135 results on '"Garone C"'
Search Results
2. Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies
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Feichtinger R. G., Olahova M., Kishita Y., Garone C., Kremer L. S., Yagi M., Uchiumi T., Jourdain A. A., Thompson K., D'Souza A. R., Kopajtich R., Alston C. L., Koch J., Sperl W., Mastantuono E., Strom T. M., Wortmann S. B., Meitinger T., Pierre G., Chinnery P. F., Chrzanowska-Lightowlers Z. M., Lightowlers R. N., DiMauro S., Calvo S. E., Mootha V. K., Moggio M., Sciacco M., Comi G. P., Ronchi D., Murayama K., Ohtake A., Rebelo-Guiomar P., Kohda M., Kang D., Mayr J. A., Taylor R. W., Okazaki Y., Minczuk M., Prokisch H., Garone, Caterina [0000-0003-4928-1037], Chinnery, Patrick [0000-0002-7065-6617], Minczuk, Michal [0000-0001-8242-1420], Apollo - University of Cambridge Repository, Feichtinger R.G., Olahova M., Kishita Y., Garone C., Kremer L.S., Yagi M., Uchiumi T., Jourdain A.A., Thompson K., D'Souza A.R., Kopajtich R., Alston C.L., Koch J., Sperl W., Mastantuono E., Strom T.M., Wortmann S.B., Meitinger T., Pierre G., Chinnery P.F., Chrzanowska-Lightowlers Z.M., Lightowlers R.N., DiMauro S., Calvo S.E., Mootha V.K., Moggio M., Sciacco M., Comi G.P., Ronchi D., Murayama K., Ohtake A., Rebelo-Guiomar P., Kohda M., Kang D., Mayr J.A., Taylor R.W., Okazaki Y., Minczuk M., and Prokisch H.
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Male ,Mitochondrial Diseases ,Protein Conformation ,Sequence Homology ,Severity of Illness Index ,Cohort Studies ,Mice ,Mitochondrial Disease ,Age of Onset ,Cells, Cultured ,Allele ,multiple mtDNA deletions ,Middle Aged ,Pedigree ,mitochondria ,Child, Preschool ,Adult ,Aged ,Alleles ,Amino Acid Sequence ,Animals ,Cardiomyopathies/complications ,Cardiomyopathies/genetics ,Cardiomyopathies/pathology ,Carrier Proteins/chemistry ,Carrier Proteins/genetics ,Carrier Proteins/metabolism ,DNA, Mitochondrial ,Electron Transport/physiology ,Embryo, Mammalian/metabolism ,Embryo, Mammalian/pathology ,Female ,Fibroblasts/metabolism ,Fibroblasts/pathology ,Humans ,Infant, Newborn ,Mitochondrial Diseases/complications ,Mitochondrial Diseases/genetics ,Mitochondrial Diseases/pathology ,Mitochondrial Proteins/chemistry ,Mitochondrial Proteins/genetics ,Mitochondrial Proteins/metabolism ,Mutation ,Oxidative Phosphorylation ,Young Adult ,MAM33 ,PEO ,lactate ,myopathy ,oxidative phosphorylation ,p32 ,progressive external ophthalmoplegia ,multiple mtDNA deletion ,Fibroblast ,Cardiomyopathies ,Human ,Article ,Electron Transport ,Mitochondrial Proteins ,Mitochondrial Protein ,Cardiomyopathie ,Animal ,Fibroblasts ,Embryo, Mammalian ,Cohort Studie ,Carrier Protein ,Carrier Proteins - Abstract
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp -/- mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp -/- MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.
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- 2017
3. Open prospective study on oxcarbazepine in epilepsy in children: A preliminary report
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Franzoni, E., Garone, C., Sarajlija, J., Gualandi, S., Malaspina, E., Cecconi, I., Moscano, F.C., and Marchiani, V.
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- 2006
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4. MITOCHONDRIAL DISEASES & METABOLIC MYOPATHIES
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Domínguez-González, C., primary, Garone, C., additional, D'Souza, G., additional, Thompson, B., additional, Morton, M., additional, Quan, J., additional, and Hirano, M., additional
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- 2020
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5. Topiramate: effects on serum lipids and lipoproteins levels in children
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Franzoni, E., Verrotti, A., Sarajlija, J., Garone, C., Matricardi, S., Salerno, G. G., Monti, M., and Chiarelli, F.
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- 2007
6. Preliminary report on effects of oxcarbazepine-treatment on serum lipid levels in children
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Franzoni, E., Marchiani, V., Cecconi, I., Moscano, F. C., Gualandi, S., Garone, C., Sarajlija, J., and Malaspina, E.
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- 2006
7. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency
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Lopez-Gomez C., Levy R. J., Sanchez-Quintero M. J., Juanola-Falgarona M., Barca E., Garcia-Diaz B., Tadesse S., Garone C., Hirano M., Lopez-Gomez C., Levy R.J., Sanchez-Quintero M.J., Juanola-Falgarona M., Barca E., Garcia-Diaz B., Tadesse S., Garone C., and Hirano M.
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nucleosides, tk2 deficiency - Abstract
Objective: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2–/–) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy. Methods: To test these hypotheses, we assessed two therapies in Tk2–/– mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. Results: We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2–/– animals compared to dCMP+dTMP. Interpretation: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641–652.
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- 2017
8. P.60A retrospective study of the combination of pyrimidine nucleos(t)ides in patients with thymidine kinase 2 (TK2) deficiency
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Quan, J., primary, Domínguez-González, C., additional, Paradas, C., additional, Madruga-Garrido, M., additional, Nascimento Osorio, A., additional, Munell, F., additional, Mandel, H., additional, Falik-Zaccai, T., additional, Ginsberg, M., additional, Tal, G., additional, Garone, C., additional, Barca, E., additional, Moors, T., additional, and Hirano, M., additional
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- 2019
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9. Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family
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Kullar, P. J. (Peter J.), Gomez-Duran, A. (Aurora), Gammage, P. A. (Payam A.), Garone, C. (Caterina), Minczuk, M. (Michal), Golder, Z. (Zoe), Wilson, J. (Janet), Montoya, J. (Julio), Häkli, S. (Sanna), Kärppä, M. (Mikko), Horvath, R. (Rita), Majamaa, K. (Kari), Chinnery, P. F. (Patrick F.), Kullar, P. J. (Peter J.), Gomez-Duran, A. (Aurora), Gammage, P. A. (Payam A.), Garone, C. (Caterina), Minczuk, M. (Michal), Golder, Z. (Zoe), Wilson, J. (Janet), Montoya, J. (Julio), Häkli, S. (Sanna), Kärppä, M. (Mikko), Horvath, R. (Rita), Majamaa, K. (Kari), and Chinnery, P. F. (Patrick F.)
- Abstract
The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.
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- 2018
10. MITOCHONDRIAL DISEASES II (Oral)
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Hirano, M., primary, Lopez-Garcia, C., additional, Rosales, X., additional, Engelstad, K., additional, Uddin, J., additional, Dominguez, C., additional, Paradas, C., additional, Marti, R., additional, and Garone, C., additional
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- 2018
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11. Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal spikes (BECTS): An open-label, parallel group trial. Brain Dev. Oct ; [Epub ahead of print] PMID: 17055681 [PubMed - as supplied by publisher
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COPPOLA G, FRANZONI E, VERROTTI A, GARONE C, SARAJLIJA J, FELICIA OPERTO F, PASCOTTO, Antonio, Coppola, G, Franzoni, E, Verrotti, A, Garone, C, Sarajlija, J, FELICIA OPERTO, F, and Pascotto, Antonio
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- 2007
12. FA2H-related disorders: A novel c.270+3A>T splice-site mutation leads to a complex neurodegenerative phenotype
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Garone, C, Pippucci, T, Cordelli, Dm, Zuntini, R, Castegnaro, G, Marconi, C, Graziano, C, Marchiani, V, VERROTTI DI PIANELLA, Alberto, Seri, M, and Franzoni, E.
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Male ,Adolescent ,DNA Mutational Analysis ,Neurodegenerative Diseases ,Perinatology and Child Health ,Magnetic Resonance Imaging ,Pediatrics ,Mixed Function Oxygenases ,Young Adult ,Developmental Neuroscience ,Mutation ,Humans ,Neurology (clinical) ,Follow-Up Studies ,Pediatrics, Perinatology and Child Health - Published
- 2011
13. Progressive cerebral white matter involvement in a patient with Congenital Cataracts Facial Dysmorphisms Neuropathy (CCFDN)
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Cordelli, D.M., Garone, C., Marchiani, V., Lodi, R., Tonon, C., Ferrari, S., Seri, M., and Franzoni, E.
