute metabolic decompensation, cause mortality due to metabolic crisis and pathologically lead to intracellular lipid accumulation. Riboflavin supplementation has shown its efficacy in the MADD patients, particularly with ETFDH mutations and later onset form. As MADD may be the most common hereditary disorder of lipid metabolism in southern Chinese population and it is potentially treatable, we used different analyses in vitro to show the pathogenesis of MADD caused by this common mutation, c.250G > A in ETFDH, including assessments of lipid and acylcarnitines accumulation, neurite outgrowth and reactive oxygen species (ROS) production. We successfully observed increased intracellular lipid droplets, elevated acylcarnitine concentration, neurite shortening and augmented ROS production in transfected cells which recapitulates the pathological and biochemical phenotypes in human. These results prove that this hot spot mutation is a true pathogenic mutation, not a polymorphism. Screening this hot spot mutation for Chinese patients clinically suspected to have MADD would be helpful for early diagnosis of MADD for which riboflavin supplementation may be effective. In addition, this in vitro system may be also useful for screening potential therapeutic strategies and further exploring the pathomechanism of MADD.
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adult onset multiple acyl coa dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase
Neuromuscular Disorders, 2012Co-Authors: Fuminobu Sugai, Wenchen Liang, Ichizo Nishino, Kousuke Baba, Keiko Toyooka, Misaki Yamadera, Hisae Sumi, Harutoshi Fujimura, Yoshiro NishikawaAbstract:We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content.
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high resolution melting analysis facilitates mutation screening of ETFDH gene applications in riboflavin responsive multiple acyl coa dehydrogenase deficiency
Clinica Chimica Acta, 2010Co-Authors: Wenchen Liang, Jangowth Chang, Yuhjyh JongAbstract:Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MADD) or gluaric aciduria type II is an autosomal recessive disease caused by defects in mitochondrial electron transfer system and metabolism of fatty acid. Recently, ETFDH mutations were reported to be major causes of riboflavin-responsive MADD. The present study is aimed at screening ETFDH mutations. Methods High resolution melting (HRM) analysis was performed to screen ETFDH mutations. Genomic DNA was extracted from peripheral blood samples of the 9 patients with MADD and normal controls. Total 13 exons of ETFDH were screened by HRM analysis. The results were subsequently confirmed by direct DNA sequencing. Results This diagnostic strategy proved to be feasible in detecting 3 known (c.250G > A, c380T > A, c.524G > T) and 1 novel (c.1831G > A) ETFDH mutations. Each mutation could be readily and accurately identified in the difference plot curves. We estimated the carrier frequency of the hotspot mutation, c.250G > A, in the Taiwanese population to be 1:125 (0.8%). Conclusions HRM analysis can be successfully applied to screen ETFDH mutations. Since riboflavin-responsive MADD is often treatable, especially with mutations in ETFDH, identifying ETFDH mutations is crucial for these patients.
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ETFDH mutations coq10 levels and respiratory chain activities in patients with riboflavin responsive multiple acyl coa dehydrogenase deficiency
Neuromuscular Disorders, 2009Co-Authors: Wenchen Liang, Yuhjyh Jong, Aya Ohkuma, Yukiko K Hayashi, Luis C Lopez, Michio Hirano, Ikuya Nonaka, Satoru Noguchi, Lianghui Chen, Ichizo NishinoAbstract: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 CoQ10 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 CoQ10 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 CoQ10 deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD.
Rikke K. J. Olsen - One of the best experts on this subject based on the ideXlab platform.
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A Novel Truncating FLAD1 Variant, Causing Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in an 8-Year-Old Boy.
JIMD reports, 2018Co-Authors: B. Ryder, Zahra Nochi, Maria Tolomeo, Matilde Colella, Maria Barile, Rikke K. J. Olsen, M. Inbar-feigenbergAbstract:Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) is a clinically heterogeneous disorder affecting fatty acid and amino acid metabolism. Presentations range from a severe neonatal form with hypoglycemia, metabolic acidosis, and hepatomegaly with or without congenital anomalies to later-onset lipid storage myopathy. Genetic testing for MADD traditionally comprises analysis of ETFA, ETFB, and ETFDH. Patients may respond to pharmacological doses of riboflavin, particularly those with late-onset MADD due to variants in ETFDH. Increasingly other genes involved in riboflavin transport and flavoprotein biosynthesis are recognized as causing a MADD phenotype. Flavin adenine dinucleotide synthase (FADS) deficiency caused by biallelic variants in FLAD1 has been identified in nine previous cases of MADD. FLAD1 missense mutations have been associated with a riboflavin-responsive phenotype; however the effect of riboflavin with biallelic loss of function FLAD1 mutations required further investigation. Herein we describe a novel, truncating variant in FLAD1 causing MADD in an 8-year-old boy. Fibroblast studies showed a dramatic reduction in FADS protein with corresponding reduction in the FAD synthesis rate and FAD cellular content, beyond that previously documented in FLAD1-related MADD. There was apparent biochemical and clinical response to riboflavin treatment, beyond that previously reported in cases of biallelic loss of function variants in FLAD1. Early riboflavin treatment may have attenuated an otherwise severe phenotype.
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mitochondrial fatty acid oxidation defects remaining challenges
Journal of Inherited Metabolic Disease, 2008Co-Authors: Niels Gregersen, Thomas J Corydon, Rikke K. J. Olsen, Brage S Andresen, Christina Bak Pedersen, Peter BrossAbstract:Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3–4 ‘new’ disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the ‘old’ defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only ∼50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q10. With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.
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ETFDH mutations as a major cause of riboflavin responsive multiple acyl coa dehydrogenation deficiency
Brain, 2007Co-Authors: Rikke K. J. Olsen, Frank E. Frerman, Michael W Beresford, Morteza Pourfarzam, S E Olpin, Brage S Andresen, Zofia Miedzybrodzka, B Merinero, John Dean, Nanna CorneliusAbstract:Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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late onset form of β electron transfer flavoprotein deficiency
Molecular Genetics and Metabolism, 2003Co-Authors: A Curcoy, Rikke K. J. Olsen, Brage S Andresen, Antonia Ribes, V Trenchs, M A Vilaseca, Jaume Campistol, Jose Henry Osorio, Niels GregersenAbstract:Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild beta-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis.