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Salvatore Dimauro - One of the best experts on this subject based on the ideXlab platform.
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functional cellular analyses reveal energy metabolism defect and Mitochondrial DNA Depletion in a case of Mitochondrial aconitase deficiency
Molecular Genetics and Metabolism, 2016Co-Authors: Roa Sadat, Ali Naini, Salvatore Dimauro, Darryl C De Vivo, Emanuele Barca, Ruchi Masand, Taraka R Donti, Neil A Hanchard, Brett H GrahamAbstract:Defects in the tricarboxylic acid cycle (TCA) are associated with a spectrum of neurological phenotypes that are often difficult to diagnose and manage. Whole-exome sequencing (WES) led to a rapid expansion of diagnostic capabilities in such disorders and facilitated a better understanding of disease pathogenesis, although functional characterization remains a bottleneck to the interpretation of potential pathological variants. We report a 2-year-old boy of Afro-Caribbean ancestry, who presented with neuromuscular symptoms without significant abnormalities on routine diagnostic evaluation. WES revealed compound heterozygous missense variants of uncertain significance in Mitochondrial aconitase (ACO2), which encodes the TCA enzyme ACO2. Pathogenic variants in ACO2 have been described in a handful of families as the cause of infantile cerebellar-retinal degeneration syndrome. Using biochemical and cellular assays in patient fibroblasts, we found that ACO2 expression was quantitatively normal, but ACO2 enzyme activity was <20% of that observed in control cells. We also observed a deficiency in cellular respiration and, for the first time, demonstrate evidence of Mitochondrial DNA Depletion and altered expression of some TCA components and electron transport chain subunits. The observed cellular defects were completely restored with ACO2 gene rescue. Our findings demonstrate the pathogenicity of two VUS in ACO2, provide novel mechanistic insights to TCA disturbances in ACO2 deficiency, and implicate Mitochondrial DNA Depletion in the pathogenesis of this recently described disorder.
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Clinical spectrum of Mitochondrial DNA Depletion due to mutations in the thymidine kinase 2 gene.
Archives of neurology, 2006Co-Authors: M. Oskoui, Eduardo Bonilla, Sara Shanske, Darryl C De Vivo, Guido Davidzon, Juan M. Pascual, Ricardo Erazo, Juliana Gurgel-giannetti, Sindu Krishna, Salvatore DimauroAbstract:Background Mitochondrial DNA Depletion syndrome is an autosomal recessive disorder characterized by decreased Mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 ( TK2 ), deoxyguanosine kinase ( DGUOK ), polymerase gamma ( POLG ), and SUCLA2 , the gene encoding the β-subunit of the adenosine diphosphate–forming succinyl coenzyme A synthetase ligase. Objective To highlight the variability in the clinical spectrum of TK2 -related Mitochondrial DNA Depletion syndrome. Design Review of patients and the literature. Setting Tertiary care university. Patients Four patients with Mitochondrial DNA Depletion syndrome and mutations in the TK2 gene. Main Outcome Measures Definition of clinical variability. Results Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive Mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. Conclusion The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3–like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.
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New DGK gene mutations in the hepatocerebral form of Mitochondrial DNA Depletion syndrome.
Archives of neurology, 2005Co-Authors: Michelangelo Mancuso, Silvio Ferraris, Jacklyn Pancrudo, Annette Feigenbaum, Julian Raiman, John Christodoulou, David R. Thorburn, Salvatore DimauroAbstract:Objective To document novel homozygous mutations in the gene for deoxyguanosine kinase ( DGK ) in 3 children with Mitochondrial DNA Depletion. Design Clinical features included liver failure, hypotonia, and nystagmus in 2 siblings, and liver cirrhosis, optic dysplasia, nystagmus, and microcephaly in the third patient. We sequenced the whole coding region of the DGK gene. Results We identified 2 novel homozygous mutations, G352A and C269T, that lead to truncated proteins. Conclusion These data confirm that DGK mutations typically affect the liver and brain.