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- 2010
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14. P17.19 Deoxypyrimidine monophosphates treatment for thymidine kinase 2 deficiency
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Garone, C., primary, Garcia-Diaz, B., additional, Emmanuele, V., additional, Tadesse, S., additional, Akman, H.O., additional, Tanji, K., additional, Quinzii, C.M., additional, and Hirano, M., additional
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- 2013
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15. P.5.19 Fhl1 W122S knock-in mice manifest late-onset mild myopathy
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Emmanuele, V., primary, Kubota, A., additional, Garcia-Diaz, B., additional, Garone, C., additional, Akman, H.O., additional, Tanji, K., additional, Quinzii, C.M., additional, and Hirano, M., additional
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- 2013
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16. Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions
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Ronchi, D., primary, Garone, C., additional, Bordoni, A., additional, Gutierrez Rios, P., additional, Calvo, S. E., additional, Ripolone, M., additional, Ranieri, M., additional, Rizzuti, M., additional, Villa, L., additional, Magri, F., additional, Corti, S., additional, Bresolin, N., additional, Mootha, V. K., additional, Moggio, M., additional, DiMauro, S., additional, Comi, G. P., additional, and Sciacco, M., additional
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- 2012
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17. New MPV17 Mutations Associated with Multiple Deletions in Skeletal Muscle (S55.002)
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Garone, C., primary, Rubio, J. C., additional, Calvo, S., additional, Naini, A., additional, Tanji, K., additional, DiMauro, S., additional, Mootha, V., additional, and Hirano, M., additional
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- 2012
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18. New MPV17 Mutations Associated with Multiple Deletions in Skeletal Muscle (IN7-2.003)
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Garone, C., primary, Rubio, J. C., additional, Calvo, S., additional, Naini, A., additional, Tanji, K., additional, DiMauro, S., additional, Mootha, V., additional, and Hirano, M., additional
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- 2012
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19. MitoExome Sequencing Reveals a Mutation in the Mitochondrial MRPL51 Gene Causing Infantile Encephalopathy (P05.139)
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Garone, C., primary, Calvo, S., additional, Emmanuele, V., additional, Akman, O. H., additional, Kaplan, P., additional, Krishna, S., additional, Mootha, V., additional, DiMauro, S., additional, and Hirano, M., additional
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- 2012
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20. Metabolic disorders of fetal life: Glycogenoses and mitochondrial defects of the mitochondrial respiratory chain
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DiMauro, S., primary and Garone, C., additional
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- 2011
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21. LEVETIRACETAM: 2 YEARS EXPERIENCE IN CHILDREN
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Franzoni, E, primary, Sarajlija, J, additional, Garone, C, additional, Celotti, C, additional, Cecconi, I, additional, Marchiani, V, additional, Malaspina, E, additional, and Moscano, FC, additional
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- 2006
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22. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
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Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
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Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1. [ABSTRACT FROM AUTHOR]
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- 2010
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23. From the Structural and (Dys)Function of ATP Synthase to Deficiency in Age-Related Diseases
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Caterina Garone, Andrea Pietra, Salvatore Nesci, Garone C., Pietra A., Nesci S., DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, and DIPARTIMENTO DI SCIENZE MEDICHE VETERINARIE
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Cell death ,mitochondria ,Space and Planetary Science ,Neurodegenerative diseases ,biochemistry ,Paleontology ,ATP synthase ,General Biochemistry, Genetics and Molecular Biology ,Ecology, Evolution, Behavior and Systematics - Abstract
open 3 no This research was funded by CARISBO Foundation, grants numbers 2021.0058 to C.G and 2021.0173 to S.N.; Italian Minister of University and Research—Rita Levi Montalcini Program-Rientro cervelli RLM2017 to C.G. The ATP synthase is a mitochondrial inner membrane complex whose function is essential for cell bioenergy, being responsible for the conversion of ADP into ATP and playing a role in mitochondrial cristae morphology organization. The enzyme is composed of 18 protein subunits, 16 nuclear DNA (nDNA) encoded and two mitochondrial DNA (mtDNA) encoded, organized in two domains, FO and F1. Pathogenetic variants in genes encoding structural subunits or assembly factors are responsible for fatal human diseases. Emerging evidence also underlines the role of ATP-synthase in neurodegenerative diseases as Parkinson’s, Alzheimer’s, and motor neuron diseases such as Amyotrophic Lateral Sclerosis. Post-translational modification, epigenetic modulation of ATP gene expression and protein level, and the mechanism of mitochondrial transition pore have been deemed responsible for neuronal cell death in vivo and in vitro models for neurodegenerative diseases. In this review, we will explore ATP synthase assembly and function in physiological and pathological conditions by referring to the recent cryo-EM studies and by exploring human disease models. open Garone C.; Pietra A.; Nesci S. Garone C.; Pietra A.; Nesci S.
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- 2022
24. P.5.19 Fhl1 W122S knock-in mice manifest late-onset mild myopathy.
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Kubota, A., Garcia-Diaz, B., Garone, C., Akman, H.O., Tanji, K., Quinzii, C.M., and Hirano, M.
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MUSCLE diseases , *LABORATORY mice , *SKELETAL muscle , *GENE expression , *MUSCLE growth , *CELL differentiation , *BIOMECHANICS , *PHYSIOLOGICAL stress - Abstract
FHL1 is a member of the four-and-a half-LIM (FHL) domain protein family and it is highly expressed in adult human skeletal muscle. It is believed to participate in sarcomere assembly, muscle growth and differentiation, and in the biomechanical stress responses. Mutations in FHL1 gene have been associated with different myopathies, including reducing body myopathy, scapuloperoneal (SP) myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS), and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We have generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and have investigated the effects of this mutation at pre-symptomatic, phenotypic-onset, and late-stage of the disease, in hemizygous males and heterozygous females mice. Survival was comparable in mutant and wild-type animals. Adult hemizygous males mice showed a slowly progressive phenotype similar to human patients with relatively late-onset muscle weakness. In particular, we observed reduced forelimb strength and exercise capacity. Western blot analysis showed absence of FHL1 protein in muscle of hemizygous males at advanced stages. This animal model may help to elucidate the role of FHL1 in skeletal muscle and the pathomechanism of FHL1 mutations in X-linked dominant scapuloperoneal myopathy. [Copyright &y& Elsevier]
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- 2013
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25. SARS-CoV-2 infection in patients with primary mitochondrial diseases: Features and outcomes in Italy
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Anna Ardissone, Serenella Servidei, Olimpia Musumeci, Valerio Carelli, Chiara La Morgia, Maria Lucia Valentino, Michelangelo Mancuso, Caterina Garone, Guido Primiano, Costanza Lamperti, Gabriele Siciliano, Antonio Toscano, Elena Procopio, Mancuso M., La Morgia C., Valentino M.L., Ardissone A., Lamperti C., Procopio E., Garone C., Siciliano G., Musumeci O., Toscano A., Primiano G., Servidei S., and Carelli V.
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0301 basic medicine ,myalgia ,Adult ,Male ,medicine.medical_specialty ,Mitochondrial Diseases ,Adolescent ,medicine.drug_class ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Antibiotics ,Primary mitochondrial disease ,Outcomes ,Azithromycin ,Asymptomatic ,Article ,Comorbidities ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Mitochondrial Disease ,Humans ,Medicine ,COVID-19 ,SARS-CoV-2 ,Child ,Molecular Biology ,Outcome ,Aged ,business.industry ,Infant ,Cell Biology ,Heparin ,Middle Aged ,medicine.disease ,Pneumonia ,030104 developmental biology ,Italy ,Child, Preschool ,Cohort ,Molecular Medicine ,Female ,Comorbiditie ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug ,Human - Abstract
Patients with mitochondrial diseases, who usually manifest a multisystem disease, are considered potentially at-risk for a severe coronavirus disease 2019 (COVID-19). The objective of this study is to analyze the clinical features, prognosis and outcomes of COVID-19 in patients with primary mitochondrial diseases in a cohort of patients followed in Italy. We searched for patients with primary mitochondrial diseases and COVID-19 followed by the Italian Collaborative Network of Mitochondrial Diseases. In a total of 1843 patients followed by the National Network, we have identified from March 1st to January 30th, 2021, 27 SARS-CoV-2 infection. Most of the patients were pauci or asymptomatic (85%) and treated at home. The most common signs of COVID-19 were fever (78,9%), fatigue (47,4%), myalgia (42,1%), cough and headache (36,8%), and dyspnea (31,6%). Those who required COVID-19 therapy were treated with low-molecular-weight heparin, glucocorticoids, and antibiotics (mainly azithromycin) without serious side effects related to the therapy. Five patients (18,5%) clinically deteriorated during the infection, and one of them died for pneumonia. Primary mitochondrial diseases infected individuals seemed to be similarly affected by SARS-CoV-2 compared with the general Italian population in terms of clinical presentation and outcome.
