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Eli Sprecher - One of the best experts on this subject based on the ideXlab platform.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
Dana Fuchstelem - One of the best experts on this subject based on the ideXlab platform.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
Ann Saada - One of the best experts on this subject based on the ideXlab platform.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
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Leigh Disease presenting in utero due to a novel missense mutation in the mitochondrial dna nd3
Molecular Genetics and Metabolism, 2010Co-Authors: Esther Leshinskysilver, Dorit Lev, G Malinger, Daniel Shapira, Sarit Cohen, Tally Lermansagie, Ann SaadaAbstract:Leigh syndrome can be caused by defects in both nuclear and mitochondrial genes involved in energy metabolism. Recently, an increasing number of mutations in mitochondrial DNA encoding regions, especially in NADH dehydrogenase (respiratory chain complex I) subunits, have been reported as causative of early onset Leigh syndrome. We describe a patient whose fetal brain ultrasound demonstrated periventricular pseudocyst suggestive of a possible mitochondrial disorder who presented postnatally with Leigh syndrome. A muscle biopsy demonstrated a partial decrease in complex I and pyruvate dehydrogenase (PDH-E1 alpha) activity. Sequencing of the PDH-E1 alpha gene did not reveal any mutation. Sequencing of the mtDNA revealed a novel heteroplasmic G10254A (D66N) mutation in the ND3 gene. This change results in a substitution of aspartic acid to asparagine in a highly conserved domain of the ND3 subunit. The mutation could not be detected in the mother's blood or urine sediment. Blue native gel electrophoresis of muscle mitochondria revealed a normal size, albeit a decreased level of complex I. The G10254A substitution in the mtDNA-ND3 gene is another cause of maternally inherited Leigh syndrome. This case demonstrates that periventricular pseudocysts may be the initial in utero presentation in patients with mitochondrial disorders. We emphasize the importance of screening the mtDNA in pediatric patients as the first step in molecular diagnosis of Leigh syndrome.
Richard J. Rodenburg - One of the best experts on this subject based on the ideXlab platform.
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NDUFA10 mutations cause complex I deficiency in a patient with Leigh Disease
European Journal of Human Genetics, 2011Co-Authors: Saskia J G Hoefs, Jan A.m. Smeitink, Richard J. Rodenburg, Leo G J Nijtmans, Francjan J Van Spronsen, Ellen W H Lenssen, Lambert P Van Den HeuvelAbstract:Mitochondrial complex I deficiency is the most common defect of the oxidative phosphorylation system. We report a patient with Leigh syndrome who showed a complex I deficiency expressed in cultured fibroblasts and muscle tissue. To find the genetic cause of the complex I deficiency, we screened the mitochondrial DNA and the nuclear-encoded subunits of complex I. We identified compound-heterozygous mutations in the NDUFA10 gene, encoding an accessory subunit of complex I. The first mutation disrupted the start codon and the second mutation resulted in an amino acid substitution. The fibroblasts of the patient displayed decreased amount and activity, and a disturbed assembly of complex I. These results indicate that NDUFA10 is a novel candidate gene to screen for Disease-causing mutations in patients with complex I deficiency.
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Leigh Disease with brainstem involvement in complex i deficiency due to assembly factor ndufaf2 defect
Neuropediatrics, 2010Co-Authors: Martina Herzer, Richard J. Rodenburg, Jan C Koch, Holger Prokisch, Christian Rauscher, W Radauer, R Forstner, P Pilz, Boris Rolinski, P FreisingerAbstract:Mitochondrial NADH: ubiquinone oxidoreductase (complex I) deficiency accounts for most defects in mitochondrial oxidative phosphorylation. Pathogenic mutations have been described in all 7 mitochondrial and 12 of the 38 nuclear encoded subunits as well as in assembly factors by interfering with the building of the mature enzyme complex within the inner mitochondrial membrane. We now describe a male patient with a novel homozygous stop mutation in the NDUFAF2 gene. The boy presented with severe apnoea and nystagmus. MRI showed brainstem lesions without involvement of basal ganglia and thalamus, plasma lactate was normal or close to normal. He died after a fulminate course within 2 months after the first crisis. Neuropathology verified Leigh Disease. We give a synopsis with other reported patients. Within the clinical spectrum of Leigh Disease, patients with mutations in NDUFAF2 present with a distinct clinical pattern with predominantly brainstem involvement on MRI. The diagnosis should not be missed in spite of the normal lactate and lack of thalamus and basal ganglia changes on brain MRI.