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Mitochondrial Myopathy of Childhood Associated With Mitochondrial DNA Depletion and a Homozygous Mutation (T77M) in the TK2 Gene
Archives of neurology, 2003Co-Authors: Michelangelo Mancuso, Eduardo Bonilla, Sara Shanske, Massimiliano Filosto, Michio Hirano, Salvatore DimauroAbstract:Background The Mitochondrial DNA Depletion syndrome is an autosomal recessive disorder of infancy or childhood characterized by decreased Mitochondrial DNA copy number in affected tissues. Mutations in 2 genes involved in deoxyribonucleotide metabolism, the deoxyguanosine kinase gene ( DGK ) and the thymidine kinase 2 gene ( TK2 ), have been related to this syndrome. Objective To describe 3 siblings with the myopathic form of Mitochondrial DNA Depletion syndrome and a homozygous mutation in the TK2 gene. Patients and Methods These children developed normally until 12 to 16 months of age, when they started showing difficulty walking, which rapidly progressed to severe limb weakness. They died of respiratory failure between the ages of 23 and 40 months. Histochemical and biochemical studies of respiratory chain complexes were performed in muscle biopsy specimens. The whole coding region of the TK2 gene was sequenced. Results Muscle biopsy showed ragged-red cytochrome- c oxidase–negative fibers. All affected siblings had markedly decreased activities of respiratory chain complexes. Southern blot analysis showed severe reduction of the Mitochondrial DNA–nuclear DNA ratio in muscle biopsy specimens from all patients, indicating 80% to 90% Mitochondrial DNA Depletion. Sequencing of the TK2 gene showed a homozygous C→T transition at nucleotide 228 in exon 5, which changes a threonine to a methionine at position 77 (T77M). Conclusions These results document the importance of screening the TK2 gene in patients with myopathic Mitochondrial DNA Depletion syndrome and confirm that exon 5 is a "hot spot" for TK2 mutations.
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Mitochondrial myopathy simulating spinal muscular atrophy
Pediatric Neurology, 1996Co-Authors: Roser Pons, Francesca Andreetta, Tuan H. Vu, Ching H Wang, Eduardo Bonilla, Salvatore Dimauro, Darryl C De VivoAbstract:A patient with a severe progressive neuromuscular disorder resembling spinal muscular atrophy is reported. The initial muscle biopsy was consistent with a denervating process. DNA analysis did not reveal deletions in exons 7 and 8 of the survival motor neuron gene. Histology, histochemistry, and biochemistry of a second muscle biopsy suggested Mitochondrial myopathy accompanying the denervating features. Immunohistochemistry using anti-DNA antibodies revealed only nuclear staining in skeletal muscle, suggesting Mitochondrial DNA Depletion. In patients with clinical features of spinal muscular atrophy and no deletions in the survival motor neuron gene, Mitochondrial DNA Depletion should be considered.
Sara Shanske - One of the best experts on this subject based on the ideXlab platform.
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Hepatocerebral form of Mitochondrial DNA Depletion syndrome: novel MPV17 mutations.
Archives of neurology, 2008Co-Authors: Antonella Spinazzola, Jaya Ganesh, Sara Shanske, René Santer, Orhan H. Akman, Kostas Tsiakas, Hansjoerg Schaefer, Xiaoqi Ding, Charalampos Karadimas, Salvatore Di MauroAbstract:Background Autosomal recessive mutations in MPV17 (OMIM*137960) have been identified in the hepatocerebral form of Mitochondrial DNA Depletion syndrome (MDS). Objective To describe the clinical, morphologic, and genetic findings in 3 children with MPV17 -related MDS from 2 unrelated families. Design Case report. Setting Academic research. Main Outcome Measures We identified 3 novel pathogenic mutations in 3 children. Results Two children were homozygous for nonsense mutation p.W120X. A third child was compound heterozygous for missense mutation p.G24W and for a macrodeletion spanning MPV17 exon 8. All patients demonstrated lactic acidosis, hypoglycemia, hepatomegaly, and progressive liver failure. Neurologic symptoms manifested at a later stage of the disease. Death occurred within the first year of life in all 3 patients. Conclusions These data confirm that MPV17 mutations are associated with a 2-stage syndrome. The first symptoms are metabolic and rapidly progress to hepatic failure. This stage is followed by neurologic involvement affecting the central and peripheral systems.
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Mitochondrial DNA Depletion syndrome due to mutations in the RRM2B gene
Neuromuscular Disorders, 2008Co-Authors: Belen Bornstein, Estela Area, Jaya Ganesh, Parul Jayakar, Jorida Coku, Ali Naini, Sara Shanske, Kevin M. Flanigan, Kathryn J Swoboda, Kurenai TanjiAbstract:Abstract Mitochondrial DNA Depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in Mitochondrial nucleotide metabolism ( POLG , TK2 , DGUOK , SUCLA2 , SUCLG1 , PEO1 ) and MPV17 . Recently, mutations in the RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in seven infants from four families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age. We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA Depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at 3 months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months. All three patients had lactic acidosis and severe Depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exons 6, 8, and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.