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- 2021
26. The Transcriptome of SH-SY5Y at Single-Cell Resolution: A CITE-Seq Data Analysis Workflow
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Caterina Garone, Francesca De Giorgio, Nicola Balboni, Emanuela Aleo, Daniele Mercatelli, Federico M. Giorgi, Mercatelli D., Balboni N., De Giorgio F., Aleo E., Garone C., and Giorgi F.M.
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Computer science ,QH301-705.5 ,genetic processes ,Gene regulatory network ,Computational biology ,Barcode ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Unsupervised learning ,Article ,law.invention ,Transcriptome ,03 medical and health sciences ,transcriptomics ,Neuroblastoma ,0302 clinical medicine ,Single-cell analysis ,Structural Biology ,law ,natural sciences ,Biology (General) ,Gene ,gene regulatory networks ,030304 developmental biology ,0303 health sciences ,Single-cell ,Cell sorting ,Housekeeping gene ,Workflow ,CITE-seq ,Transcriptomic ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) is a recently established multimodal single cell analysis technique combining the immunophenotyping capabilities of antibody labeling and cell sorting with the resolution of single-cell RNA sequencing (scRNA-seq). By simply adding a 12-bp nucleotide barcode to antibodies (cell hashing), CITE-seq can be used to sequence antibody-bound tags alongside the cellular mRNA, thus reducing costs of scRNA-seq by performing it at the same time on multiple barcoded samples in a single run. Here, we illustrate an ideal CITE-seq data analysis workflow by characterizing the transcriptome of SH-SY5Y neuroblastoma cell line, a widely used model to study neuronal function and differentiation. We obtained transcriptomes from a total of 2879 single cells, measuring an average of 1600 genes/cell. Along with standard scRNA-seq data handling procedures, such as quality checks and cell filtering procedures, we performed exploratory analyses to identify most stable genes to be possibly used as reference housekeeping genes in qPCR experiments. We also illustrate how to use some popular R packages to investigate cell heterogeneity in scRNA-seq data, namely Seurat, Monocle, and slalom. Both the CITE-seq dataset and the code used to analyze it are freely shared and fully reusable for future research.
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- 2021
27. Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy
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Maria Lucia Tardio, Anna Accarino, Carla Giordano, Giovanna Cenacchi, Antonietta D'Errico, Catia Sternini, Rita Rinaldi, Vitaliano Tugnoli, Roberto De Giorgio, Loris Pironi, Valeria Righi, Giacomo Caio, Roberta Costa, Paolo Clavenzani, Maria Teresa Dotti, Valerio Carelli, Vincenzo Stanghellini, Roberto D'Angelo, Elisa Boschetti, Caterina Garone, Carolina Malagelada, Boschetti E., D'Angelo R., Tardio M.L., Costa R., Giordano C., Accarino A., Malagelada C., Clavenzani P., Tugnoli V., Caio G., Righi V., Garone C., D'Errico A., Cenacchi G., Dotti M.T., Stanghellini V., Sternini C., Pironi L., Rinaldi R., Carelli V., and De Giorgio R.
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Submucosal vessels ,Fibrosi ,Physiology ,Angiogenesis ,Angiopathy ,NO ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Fibrosis ,Physiology (medical) ,Humans ,Medicine ,Thymidine phosphorylase ,Sirius Red ,Gastrointestinal bleeding ,Thymidine Phosphorylase ,Ophthalmoplegia ,Neovascularization, Pathologic ,Hepatology ,business.industry ,Intestinal Pseudo-Obstruction ,Microangiopathy ,Gastroenterology ,Platelet-derived endothelial cell growth factor 1 ,Hypoxia (medical) ,medicine.disease ,Pathophysiology ,Gastrointestinal Tract ,Angiogenesi ,030104 developmental biology ,chemistry ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Research Article ,angiogenesis ,fibrosis ,gastrointestinal bleeding ,platelet derived endothelial cell growth factor ,submucosal vessels - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm(2) with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE. NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.
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- 2021
28. Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement
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Maria Alice Donati, Margherita Protasoni, Claudio Bruno, Alan J. Robinson, Aurelio Reyes, Khadra Mohamoud, Anna Allegri, Mariasavina Severino, Massimo Zeviani, Caterina Garone, Protasoni M., Bruno C., Donati M.A., Mohamoud K., Severino M., Allegri A., Robinson A.J., Reyes A., Zeviani M., Garone C., Robinson, Alan [0000-0001-9943-0059], Reyes Tellez, Aurelio [0000-0003-2876-2202], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,Endocrinology, Diabetes and Metabolism ,030105 genetics & heredity ,Compound heterozygosity ,medicine.disease_cause ,Biochemistry ,NUBPL ,Leukoencephalopathy ,0302 clinical medicine ,Endocrinology ,Leukoencephalopathies ,Child ,Exome sequencing ,Mutation ,Brain ,Magnetic Resonance Imaging ,Human complex I ,Mitochondria ,Mitochondrial disorder ,Complex I assembly ,Female ,Adult ,Heterozygote ,Adolescent ,Mitochondrial disease ,Biology ,DNA, Mitochondrial ,Complex I assembly factor ,Mitochondrial Proteins ,03 medical and health sciences ,Young Adult ,Genetics ,medicine ,Humans ,Molecular Biology ,Mitochondrial disorders ,Binding protein ,Infant, Newborn ,Genetic Variation ,Infant ,Heterozygote advantage ,Complex I assembly factors ,medicine.disease ,Molecular biology ,Brain MRI ,Coenzyme Q – cytochrome c reductase ,030217 neurology & neurosurgery - Abstract
NUBPL (Nucleotide-binding protein like) protein encodes a member of the Mrp/NBP35 ATP-binding proteins family, deemed to be involved in mammalian complex I (CI) assembly process. Exome sequencing of a patient presenting with infantile-onset hepatopathy, renal tubular acidosis, developmental delay, short stature, leukoencephalopathy with minimal cerebellar involvement and multiple OXPHOS deficiencies revealed the presence of two novel pathogenic compound heterozygous variants in NUBPL (p.Phe242Leu/p.Leu104Pro). We investigated patient's and control immortalised fibroblasts and demonstrated that both the peripheral and the membrane arms of complex I are undetectable in mutant NUBPL cells, resulting in virtually absent CI holocomplex and loss of enzyme activity. In addition, complex III stability was moderately affected as well. Lentiviral-mediated expression of the wild-type NUBPL cDNA rescued both CI and CIII assembly defects, confirming the pathogenicity of the variants. In conclusion, this is the first report describing a complex multisystemic disorder due to NUBPL defect. In addition, we confirmed the role of NUBPL in Complex I assembly associated with secondary effect on Complex III stability and we demonstrated a defect of mtDNA-related translation which suggests a potential additional role of NUBPL in mtDNA expression.
- Published
- 2020
29. Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome
- Author
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Salvatore DiMauro, Martino Montomoli, Michal Minczuk, Cristina Dallabona, Tiziana Lodi, Sarah E. Calvo, Pedro Rebelo-Guiomar, Joanna Rorbach, Ileana Ferrero, Elena Procopio, Massimo Zeviani, Caterina Garone, Maria Alice Donati, Renzo Guerrini, Vamsi K. Mootha, Aaron R. D’Souza, Garone C., D'Souza A.R., Dallabona C., Lodi T., Rebelo-Guiomar P., Rorbach J., Donati M.A., Procopio E., Montomoli M., Guerrini R., Zeviani M., Calvo S.E., Mootha V.K., DiMauro S., Ferrero I., Minczuk M., Garone, Caterina [0000-0003-4928-1037], Minczuk, Michal [0000-0001-8242-1420], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,16S ,Mitochondrial translation ,Saccharomyces cerevisiae ,Mitochondrion ,Biology ,medicine.disease_cause ,MELAS syndrome ,DNA, Mitochondrial ,Mitochondrial Encephalomyopathie ,03 medical and health sciences ,Mitochondrial Encephalomyopathies ,RNA, Ribosomal, 16S ,Genetics ,medicine ,MELAS Syndrome ,Humans ,Amino Acid Sequence ,Child ,Methyltransferase ,Molecular Biology ,Gene ,Genetics (clinical) ,Exome sequencing ,Nuclear Protein ,Ribosomal ,Mutation ,Methyltransferases ,Mitochondria ,Nuclear Proteins ,RNA, Ribosomal ,General Medicine ,DNA ,Articles ,medicine.disease ,Molecular biology ,3. Good health ,Mitochondrial ,Complementation ,030104 developmental biology ,RNA ,Human - Abstract
Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encepha- lomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial en- cephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was ex- cluded. Targeted exome sequencing of genes encoding the mitochondrial proteome identified a damaging mutation, c.567 G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a hu- man disease and encodes an enzyme responsible for 2’-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. We generated a knockout yeast model for the orthologous gene that showed a defect in respiration and the reduction of the 2’-O-methyl modification at the equivalent position (U2791) in the yeast mitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead com- pletely rescued by expressing the wild-type allele. Our findings establish that defective MRM2 causes a MELAS-like phenotype, and suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation.