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ndufa2 complex i mutation leads to Leigh Disease
American Journal of Human Genetics, 2008Co-Authors: Saskia J G Hoefs, Richard J. Rodenburg, Cindy E J Dieteren, Felix Distelmaier, Rolf J R J Janssen, Andrea Epplen, H G P Swarts, Marleen Forkink, Leo G J NijtmansAbstract:Mitochondrial isolated complex I deficiency is the most frequently encountered OXPHOS defect. We report a patient with an isolated complex I deficiency expressed in skin fibroblasts as well as muscle tissue. Because the parents were consanguineous, we performed homozygosity mapping to identify homozygous regions containing candidate genes such as NDUFA2 on chromosome 5. Screening of this gene on genomic DNA revealed a mutation that interferes with correct splicing and results in the skipping of exon 2. Exon skipping was confirmed on the mRNA level. The mutation in this accessory subunit causes reduced activity and disturbed assembly of complex I. Furthermore, the mutation is associated with a mitochondrial depolarization. The expression and activity of complex I and the depolarization was (partially) rescued with a baculovirus system expressing the NDUFA2 gene.
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association of 3 methylglutaconic aciduria with sensori neural deafness encephalopathy and Leigh like syndrome megdel association in four patients with a disorder of the oxidative phosphorylation
Molecular Genetics and Metabolism, 2006Co-Authors: Saskia B Wortmann, Ference J Loupatty, T J De Koning, Marjan Huizing, Ron A Wevers, Jan A.m. Smeitink, Richard J. Rodenburg, Leo A J Kluijtmans, Udo F H Engelke, Eva MoravaAbstract:In this paper, we describe a distinct clinical subtype of 3-methylglutaconic aciduria. 3-Methylglutaconic aciduria is a group of different metabolic disorders biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. We performed biochemical and genetic investigations, including urine organic acid analysis, NMR spectroscopy, measurement of 3-methylglutaconyl-CoA hydratase activity, cardiolipin levels, OPA3 gene analysis and measurement of the oxidative phosphorylation in four female patients with 3-methylglutaconic aciduria. 3-Methylglutaconic aciduria type I, Barth syndrome, and Costeff syndrome were excluded as the activity of 3-methylglutaconyl-CoA hydratase, the cardiolipin levels, and molecular analysis of the OPA3 gene, respectively, showed no abnormalities. The children presented with characteristic association of hearing loss and the neuro-radiological evidence of Leigh Disease. They also had neonatal hypotonia, recurrent lactic acidemia, episodes with hypoglycemia and severe recurrent infections, feeding difficulties, failure to thrive, developmental delay, and progressive spasticity with extrapyramidal symptoms. Our patients were further biochemically characterized by a mitochondrial dysfunction and persistent urinary excretion of 3-methylglutaconic acid.
Ofer Sarig - One of the best experts on this subject based on the ideXlab platform.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.
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infantile mitochondrial hepatopathy is a cardinal feature of megdel syndrome 3 methylglutaconic aciduria type iv with sensorineural deafness encephalopathy and Leigh like syndrome caused by novel mutations in serac1
American Journal of Medical Genetics Part A, 2013Co-Authors: Ofer Sarig, Ann Saada, Dorit Goldsher, Janna Nousbeck, Dana Fuchstelem, Ksenya Cohenkatsenelson, Theodore C Iancu, Irena Manov, Eli SprecherAbstract:3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh Disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the Disease MEGDHEL syndrome. © 2013 Wiley Periodicals, Inc.