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Clinical spectrum of Mitochondrial DNA Depletion due to mutations in the thymidine kinase 2 gene.
Archives of neurology, 2006Co-Authors: M. Oskoui, Eduardo Bonilla, Sara Shanske, Darryl C De Vivo, Guido Davidzon, Juan M. Pascual, Ricardo Erazo, Juliana Gurgel-giannetti, Sindu Krishna, Salvatore DimauroAbstract:Background Mitochondrial DNA Depletion syndrome is an autosomal recessive disorder characterized by decreased Mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 ( TK2 ), deoxyguanosine kinase ( DGUOK ), polymerase gamma ( POLG ), and SUCLA2 , the gene encoding the β-subunit of the adenosine diphosphate–forming succinyl coenzyme A synthetase ligase. Objective To highlight the variability in the clinical spectrum of TK2 -related Mitochondrial DNA Depletion syndrome. Design Review of patients and the literature. Setting Tertiary care university. Patients Four patients with Mitochondrial DNA Depletion syndrome and mutations in the TK2 gene. Main Outcome Measures Definition of clinical variability. Results Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive Mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. Conclusion The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3–like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.
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Mitochondrial Myopathy of Childhood Associated With Mitochondrial DNA Depletion and a Homozygous Mutation (T77M) in the TK2 Gene
Archives of neurology, 2003Co-Authors: Michelangelo Mancuso, Eduardo Bonilla, Sara Shanske, Massimiliano Filosto, Michio Hirano, Salvatore DimauroAbstract:Background The Mitochondrial DNA Depletion syndrome is an autosomal recessive disorder of infancy or childhood characterized by decreased Mitochondrial DNA copy number in affected tissues. Mutations in 2 genes involved in deoxyribonucleotide metabolism, the deoxyguanosine kinase gene ( DGK ) and the thymidine kinase 2 gene ( TK2 ), have been related to this syndrome. Objective To describe 3 siblings with the myopathic form of Mitochondrial DNA Depletion syndrome and a homozygous mutation in the TK2 gene. Patients and Methods These children developed normally until 12 to 16 months of age, when they started showing difficulty walking, which rapidly progressed to severe limb weakness. They died of respiratory failure between the ages of 23 and 40 months. Histochemical and biochemical studies of respiratory chain complexes were performed in muscle biopsy specimens. The whole coding region of the TK2 gene was sequenced. Results Muscle biopsy showed ragged-red cytochrome- c oxidase–negative fibers. All affected siblings had markedly decreased activities of respiratory chain complexes. Southern blot analysis showed severe reduction of the Mitochondrial DNA–nuclear DNA ratio in muscle biopsy specimens from all patients, indicating 80% to 90% Mitochondrial DNA Depletion. Sequencing of the TK2 gene showed a homozygous C→T transition at nucleotide 228 in exon 5, which changes a threonine to a methionine at position 77 (T77M). Conclusions These results document the importance of screening the TK2 gene in patients with myopathic Mitochondrial DNA Depletion syndrome and confirm that exon 5 is a "hot spot" for TK2 mutations.
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clinical manifestations of Mitochondrial DNA Depletion
Neurology, 1998Co-Authors: Monica Sciacco, Eduardo Bonilla, Kurenai Tanji, Sara Shanske, Jerry R. Mendell, C Nichter, S Chatkupt, Paul Maertens, M R Koenigsberger, Leroy R SharerAbstract:Objective We studied five new patients with Mitochondrial DNA (mtDNA) Depletion to better define the clinical spectrum of this disorder. Background mtDNA Depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. Methods We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. Results Age at onset ranged from 3 months to 5 years, and one patient survived until age 10% years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. Conclusions Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA Depletion. mtDNA Depletion should be considered in children with mitochondria1 disorders of uncertain etiology, and criteria for diagnosis are proposed.
Leejun C Wong - One of the best experts on this subject based on the ideXlab platform.
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Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other Mitochondrial oxidative enzymes in skeletal muscle without Mitochondrial DNA Depletion.