- Published
- 2017
30. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy
- Author
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Francisco Javier Aguirre‐Rodríguez, Susana G. Kalko, Elena Martín-Hernández, Fabiola Mavillard, Michio Hirano, Javier Torres-Torronteras, Bruce Levin, Marcos Madruga-Garrido, Cecilia Jimenez-Mallebrera, Yuqi Tu, Juan P. Morealejo‐Aycinena, Yuelin Long, Karin Kleinsteuber, Ramon Martí, Itxaso Marti, Jasim Uddin, Olga Serrano, Caterina Garone, Concepcion Álvarez del Vayo, M. Alice Donati, Francina Munell, John L.P. Thompson, Carmen Paradas, Cristina Domínguez-González, Andrés Nascimento, M. Dolores Sardina, Kristen Engelstad, Dominguez-Gonzalez C., Madruga-Garrido M., Mavillard F., Garone C., Aguirre-Rodriguez F.J., Donati M.A., Kleinsteuber K., Marti I., Martin-Hernandez E., Morealejo-Aycinena J.P., Munell F., Nascimento A., Kalko S.G., Sardina M.D., Alvarez del Vayo C., Serrano O., Long Y., Tu Y., Levin B., Thompson J.L.P., Engelstad K., Uddin J., Torres-Torronteras J., Jimenez-Mallebrera C., Marti R., Paradas C., Hirano M., Instituto de Salud Carlos III, Generalitat de Catalunya, European Commission, Muscular Dystrophy Association (US), and Arturo Estopinan TK2 Research Fund
- Subjects
0301 basic medicine ,Adult ,Compassionate Use Trials ,Male ,medicine.medical_specialty ,Neurology ,Side effect ,medicine.medical_treatment ,Deoxyribonucleosides ,Walk Test ,Gastroenterology ,Thymidine Kinase ,Article ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,Internal medicine ,tk2, myopathy, nucleosides, therapy ,medicine ,Humans ,Myopathy ,Child ,Feeding tube ,Mechanical ventilation ,business.industry ,Discontinuation ,Diarrhea ,030104 developmental biology ,Child, Preschool ,Female ,Neurology (clinical) ,GDF15 ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
[Objective] Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies., [Methods] We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2‐deficient patients under a compassionate use program., [Results] In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6‐minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose‐dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy., [Interpretation] This open‐label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293–303, This work was supported in part by grants from the Spanish Carlos III Health Institute (PMP15/00025 for C.P., F.Ma., and R.M.; PI16/00579 and CP09/00011 for C.J.‐M.), Muscular Dystrophy Association (577391), Arturo Estopinan TK2 Research Fund, Generalitat de Catalunya PERIS program (SLT002/16/00370 for J.T‐T.), and European Regional Development Fund.
- Published
- 2019
31. Retrospective natural history of thymidine kinase 2 deficiency
- Author
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Miguel A. Martín, Andrés Nascimento, D. Ram, Julio Montoya, Marcos Madruga-Garrido, Christoph Karch, Sandeep Jayawant, M Imelda Hughes, Patrick F. Chinnery, Maria Alice Donati, Joshua Kriger, Emanuele Barca, Yolanda Cámara, Michio Hirano, Robert W. Taylor, Robert Schoenaker, Pirjo Isohanni, Carlos Ortez, John L.P. Thompson, Carlos Lopez Gomez, Mariana Loos, Carl Fratter, Salvatore DiMauro, Karin Kleinsteuber, J. Domínguez-Carral, Monika Hofer, Anu Suomalainen, Jeffrey W. Ralph, Ewen W. Sommerville, Bruce Levin, Caterina Garone, Cristina Domínguez-González, Grainne S. Gorman, Robert McFarland, Julie Evans, Sonia Emperador, Yuelin Long, Adnan Y. Manzur, Shamima Rahman, Neil D Thomas, Joanna Poulton, Timothy Kerr, Anupam Chakrapani, Garone C., Taylor R.W., Nascimento A., Poulton J., Fratter C., Dominguez-Gonzalez C., Evans J.C., Loos M., Isohanni P., Suomalainen A., Ram D., Imelda Hughes M., McFarland R., Barca E., Gomez C.L., Jayawant S., Thomas N.D., Manzur A.Y., Kleinsteuber K., Martin M.A., Kerr T., Gorman G.S., Sommerville E.W., Chinnery P.F., Hofer M., Karch C., Ralph J., Camara Y., Madruga-Garrido M., Dominguez-Carral J., Ortez C., Emperador S., Montoya J., Chakrapani A., Kriger J.F., Schoenaker R., Levin B., Thompson J.L.P., Long Y., Rahman S., Donati M.A., Dimauro S., Hirano M., Doctoral Programme in Clinical Research, Research Programs Unit, Anu Wartiovaara / Principal Investigator, Research Programme for Molecular Neurology, Children's Hospital, Clinicum, Lastenneurologian yksikkö, University of Helsinki, Doctoral Programme Brain & Mind, Neurologian yksikkö, Neuroscience Center, HUS Children and Adolescents, Lopez Gomez, Carlos [0000-0003-2699-451X], Martin, Miguel A [0000-0003-4741-772X], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Oncology ,metabolic disorder ,Male ,0302 clinical medicine ,Retrospective Studie ,Medicine ,Age of Onset ,Child ,Genetics (clinical) ,SPINAL MUSCULAR-ATROPHY ,MYOPATHIC FORM ,Facial weakness ,metabolic disorders ,MITOCHONDRIAL-DNA DEPLETION ,Middle Aged ,3. Good health ,Phenotypes ,Phenotype ,MTDNA DEPLETION ,muscle disease ,Child, Preschool ,Female ,Survival Analysi ,medicine.symptom ,clinical genetics ,TK2 GENE ,Natural history study ,Human ,Adult ,medicine.medical_specialty ,Weakness ,Neuromuscular disease ,Adolescent ,Genes, Recessive ,Genetic Association Studie ,PATIENT ,Thymidine Kinase ,Ophthalmoparesis ,Mitochondrial Proteins ,03 medical and health sciences ,Young Adult ,Muscular Diseases ,neuromuscular disease ,Internal medicine ,Genetics ,Humans ,Mitochondrial Protein ,Genetic Predisposition to Disease ,Genetic Testing ,Myopathy ,Muscle, Skeletal ,Genetic Association Studies ,Retrospective Studies ,Aged ,SPECTRUM ,MUTATIONS ,business.industry ,Muscular Disease ,clinical genetic ,Infant, Newborn ,Infant ,Spinal muscular atrophy ,medicine.disease ,Survival Analysis ,DELETIONS ,030104 developmental biology ,DEFECT ,Mutation ,3111 Biomedicine ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.ObjectiveTo perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.MethodsThe study was conducted by 42 investigators across 31 academic medical centres.ResultsWe identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion.ConclusionsIn TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.
- Published
- 2018
32. Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family
- Author
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Kullar, Peter J., Gomez-Duran, Aurora, Gammage, Payam A., Garone, Caterina, Minczuk, Michal, Golder, Zoe, Wilson, Janet, Montoya, Julio, Häkli, Sanna, Kärppä, Mikko, Horvath, Rita, Majamaa, Kari, Chinnery, Patrick F., Kullar P.J., Gomez-Duran A., Gammage P.A., Garone C., Minczuk M., Golder Z., Wilson J., Montoya J., Hakli S., Karppa M., Horvath R., Majamaa K., Chinnery P.F., Garone, Caterina [0000-0003-4928-1037], Minczuk, Michal [0000-0001-8242-1420], Horvath, Rita [0000-0002-9841-170X], Chinnery, Patrick [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
- Subjects
Male ,Heterozygote ,Mitochondrial Diseases ,Mitochondrial Proton-Translocating ATPase ,Adolescent ,DNA-Binding Protein ,DNA Mutational Analysis ,Mitochondrial Proteins ,DNA Mutational Analysi ,Electron Transport Complex IV ,Young Adult ,otorhinolaryngologic diseases ,Mitochondrial Disease ,Humans ,Mitochondrial Protein ,genetics ,Hearing Loss ,Child ,Muscle, Skeletal ,Hearing Lo ,Family Health ,mitochondrial diseases ,Electron Transport Complex II ,neurodegeneration ,Infant ,Fibroblasts ,Mitochondrial Proton-Translocating ATPases ,DNA-Binding Proteins ,hearing ,muscle disease ,Child, Preschool ,Mutation ,Fibroblast ,Female ,genetic ,Reports ,Human - Abstract
The m.1555A>G mitochondrial DNA variant causes maternally inherited deafness, but shows highly variable clinical penetrance. Using exome sequencing, Kullar et al. identify a hypomorphic mutation in SSBP1 that segregates with hearing loss in a family transmitting m.1555A>G, and serves as a trans-acting genetic modifier of clinical penetrance., The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.