Molecular genetics and metabolism, 2016Co-Authors: Xiaoping Huang, Leejun C Wong, Jirair K. Bedoyan, Didem Demirbas, David J. Harris, Alexander Miron, Simone Edelheit, George Grahame, Suzanne D. Debrosse, Charles L. HoppelAbstract:Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a Mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 developed Leigh syndrome, severe GI dysmotility, intermittent anemia, hypogammaglobulinemia and eventually succumbed to his disorder. The Mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings. Pyruvate dehydrogenase complex, ketoglutarate dehydrogenase complex, and several Mitochondrial electron transport chain (ETC) activities were low or at the low end of the reference range in frozen SM from S1 and/or S2. In contrast, activities of PDC, other Mitochondrial enzymes of pyruvate metabolism, ETC and, integrated oxidative phosphorylation, in skin fibroblasts were not significantly impaired. Although we show that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM. A better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of Mitochondrial enzymes of oxidative metabolism, and independently Mitochondrial DNA Depletion (common in other cases of A-SCS deficiency), is needed given the implications for control of lactic acidosis and possible clinical management.
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Quantitative Evaluation of the Mitochondrial DNA Depletion Syndrome
Clinical Chemistry, 2010Co-Authors: David Dimmock, Eric S. Schmitt, L. Tang, Leejun C WongAbstract:Background: The Mitochondrial DNA (mtDNA) Depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a reduction in cellular mtDNA content. Mutations in at least 9 genes [ POLG , polymerase (DNA directed), gamma; DGUOK , deoxyguanosine kinase; TK2 , thymidine kinase, Mitochondrial; TYMP , thymidine phosphorylase; MPV17 , MpV17 Mitochondrial inner membrane protein; SUCLA2 , succinate-CoA ligase, ADP-forming, beta subunit; SUCLG1 , succinate-CoA ligase, alpha subunit; RRM2B , RRM2B , ribonucleotide reductase M2 B (TP53 inducible); and C10orf2 , chromosome 10 open reading frame 2 (also known as TWINKLE )] have been reported to cause mtDNA Depletion. In the clinical setting, a simple method to quantify mtDNA Depletion would be useful before undertaking gene sequence analysis. Methods: Real-time quantitative PCR (qPCR) was used to measure the mtDNA content in blood, muscle, and liver samples and in skin fibroblast cultures from individuals suspected of Mitochondrial disorders, with or without deleterious mutations in genes responsible for MDDS. Results: The mtDNA content was quantified in 776 tissue samples (blood, n = 341; muscle, n = 325; liver, n = 63; skin fibroblasts, n = 47) from control individuals. mtDNA content increased with age in muscle tissue, decreased with age in blood samples, and appeared to be unaffected by age in liver samples. In 165 samples (blood, n = 122; muscle, n = 21; liver, n = 15; skin fibroblasts, n = 7) from patients with molecularly proven MDDSs, severe mtDNA Depletion was detected in liver and muscle tissue with high specificity and sensitivity. Blood samples were specific but not sensitive for detecting mtDNA Depletion, and skin fibroblasts were not valuable for evaluating mtDNA Depletion. Mutations in the POLG , RRM2B , and MPV17 genes were prospectively identified in 1 blood, 1 liver, and 3 muscle samples. Conclusions: Muscle and liver tissues, but not blood or skin fibroblasts, are potentially useful for rapid screening for mtDNA Depletion with real-time qPCR.
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MPV17-associated hepatocerebral Mitochondrial DNA Depletion syndrome: New patients and novel mutations
Molecular genetics and metabolism, 2009Co-Authors: Ayman W. El-hattab, Eric S. Schmitt, Shulin Na Zhang, William J. Craigen, Leejun C WongAbstract:Mitochondrial DNA Depletion syndromes are autosomal recessive diseases characterized by a severe decrease in Mitochondrial DNA content leading to dysfunction of the affected organ. They are phenotypically heterogeneous and classified as myopathic, encephalomyopathic, or hepatocerebral. The latter group has been associated with mutations in TWINKLE,POLG1, DGUOK genes and recently with mutations in the MPV17 gene. MPV17 encodes a Mitochondrial inner membrane protein and plays an as yet poorly understood role in Mitochondrial DNA maintenance. Mutations in the MPV17 gene have been reported in patients who came to medical attention during infancy with liver failure, hypoglycemia, failure-to-thrive and neurological symptoms. In addition, a homozygous p.R50Q mutation has been identified in patients with Navajo neurohepatopathy. To date, 13 different mutations in 21 patients have been reported. We report eight new patients with seven novel mutations, including four missense mutations (c.262A>G (p.K88E), c.280G>C (p.G94R), c.293C>T (p.P98L), and c.485C>A (p.A162D)), one in-frame deletion (c.271_273del3 (p.L91del)), one splice site substitution (c.186+2T>C), and one insertion (c.22_23insC). The p.R50Q mutation, which occurs in a CpG dinucleotide, is the most common MPV17 mutation and, to date, has only been found in the homozygous state. Clinically, patients homozygous for p.R50Q or compound heterozygous for the p.G94R and p.P98L mutations have a better prognosis, with all the other mutations associated with early death if not treated by liver transplantation. Localizing the mutations within the predicted MPV17 protein structure reveals clustering of mutations in the region of the putative protein kinase C phosphorylation site.
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Progressive myofiber loss with extensive fibro-fatty replacement in a child with Mitochondrial DNA Depletion syndrome and novel thymidine kinase 2 gene mutations.
Neuromuscular disorders : NMD, 2009Co-Authors: James J. Collins, Leejun C Wong, David Dimmock, Kevin E. Bove, P. Morehart, Brenda WongAbstract:The Mitochondrial DNA Depletion syndromes (MDS) are autosomal recessive disorders with a decreased Mitochondrial DNA copy number. Mutations in thymidine kinase 2 (TK2) have been responsible for the myopathic form of MDS. We describe a child with congenital muscle weakness who had a progressive Mitochondrial myopathy associated with extensive fibro-fatty replacement of myofibers resembling muscular dystrophy. MDS was suspected based upon findings in the initial muscle biopsy. Sequence analysis of the TK2 gene revealed two novel heterozygous mutations: the frame shift mutation, c.255_c.258delAGAA, and the heterozygous missense mutation, c.515G>A, (p.R172Q). This report extends the phenotype and genotype of TK2 defects.
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Simultaneous detection of Mitochondrial DNA Depletion and single-exon deletion in the deoxyguanosine gene using array-based comparative genomic hybridisation
Archives of disease in childhood, 2009Co-Authors: Ni-chung Lee, D. Dimmock, Wuh-liang Hwu, L. Y. Tang, Wei Chen Huang, A. C. Chinault, Leejun C WongAbstract:Intragenic exonic deletions, which cannot be detected by direct DNA sequencing, are a common cause of Mendelian disease. Array-based comparative genomic hybridisation (aCGH) is now widely used for the clinical diagnosis of large chromosomal deletions, but not small deletions or analysis of the Mitochondrial genome. An oligonucleotide-based microarray that provides high-density coverage of the entire Mitochondrial genome and nuclear genes related to Mitochondrial disorders has been developed. In this report, the case of an infant referred with tyrosinaemia on newborn screening who developed liver failure is presented. DNA sequencing revealed a heterozygous missense mutation (c.679G>A, p.E227K) in the deoxyguanosine gene (DGUOK). Oligonucleotide aCGH allowed simultaneous detection of an intragenic heterozygous deletion of exon 4 of DGUOK and Mitochondrial DNA Depletion in blood and liver. Screening of the parents' DNA samples indicated that the patient was compound heterozygous for these mutations. An older sibling who had died from liver failure was then retrospectively diagnosed with the same mutations. This report shows the clinical utility of this oligoarray in the detection of changes in DNA copy number in both the Mitochondrial and nuclear genomes, thus greatly improving the molecular diagnosis of Mitochondrial disorders caused by nuclear genes involved in Mitochondrial DNA biosynthesis.
Eduardo Bonilla - One of the best experts on this subject based on the ideXlab platform.
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Clinical spectrum of Mitochondrial DNA Depletion due to mutations in the thymidine kinase 2 gene.