- Published
- 2018
33. A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder
- Author
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Ali Naini, Michio Hirano, Caterina Garone, Sindu Krishna, Catarina M. Quinzii, Juliana Gurgel-Giannetti, Simone Sanna-Cherchi, Garone C., Gurgel-Giannetti J., Sanna-Cherchi S., Krishna S., Naini A., Quinzii C.M., and Hirano M.
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Movement disorders ,Ataxia ,Mitochondrial Diseases ,brain MRI ,SUCLA2 ,Ubiquinone ,Biology ,Article ,Diagnosis, Differential ,03 medical and health sciences ,Internal medicine ,coenzyme Q10 ,Succinate-CoA Ligases ,medicine ,Mitochondrial Disease ,Humans ,Movement Disorder ,Myopathy ,Child ,Muscle, Skeletal ,Genetics ,Dystonia ,Movement Disorders ,Muscle Weakness ,Succinate-CoA Ligase ,Homozygote ,Muscle weakness ,Brain ,Chorea ,medicine.disease ,Hypotonia ,030104 developmental biology ,Endocrinology ,Pediatrics, Perinatology and Child Health ,Mutation ,Neurology (clinical) ,medicine.symptom ,Human ,Muscle Weakne - Abstract
SUCLA2 defects have been associated with mitochondrial DNA (mtDNA) depletion and the triad of hypotonia, dystonia/Leigh-like syndrome, and deafness. A 9-year-old Brazilian boy of consanguineous parents presented with psychomotor delay, deafness, myopathy, ataxia, and chorea. Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while 1H-magnetic resonance spectroscopy (MRS) showed lactate peaks in the cerebral cortex and lateral ventricles. Decreased biochemical activities of mitochondrial respiratory chain enzymes containing mtDNA-encoded subunits and mtDNA depletion were observed in muscle and fibroblasts. A novel homozygous mutation in SUCLA2, the first one in the ligase coenzyme A (CoA) domain of the protein, was identified. Escalating doses of CoQ10 up to 2000 mg daily were associated with improvement of muscle weakness and stabilization of the disease course. The findings indicate the importance of screening for mitochondrial dysfunction in patients with complex movement disorders without brain MRI lesions and further investigation for potential secondary CoQ10 deficiency in patients with SUCLA2 mutations.
- Published
- 2017
34. CoQ10 deficiencies and MNGIE: Two treatable mitochondrial disorders
- Author
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Catarina M. Quinzii, Michio Hirano, Caterina Garone, Hirano M., Garone C., and Quinzii C.M.
- Subjects
Mitochondrial Diseases ,Ubiquinone ,Mitochondrial disease ,Biophysics ,Biochemistry ,Article ,Mitochondrial Encephalomyopathie ,chemistry.chemical_compound ,Mitochondrial Encephalomyopathies ,Mitochondrial Disease ,medicine ,Humans ,Molecular Biology ,Coenzyme Q10 ,Genetics ,Thymidine Phosphorylase ,business.industry ,food and beverages ,Coenzyme Q ,medicine.disease ,Mitochondrial DNA ,Mitochondria ,chemistry ,MNGIE ,business ,Human - Abstract
Background: Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q 10 (CoQ 10 or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Scope of review: Here, we describe clinical and molecular features of CoQ 10 deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ 10 deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ 10 biosynthesis, often improve with CoQ 10 supplementation. In vitro and in vivo studies of CoQ 10 deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ 10 deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE. Major conclusions: CoQ 10 deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules. General significance: Studies of CoQ 10 deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010. © 2012 Elsevier B.V.
- Published
- 2012
35. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy
- Author
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Michio Hirano, Saba Tadesse, Caterina Garone, Garone C., Tadesse S., and Hirano M.
- Subjects
Adult ,Intestinal pseudo-obstruction ,medicine.medical_specialty ,Pathology ,Adolescent ,Gastrointestinal Diseases ,Gastrointestinal Disease ,medicine.medical_treatment ,TYMP ,Disease ,Hematopoietic stem cell transplantation ,Biology ,Diagnostic Error ,Mitochondrial Encephalomyopathie ,Muscular Dystrophy, Oculopharyngeal ,encephalomyopathy ,Mitochondrial Encephalomyopathies ,Internal medicine ,medicine ,Humans ,Age of Onset ,Diagnostic Errors ,Thymidine phosphorylase ,Child ,Muscle, Skeletal ,Exocrine pancreatic insufficiency ,Thymidine Phosphorylase ,Ophthalmoplegia ,BMT ,Intestinal Pseudo-Obstruction ,Infant ,Original Articles ,Middle Aged ,medicine.disease ,Transplantation ,mitochondrial disease ,Child, Preschool ,MNGIE ,Mutation ,Disease Progression ,Neurology (clinical) ,Age of onset ,Gastrointestinal Motility ,Human - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype–phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan–Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.
- Published
- 2011
36. Historical perspective on mitochondrial medicine
- Author
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Salvatore DiMauro, Caterina Garone, DiMauro S., and Garone C.
- Subjects
Genetics ,Cognitive science ,Mitochondrial DNA ,Mitochondrial Diseases ,Intergenomic signaling ,Maternal inheritance ,Developmental Disabilities ,Developmental Disabilitie ,Perspective (graphical) ,Uniparental inheritance ,History, 20th Century ,Biology ,DNA, Mitochondrial ,Article ,Mitochondria ,Psychiatry and Mental health ,Muscle morphology ,Pediatrics, Perinatology and Child Health ,Developmental and Educational Psychology ,Humans ,Human ,Pace - Abstract
In this review, we trace the origins and follow the development of mitochondrial medicine from the premolecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis, uniparental inheritance, intergenomic signaling and its defects, and mitochondrial dynamics. We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water. © 2010 Wiley-Liss, Inc.
- Published
- 2010
37. Prospective study on long-term treatment with oxcarbazepine in pediatric epilepsy
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Emilio Franzoni, Valentina Gentile, Duccio Maria Cordelli, Caterina Garone, Alessandro Pellicciari, Valentina Marchiani, Alessandra Errani, Luisa Iero, I. Cecconi, Filomena Moscano, Stefano Gualandi, Franzoni E., Gentile V., Pellicciari A., Garone C., Iero L., Gualandi S., Cordelli D.M., Cecconi I., Moscano F.C., Marchiani V., and Errani A.
- Subjects
Pediatrics ,medicine.medical_specialty ,Time Factors ,Neurology ,Adolescent ,Oxcarbazepine ,CHILDREN ,Epilepsy ,Humans ,Medicine ,Prospective Studies ,Child ,Adverse effect ,Prospective cohort study ,EPILEPSY ,Neuroradiology ,business.industry ,Brain ,Electroencephalography ,EFFICACY ,medicine.disease ,Carbamazepine ,Treatment Outcome ,El Niño ,Tolerability ,Child, Preschool ,TOLERABILITY ,Anticonvulsants ,Epilepsies, Partial ,Neurology (clinical) ,business ,Follow-Up Studies ,medicine.drug - Abstract
Following a previous preliminary report on a group of children suffering from partial epilepsies, we present the final considerations on the same group in order to evaluate the long-term efficacy, tolerability and safety of oxcarbazepine (OXC). We enrolled 36 patients (mean age 8.5), between January 2003 and December 2004, with new diagnosis of partial epilepsy: 25 patients were affected by idiopathic partial epilepsy, eight by symptomatic epilepsy and three by cryptogenic epilepsy. Each patient was scheduled to attend the center four times after the initial examination: 3 months (T1), 12 months (T2), 24 (T3) months and 36 (T4) months after the beginning of OXC-monotherapy (T0). At the end of our study, 20 patients were seizure free (SF): nine stopped OXC because of SF for at least 2 years, 11 were still on therapy. One patient showed a reduction of seizure frequency >or=50%, three were non responders (but still on therapy), nine stopped OXC due to a non-responder condition during follow-up before T4 and one because of adverse effects. At the end of the study no EEG focal abnormalities became generalized because of treatment. Normalization of EEG was observed in ten patients. Our preliminary findings have been confirmed. OXC can be considered an effective and well tolerated first line drug for long-term monotherapy in children with epilepsy, both for idiopathic and symptomatic/cryptogenic forms.