Archives of neurology, 2006Co-Authors: M. Oskoui, Eduardo Bonilla, Sara Shanske, Darryl C De Vivo, Guido Davidzon, Juan M. Pascual, Ricardo Erazo, Juliana Gurgel-giannetti, Sindu Krishna, Salvatore DimauroAbstract:Background Mitochondrial DNA Depletion syndrome is an autosomal recessive disorder characterized by decreased Mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 ( TK2 ), deoxyguanosine kinase ( DGUOK ), polymerase gamma ( POLG ), and SUCLA2 , the gene encoding the β-subunit of the adenosine diphosphate–forming succinyl coenzyme A synthetase ligase. Objective To highlight the variability in the clinical spectrum of TK2 -related Mitochondrial DNA Depletion syndrome. Design Review of patients and the literature. Setting Tertiary care university. Patients Four patients with Mitochondrial DNA Depletion syndrome and mutations in the TK2 gene. Main Outcome Measures Definition of clinical variability. Results Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive Mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. Conclusion The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3–like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.
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Mitochondrial Myopathy of Childhood Associated With Mitochondrial DNA Depletion and a Homozygous Mutation (T77M) in the TK2 Gene
Archives of neurology, 2003Co-Authors: Michelangelo Mancuso, Eduardo Bonilla, Sara Shanske, Massimiliano Filosto, Michio Hirano, Salvatore DimauroAbstract:Background The Mitochondrial DNA Depletion syndrome is an autosomal recessive disorder of infancy or childhood characterized by decreased Mitochondrial DNA copy number in affected tissues. Mutations in 2 genes involved in deoxyribonucleotide metabolism, the deoxyguanosine kinase gene ( DGK ) and the thymidine kinase 2 gene ( TK2 ), have been related to this syndrome. Objective To describe 3 siblings with the myopathic form of Mitochondrial DNA Depletion syndrome and a homozygous mutation in the TK2 gene. Patients and Methods These children developed normally until 12 to 16 months of age, when they started showing difficulty walking, which rapidly progressed to severe limb weakness. They died of respiratory failure between the ages of 23 and 40 months. Histochemical and biochemical studies of respiratory chain complexes were performed in muscle biopsy specimens. The whole coding region of the TK2 gene was sequenced. Results Muscle biopsy showed ragged-red cytochrome- c oxidase–negative fibers. All affected siblings had markedly decreased activities of respiratory chain complexes. Southern blot analysis showed severe reduction of the Mitochondrial DNA–nuclear DNA ratio in muscle biopsy specimens from all patients, indicating 80% to 90% Mitochondrial DNA Depletion. Sequencing of the TK2 gene showed a homozygous C→T transition at nucleotide 228 in exon 5, which changes a threonine to a methionine at position 77 (T77M). Conclusions These results document the importance of screening the TK2 gene in patients with myopathic Mitochondrial DNA Depletion syndrome and confirm that exon 5 is a "hot spot" for TK2 mutations.
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clinical manifestations of Mitochondrial DNA Depletion
Neurology, 1998Co-Authors: Monica Sciacco, Eduardo Bonilla, Kurenai Tanji, Sara Shanske, Jerry R. Mendell, C Nichter, S Chatkupt, Paul Maertens, M R Koenigsberger, Leroy R SharerAbstract:Objective We studied five new patients with Mitochondrial DNA (mtDNA) Depletion to better define the clinical spectrum of this disorder. Background mtDNA Depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. Methods We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. Results Age at onset ranged from 3 months to 5 years, and one patient survived until age 10% years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. Conclusions Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA Depletion. mtDNA Depletion should be considered in children with mitochondria1 disorders of uncertain etiology, and criteria for diagnosis are proposed.
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Mitochondrial myopathy simulating spinal muscular atrophy
Pediatric Neurology, 1996Co-Authors: Roser Pons, Francesca Andreetta, Tuan H. Vu, Ching H Wang, Eduardo Bonilla, Salvatore Dimauro, Darryl C De VivoAbstract:A patient with a severe progressive neuromuscular disorder resembling spinal muscular atrophy is reported. The initial muscle biopsy was consistent with a denervating process. DNA analysis did not reveal deletions in exons 7 and 8 of the survival motor neuron gene. Histology, histochemistry, and biochemistry of a second muscle biopsy suggested Mitochondrial myopathy accompanying the denervating features. Immunohistochemistry using anti-DNA antibodies revealed only nuclear staining in skeletal muscle, suggesting Mitochondrial DNA Depletion. In patients with clinical features of spinal muscular atrophy and no deletions in the survival motor neuron gene, Mitochondrial DNA Depletion should be considered.
David Dimmock - One of the best experts on this subject based on the ideXlab platform.
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Potentially diagnostic electron paramagnetic resonance spectra elucidate the underlying mechanism of Mitochondrial dysfunction in the deoxyguanosine kinase deficient rat model of a genetic Mitochondrial DNA Depletion syndrome.