- Published
- 2009
38. Fhl1 W122S causes loss of protein function and late-onset mild myopathy
- Author
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Catarina M. Quinzii, Shingo Kariya, Michio Hirano, Akatsuki Kubota, Valentina Emmanuele, Shunichi Homma, Daniel Sánchez-Gutiérrez, Kurenai Tanji, Luis M. Escudero, Hasan O. Akman, Caterina Garone, Beatriz Garcia-Diaz, Emmanuele V., Kubota A., Garcia-Diaz B., Garone C., Akman H.O., Sanchez-Gutierrez D., Escudero L.M., Kariya S., Homma S., Tanji K., Quinzii C.M., Hirano M., Ministerio de Ciencia e Innovación (España), Caffarelli Family Study Research Foundation, and Muscular Dystrophy Association (US)
- Subjects
Male ,Cytoplasmic inclusion ,Kemizygosity ,Myopathy ,Muscle Proteins ,Western blotting ,Mice ,Forelimb ,Missense mutation ,Gene Knock-In Techniques ,Skeletal muscles ,Muscular dystrophy ,Age of Onset ,Genetics (clinical) ,Intracellular Signaling Peptides and Proteins ,Cardiac muscle ,Articles ,General Medicine ,Anatomy ,LIM Domain Proteins ,Muscular Dystrophy, Emery-Dreifuss ,Muscle atrophy ,medicine.anatomical_structure ,Phenotype ,Knockin ,Female ,medicine.symptom ,Human ,medicine.medical_specialty ,Heterozygote ,Mutation, Missense ,Biology ,Muscle Protein ,Gene Knock-In Technique ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Molecular Biology ,Hemizygote ,Animal ,Muscular Dystrophy, Emery-Dreifu ,LIM Domain Protein ,Myocardium ,Muscle weakness ,Mice mice ,medicine.disease ,FHL1 ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Intracellular Signaling Peptides and Protein ,Mutation - Abstract
Emmanuele, Valentina et al., © The Author 2014. Published by Oxford University Press. All rights reserved. A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice., This work has been supported by the Muscular Dystrophy Association (MDA), grant number 115567; and by the Caffarelli Family Study Research (CSFR) Foundation, Inc. L.M.E. and D.S.-G. are supported by the Ramón y Cajal program (PI13/01347), and the Spanish government grants: BFU2011-25734 and PI13/01347.
- Published
- 2015
39. TMEM14C is required for erythroid mitochondrial heme metabolism
- Author
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Abhishek Dass, Eric A. Pierce, Daniel E. Bauer, Dhvanit I. Shah, Salvatore DiMauro, Barry H. Paw, Jeffrey D. Cooney, Hui Huang, Tamara A. Dailey, Naoko Takahashi-Makise, John Gary Phillips, Kyla Mohler, Yvette Y. Yien, Paul D. Kingsley, Thorsten M. Schlaeger, Harvey F. Lodish, Raymond F. Robledo, Wen Chen, Diane M. Ward, Stuart H. Orkin, Caterina Garone, Carla M. Koehler, Ellen M. Keenan, Iman J. Schultz, Gloria Yi, James Palis, Shilpa M. Hattangadi, Luanne L. Peters, Non Miyata, Jerry Kaplan, Alan B. Cantor, Babette Gwynn, Liangtao Li, Harry A. Dailey, Gordon J. Hildick-Smith, Yien Y.Y., Robledo R.F., Schultz I.J., Takahashi-Makise N., Gwynn B., Bauer D.E., Dass A., Yi G., Li L., Hildick-Smith G.J., Cooney J.D., Pierce E.L., Mohler K., Dailey T.A., Miyata N., Kingsley P.D., Garone C., Hattangadi S.M., Huang H., Chen W., Keenan E.M., Shah D.I., Schlaeger T.M., Dimauro S., Orkin S.H., Cantor A.B., Palis J., Koehler C.M., Lodish H.F., Kaplan J., Ward D.M., Dailey H.A., Phillips J.D., Peters L.L., and Paw B.H.
- Subjects
Protoporphyrins ,Medical and Health Sciences ,Mitochondrial Membrane Transport Proteins ,chemistry.chemical_compound ,Hemoglobins ,Mice ,0302 clinical medicine ,Erythropoiesi ,Erythropoiesis ,RNA, Small Interfering ,Inner mitochondrial membrane ,Membrane Protein ,0303 health sciences ,Protoporphyrin IX ,Liver Disease ,Anemia ,General Medicine ,Hematology ,Protoporphyrin ,Protoporphyrinogen IX ,Mitochondria ,Biochemistry ,Liver ,Mitochondrial matrix ,030220 oncology & carcinogenesis ,Mitochondrial Membranes ,Intracellular ,Research Article ,Porphyrins ,Immunology ,Heme ,Biology ,Small Interfering ,Cell Line ,Porphyrin ,03 medical and health sciences ,Erythroid Cells ,Animals ,Hemoglobin ,030304 developmental biology ,Erythroid Cell ,Animal ,Membrane Proteins ,Mitochondrial Membrane Transport Protein ,chemistry ,Gene Expression Regulation ,RNA ,Mitochondrial Membrane ,Digestive Diseases - Abstract
The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liver-derived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14C-deficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias.
- Published
- 2014
40. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency
- Author
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Michio Hirano, Hasan O. Akman, Kurenai Tanji, Luis C. López, Catarina M. Quinzii, Saba Tadesse, Beatriz Garcia-Diaz, Caterina Garone, Valentina Emmanuele, Garone C., Garcia-Diaz B., Emmanuele V., Lopez L.C., Tadesse S., Akman H.O., Tanji K., Quinzii C.M., Hirano M., Garone, Caterina [0000-0003-4928-1037], and Apollo - University of Cambridge Repository
- Subjects
Mitochondrial DNA ,Mitochondrial Diseases ,Mutant ,Encephalomyopathy ,Biology ,Thymidine Kinase ,Gene Knock-In Technique ,chemistry.chemical_compound ,Mice ,encephalomyopathy ,Mitochondrial Disease ,Thymidine Monophosphate ,Animals ,Gene Knock-In Techniques ,Gene ,Research Articles ,Deoxythymidine Monophosphate ,Thymidine monophosphate ,therapy ,Animal ,deoxythymidine monophosphate ,Deoxycytidine monophosphate ,Deoxycytidine Monophosphate ,Molecular biology ,Phenotype ,Survival Analysis ,3. Good health ,Treatment Outcome ,chemistry ,Thymidine kinase ,Molecular Medicine ,Deoxycytidine ,Survival Analysi ,Therapy - Abstract
Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2−/−) knock‐in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13‐day‐old Tk2−/− mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2−/−200dCMP/dTMP) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency., This work was supported by research grants from the Muscular Dystrophy Association (MH) and the Associazione Malattie Metaboliche Congenite ereditarie (AMMeC) (CG) as well as by the Arturo Estopinan TK2 Research Fund (MH and CG) and the Marriott Mitochondrial Disease Clinic Research Fund (MMDCRF) (MH). MH acknowledges support from NIH grants (P01 HD32062, R01 HD057543, and R01 HD056103 from NICHD) and the Office of Dietary Supplements, as well as U54 NS078059 from NINDS and NICHD. LCL acknowledges support from CEIBioTic‐University of Granada, RYC‐2011‐07643, and RETICEF (Spain).
- Published
- 2014
41. Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy
- Author
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Purification Gutierrez, Hamed Mojahed, Michio Hirano, Emanuele Barca, Beatriz Garcia-Diaz, Giuseppe Pizzorno, Caterina Garone, Kurenai Tanji, Caterina M. Quinzii, Fernando Arias-Mendoza, Garcia-Diaz B., Garone C., Barca E., Mojahed H., Gutierrez P., Pizzorno G., Tanji K., Arias-Mendoza F., Quinzii C.M., and Hirano M.
- Subjects
Mitochondrial Diseases ,Respiratory chain ,Deoxyribonucleosides ,mitochondrial DNA ,Mitochondrion ,Inbred C57BL ,thymidine ,Mitochondrial Encephalomyopathie ,chemistry.chemical_compound ,Mice ,Psychomotor Disorder ,Mitochondrial Disease ,Age Factor ,Mice, Knockout ,Uridine Phosphorylase ,Ophthalmoplegia ,Age Factors ,Brain ,Skeletal ,Succinate Dehydrogenase ,Deoxyribonucleoside ,MNGIE ,Muscle ,Mitochondrial DNA ,Deoxyribonucleoside triphosphate ,Knockout ,Thymidine phosphorylase activity ,deoxyuridine ,Biology ,Motor Activity ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Animals ,Muscle Strength ,Thymidine phosphorylase ,Muscle, Skeletal ,Thymidine Phosphorylase ,Animal ,animal model ,Body Weight ,Intestinal Pseudo-Obstruction ,deoxynucleotide ,Disease Models, Animal ,Mice, Inbred C57BL ,Psychomotor Disorders ,Thymidine ,Original Articles ,Molecular biology ,Deoxyuridine ,chemistry ,Disease Models ,Neurology (clinical) - Abstract
Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis. Levels of mitochondrial DNA were depleted not only in the brain but also in the small intestine, and deoxyribonucleoside triphosphate imbalance was observed in the brain. The relative proportion, rather than the absolute amount of deoxyribonucleoside triphosphate, was critical for mitochondrial DNA maintenance. Thus, our results demonstrate that stress of exogenous pyrimidine nucleosides enhances the mitochondrial phenotype of our knockout mice. Our mouse studies provide insights into the pathogenic role of thymidine and deoxyuridine imbalance in mitochondrial neurogastrointestinal encephalopathy and an excellent model to study new therapeutic approaches. © 2014 The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
- Published
- 2014
42. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation
- Author
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Teresa Obis, Umrao R. Monani, Turgay Akay, Fusako Sera, Caterina Garone, Shingo Kariya, Shunichi Homma, Shinichi Iwata, Kariya S., Obis T., Garone C., Akay T., Sera F., Iwata S., Homma S., and Monani U.R.
- Subjects
Male ,Genetically modified mouse ,Aging ,Time Factors ,Genotype ,Time Factor ,animal diseases ,Transgene ,Neuromuscular Junction ,Mice, Transgenic ,Biology ,Motor Neuron ,Neuromuscular junction ,Mice ,medicine ,Animals ,Transgenes ,Muscle, Skeletal ,Alleles ,Motor Skill ,Motor Neurons ,Allele ,Genetics ,Gene knockdown ,Animal ,Homozygote ,General Medicine ,Spinal muscular atrophy ,Motor neuron ,medicine.disease ,Survival of Motor Neuron 1 Protein ,Synapse ,Phenotype ,nervous system diseases ,Cell biology ,medicine.anatomical_structure ,nervous system ,Motor Skills ,Gene Knockdown Techniques ,Synapses ,Gene Knockdown Technique ,RNA splicing ,Commentary ,Female ,Research Article - Abstract
Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs. © Copyright 2014 American Society for Clinical Investigation.
- Published
- 2014
43. Preliminary report on effects of oxcarbazepine-treatment on serum lipid levels in children
- Author
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I. Cecconi, Stefano Gualandi, Elisabetta Malaspina, Valentina Marchiani, Filomena Moscano, Emilio Franzoni, Caterina Garone, J. Sarajlija, Franzoni E., Marchiani V., Cecconi I., Moscano F.C., Gualandi S., Garone C., Sarajlija J., and Malaspina E.
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,CHILDREN ,chemistry.chemical_compound ,Preliminary report ,Internal medicine ,Total cholesterol ,medicine ,Humans ,Child ,Oxcarbazepine ,Triglycerides ,Normal range ,Lipoprotein cholesterol ,Epilepsy ,Cholesterol ,business.industry ,Serum lipid levels ,Cholesterol, HDL ,TREATMENT ,Lipids ,OXCARBAZEPINE ,Carbamazepine ,Endocrinology ,Neurology ,chemistry ,Child, Preschool ,Anticonvulsants ,Female ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,SERUM LIPIDS ,business ,After treatment ,Follow-Up Studies ,medicine.drug - Abstract
PURPOSE: The aim of the present study was to assess serum lipid levels before and after treatment with oxcarbazepine in children with epilepsy. METHODS: We measured total cholesterol (TC), triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C) in 28 patients whereas only TC levels in 11 patients, during baseline period and at 3 months after the beginning of therapy with oxcarbazepine. RESULTS: During baseline period, median values were: 4.38 (IQR=4.12-5.03) mmol/L for TC levels, 1.72(IQR=1.42-2.01) mmol/L for HDL-C levels and 1.54 (IQR=1.29-1.96) mmol/L for TGs levels. At three months, median values were: 4.38 (4.10-4.95) mmol/L for TC levels (p
- Published
- 2006
44. Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice
- Author
-
Sindu Krishna, Michio Hirano, Catarina M. Quinzii, Saba Tadesse, Beatriz Dorado, Caterina Garone, Valentina Emmanuele, Quinzii C.M., Garone C., Emmanuele V., Tadesse S., Krishna S., Dorado B., and Hirano M.
- Subjects
Ubiquinone ,Alkyl and Aryl Transferase ,Mitochondrion ,medicine.disease_cause ,Kidney ,Biochemistry ,DNA, Mitochondrial ,Research Communications ,Electron Transport ,Mice ,Adenosine Triphosphate ,PDSS2 ,Genetics ,medicine ,Citrate synthase ,Animals ,Humans ,Tissue Distribution ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,Alkyl and Aryl Transferases ,biology ,ATP synthase ,Animal ,food and beverages ,Kidney metabolism ,ROS ,Oxidative Stre ,Fibroblasts ,Molecular biology ,Mice, Mutant Strains ,Mitochondria ,ATP ,Adenosine Diphosphate ,Oxidative Stress ,Mitochondrial respiratory chain ,chemistry ,biology.protein ,Mice, Inbred CBA ,Fibroblast ,Polyprenyl-diphosphate synthase ,Oxidative stress ,Mice, Mutant Strain ,Biotechnology ,Human - Abstract
Primary human CoQ10 deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for CoQ10 biosynthesis. Our in vitro studies of PDSS2 mutant fibroblasts, with
- Published
- 2013
45. Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions
- Author
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Salvatore DiMauro, Michela Ranieri, Nereo Bresolin, Vamsi K. Mootha, Dario Ronchi, Stefania Corti, Caterina Garone, Francesca Magri, Mafalda Rizzuti, Purificacion Gutierrez Rios, Luisa Villa, Michela Ripolone, Monica Sciacco, Giacomo P. Comi, Sarah E. Calvo, Maurizio Moggio, Andreina Bordoni, Ronchi D., Garone C., Bordoni A., Gutierrez Rios P., Calvo S.E., Ripolone M., Ranieri M., Rizzuti M., Villa L., Magri F., Corti S., Bresolin N., Mootha V.K., Moggio M., Dimauro S., Comi G.P., and Sciacco M.
- Subjects
Adult ,Male ,Mitochondrial DNA ,Mitochondrial Diseases ,Mitochondrial disease ,Molecular Sequence Data ,autosomal recessive progressive external ophthalmoplegia ,Mitochondrion ,Biology ,DGUOK ,medicine.disease_cause ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,multiple mitochondrial DNA deletion ,DNA sequencing ,Mitochondrial myopathy ,mitochondrial DNA instability ,Mitochondrial Disease ,medicine ,Humans ,Muscle, Skeletal ,Aged ,Genetics ,Aged, 80 and over ,Mutation ,Base Sequence ,Multiple mitochondrial DNA deletions ,Original Articles ,Middle Aged ,medicine.disease ,Phosphotransferases (Alcohol Group Acceptor) ,Female ,Neurology (clinical) ,Gene Deletion ,Human - Abstract
The molecular diagnosis of mitochondrial disorders still remains elusive in a large proportion of patients, but advances in next generation sequencing are significantly improving our chances to detect mutations even in sporadic patients. Syndromes associated with mitochondrial DNA multiple deletions are caused by different molecular defects resulting in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia to multi-systemic disorders of variable severity. The mutations underlying these conditions remain undisclosed in half of the affected subjects. We applied next-generation sequencing of known mitochondrial targets (MitoExome) to probands presenting with adult-onset mitochondrial myopathy and harbouring mitochondrial DNA multiple deletions in skeletal muscle. We identified autosomal recessive mutations in the DGUOK gene (encoding mitochondrial deoxyguanosine kinase), which has previously been associated with an infantile hepatocerebral form of mitochondrial DNA depletion. Mutations in DGUOK occurred in five independent subjects, representing 5.6% of our cohort of patients with mitochondrial DNA multiple deletions, and impaired both muscle DGUOK activity and protein stability. Clinical presentations were variable, including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis in a young female who had received a liver transplant at 9 months of age and adult-onset lower motor neuron syndrome with mild cognitive impairment. These findings reinforce the concept that mutations in genes involved in deoxyribonucleotide metabolism can cause diverse clinical phenotypes and suggest that DGUOK should be screened in patients harbouring mitochondrial DNA deletions in skeletal muscle. © 2012 The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
- Published
- 2012
46. Metabolic disorders of fetal life: glycogenoses and mitochondrial defects of the mitochondrial respiratory chain
- Author
-
Caterina Garone, Salvatore DiMauro, DiMauro S., and Garone C.