Free radical biology & medicine, 2016Co-Authors: Brian Bennett, Daniel Helbling, Hui Meng, Jason A. Jarzembowski, Aron M. Geurts, Marisa W. Friederich, Johan L.k. Van Hove, Michael W. Lawlor, David DimmockAbstract:A novel rat model for a well-characterized human Mitochondrial disease, Mitochondrial DNA Depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the Mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting Mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of Mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool.
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Quantitative Evaluation of the Mitochondrial DNA Depletion Syndrome
Clinical Chemistry, 2010Co-Authors: David Dimmock, Eric S. Schmitt, L. Tang, Leejun C WongAbstract:Background: The Mitochondrial DNA (mtDNA) Depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a reduction in cellular mtDNA content. Mutations in at least 9 genes [ POLG , polymerase (DNA directed), gamma; DGUOK , deoxyguanosine kinase; TK2 , thymidine kinase, Mitochondrial; TYMP , thymidine phosphorylase; MPV17 , MpV17 Mitochondrial inner membrane protein; SUCLA2 , succinate-CoA ligase, ADP-forming, beta subunit; SUCLG1 , succinate-CoA ligase, alpha subunit; RRM2B , RRM2B , ribonucleotide reductase M2 B (TP53 inducible); and C10orf2 , chromosome 10 open reading frame 2 (also known as TWINKLE )] have been reported to cause mtDNA Depletion. In the clinical setting, a simple method to quantify mtDNA Depletion would be useful before undertaking gene sequence analysis. Methods: Real-time quantitative PCR (qPCR) was used to measure the mtDNA content in blood, muscle, and liver samples and in skin fibroblast cultures from individuals suspected of Mitochondrial disorders, with or without deleterious mutations in genes responsible for MDDS. Results: The mtDNA content was quantified in 776 tissue samples (blood, n = 341; muscle, n = 325; liver, n = 63; skin fibroblasts, n = 47) from control individuals. mtDNA content increased with age in muscle tissue, decreased with age in blood samples, and appeared to be unaffected by age in liver samples. In 165 samples (blood, n = 122; muscle, n = 21; liver, n = 15; skin fibroblasts, n = 7) from patients with molecularly proven MDDSs, severe mtDNA Depletion was detected in liver and muscle tissue with high specificity and sensitivity. Blood samples were specific but not sensitive for detecting mtDNA Depletion, and skin fibroblasts were not valuable for evaluating mtDNA Depletion. Mutations in the POLG , RRM2B , and MPV17 genes were prospectively identified in 1 blood, 1 liver, and 3 muscle samples. Conclusions: Muscle and liver tissues, but not blood or skin fibroblasts, are potentially useful for rapid screening for mtDNA Depletion with real-time qPCR.
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Progressive myofiber loss with extensive fibro-fatty replacement in a child with Mitochondrial DNA Depletion syndrome and novel thymidine kinase 2 gene mutations.
Neuromuscular disorders : NMD, 2009Co-Authors: James J. Collins, Leejun C Wong, David Dimmock, Kevin E. Bove, P. Morehart, Brenda WongAbstract:The Mitochondrial DNA Depletion syndromes (MDS) are autosomal recessive disorders with a decreased Mitochondrial DNA copy number. Mutations in thymidine kinase 2 (TK2) have been responsible for the myopathic form of MDS. We describe a child with congenital muscle weakness who had a progressive Mitochondrial myopathy associated with extensive fibro-fatty replacement of myofibers resembling muscular dystrophy. MDS was suspected based upon findings in the initial muscle biopsy. Sequence analysis of the TK2 gene revealed two novel heterozygous mutations: the frame shift mutation, c.255_c.258delAGAA, and the heterozygous missense mutation, c.515G>A, (p.R172Q). This report extends the phenotype and genotype of TK2 defects.
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clinical and molecular features of Mitochondrial DNA Depletion due to mutations in deoxyguanosine kinase
Human Mutation, 2008Co-Authors: David Dimmock, Eric S. Schmitt, L. Tang, Qing Zhang, Carlo Dionisivici, Rosalba Carrozzo, Joseph T C Shieh, Cavatina K Truong, Mara Sifryplatt, Simona LucioliAbstract:Published mutations in deoxyguanosine kinase (DGUOK) cause Mitochondrial DNA Depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.