- Subjects
medicine.medical_specialty ,Mitochondrial respiratory chain ,Neonatal presentation ,BCS1L ,GRACILE syndrome ,Respiratory chain ,Fetal Disease ,Mitochondrion ,Electron Transport ,Metabolic Diseases ,Internal medicine ,medicine ,Glycogen storage disease ,Humans ,Mitochondrial Encephalomyopathies ,business.industry ,Infant, Newborn ,Mitochondrial encephalomyopathie ,medicine.disease ,Glycogen Storage Disease ,Metabolic Disease ,Mitochondria ,Fetal Diseases ,Endocrinology ,Lactic acidosis ,Pediatrics, Perinatology and Child Health ,Fetal presentation ,business ,Glycogen ,Human - Abstract
Summary Two major groups of inborn errors of energy metabolism are reviewed –glycogenoses and defects of the mitochondrial respiratory chain – to see how often these disorders present in fetal life or neonatally. After some general considerations on energy metabolism in the pre- and postnatal development of the human infant, different glycogen storage diseases and mitochondrial encephalomyopathies are surveyed. General conclusions are that: (i) disorders of glycogen metabolism are more likely to cause ‘fetal disease' than defects of the respiratory chain; (ii) mitochondrial encephalomyopathies, especially those due to defects of the nuclear genome, are frequent causes of neonatal or infantile diseases, typically Leigh syndrome, but usually do not cause fetal distress; (iii) notable exceptions include mutations in the complex III assembly gene BCS1L resulting in the GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death), and defects of mitochondrial protein synthesis, which are the ‘new frontier' in mitochondrial translational research.
- Published
- 2011
47. FA2H-related disorders: a novel c.270+3A>T splice-site mutation leads to a complex neurodegenerative phenotype
- Author
-
Caterina Marconi, Giovanni Castegnaro, Marco Seri, Alberto Verrotti, Emilio Franzoni, Duccio Maria Cordelli, Claudio Graziano, Valentina Marchiani, Tommaso Pippucci, Roberta Zuntini, Caterina Garone, Garone C, Pippucci T, Cordelli DM, Zuntini R, Castegnaro G, Marconi C, Graziano C, Marchiani V, Verrotti A, Seri M, and Franzoni E.
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Neurodegeneration with brain iron accumulation ,DNA Mutational Analysis ,medicine.disease_cause ,Follow-Up Studie ,Mixed Function Oxygenases ,DNA Mutational Analysi ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Developmental Neuroscience ,medicine ,Spastic ,Humans ,Mixed Function Oxygenase ,030304 developmental biology ,Dystonia ,0303 health sciences ,Mutation ,Splice site mutation ,Neurodegenerative Disease ,business.industry ,Leukodystrophy ,Neurodegenerative Diseases ,medicine.disease ,Magnetic Resonance Imaging ,3. Good health ,nervous system diseases ,Globus pallidus ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Paraplegia ,business ,Neuroscience ,030217 neurology & neurosurgery ,Human ,Follow-Up Studies - Abstract
Homozygous mutations in the gene for fatty acid 2-hydroxylase (FA2H) have been associated in humans with three neurodegenerative disorders: complicated spastic paraplegia (SPG35), leukodystrophy with spastic paraparesis and dystonia, and neurodegeneration with brain iron accumulation. Here, we describe a novel homozygous c.270+3A>T mutation in an Italian consanguineous family. In two affected brothers (age at molecular diagnosis 22y and 15y; age at last follow-up 24y and 17y), altered FA2H function led to a severe phenotype, with clinical features overlapping those of the three FA2H-associated disorders. Both patients showed childhood onset progressive spastic paraparesis, mild pyramidal and cerebellar upper limb signs, severe cognitive impairment, white-matter disease, and cerebellar, brainstem, and spinal cord atrophy. However, absence of dystonia, drowsiness episodes, and a subtle globus pallidus involvement suggested that FA2H mutations result in a clinical spectrum, rather than causing distinct disorders. Although clinical heterogeneity is apparent, larger numbers of patients are needed to establish more accurate genotype-phenotype correlations. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.
- Published
- 2011
48. Metabolic myopathies
- Author
-
Ali Naini, Caterina Garone, Salvatore DiMauro, DiMauro S., Garone C., and Naini A.
- Subjects
Mitochondrial DNA ,Glycogenin ,Mitochondrial Diseases ,Mitochondrial myopathie ,DNA, Mitochondrial ,Aglycogenosi ,chemistry.chemical_compound ,Lipid storage myopathie ,Rheumatology ,Mitochondrial myopathy ,Muscular Diseases ,medicine ,Mitochondrial Disease ,Animals ,Humans ,Glycogen synthase ,Cell Nucleu ,Cell Nucleus ,Glycogen ,biology ,Ichthyosis ,Animal ,Muscular Disease ,Fatty Acids ,Mitochondrial Myopathies ,Lipid metabolism ,DNA ,medicine.disease ,Lipid Metabolism ,Glycogenose ,Mitochondrial respiratory chain ,chemistry ,Biochemistry ,Mutation ,biology.protein ,Metabolism, Inborn Error ,Fatty Acid ,Metabolism, Inborn Errors ,Human - Abstract
We consider recent developments in disorders affecting three areas of metabolism: glycogen, fatty acids, and the mitochondrial respiratory chain. Among the glycogenoses, new attention has been directed to defects of glycogen synthesis resulting in absence rather than excess of muscle glycogen ("aglycogenosis"). These include defects of glycogen synthetase and defects of glycogenin, the primer of glycogen synthesis. Considerable progress also has been made in our understanding of alterations of glycogen metabolism that result in polyglucosan storage. Among the disorders of lipid metabolism, mutations in the genes encoding two triglyceride lipases acting hand in hand cause severe generalized lipid storage myopathy, one associated with ichthyosis (Chanarin-Dorfman syndrome), the other dominated by juvenile-onset weakness. For the mitochondrial myopathies, we discuss the importance of homoplasmic mitochondrial DNA mutations and review the rapid progress made in our understanding of the coenzyme Q10 deficiencies, which are often treatable. © Springer Science+Business Media, LLC 2010.
- Published
- 2010
49. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis
- Author
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Ramesh, V, Bernardi, B, Stafa, A, Garone, Caterina, Franzoni, E, Abinun, M, Mitchell, P, Mitra, D, Friswell, M, Nelson, J, Shalev, Sa, Rice, Gi, Gornall, H, Szynkiewicz, M, Aymard, F, Ganesan, V, Prendiville, J, Livingston, Jh, Crow, Yj, Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
- Subjects
Male ,DNA Mutational Analysis ,Infant ,Proteins ,Phosphoproteins ,SAM Domain and HD Domain-Containing Protein 1 ,Exodeoxyribonucleases ,Child, Preschool ,Homeostasis ,Humans ,Point Mutation ,Carotid Stenosis ,Female ,Cerebral Arterial Diseases ,Child ,Monomeric GTP-Binding Proteins - Abstract
AIM: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHOD: We used clinical and radiological description and molecular analysis. RESULTS: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. INTERPRETATION: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1
- Published
- 2010
50. A new case of idiopathic hemiplegia hemiconvulsion syndrome
- Author
-
Caterina Tonon, Caterina Garone, Bruno De Bernardi, Daniela Brunetto, Emilio Franzoni, Valentina Marchiani, Raffaele Lodi, Franzoni E, Garone C, Marchiani V, Brunetto D, Tonon C, Lodi R, and Bernardi B
- Subjects
Male ,medicine.medical_specialty ,Neurology ,Brain Edema ,Hemiplegia ,Epilepsy, Partial, Motor ,Dermatology ,Status epilepticus ,Seizures, Febrile ,Lateralization of brain function ,Epilepsy ,Atrophy ,Convulsion ,medicine ,Humans ,Neuroradiology ,medicine.diagnostic_test ,business.industry ,Infant ,Magnetic resonance imaging ,Syndrome ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Anesthesia ,Neurology (clinical) ,medicine.symptom ,business - Abstract
We report a new case of infantile idiopathic hemiconvulsion-hemiplegia syndrome (HH). A prolonged right-sided febrile convulsion was followed 4 days later, by right hemiconvulsive status epilepticus, documented by video-electroencephalogram (EEG) recording. The child developed an ipsilateral hemiplegia, partially improved during the first month of follow-up. Sequential cerebral magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) at 6, 15, 30 days of follow-up showed a cytotoxic edema in the left hemisphere and a subsequent necrosis. At 1-year of follow-up, we performed MRI control because of febrile convulsion lasting few minutes that confirmed a non-progressive left hemisphere atrophy. After 2 years, the patient was seizure-free, with a mild right hemiplegia and language skills deficit. We discuss the unclear pathogenesis of HH through sequential neuroradiological evaluation.
- Published
- 2010
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