42 results on '"Mauro Scarpelli"'
Search Results
2. Erythrocyte Encapsulated Thymidine Phosphorylase for the Treatment of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy: Study Protocol for a Multi-Centre, Multiple Dose, Open Label Trial
- Author
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Bridget E. Bax, Michelle Levene, Murray D. Bain, Lynette D. Fairbanks, Massimiliano Filosto, Sema Kalkan Uçar, Thomas Klopstock, Cornelia Kornblum, Hanna Mandel, Shamima Rahman, Agathe Roubertie, Mauro Scarpelli, Philip M. Sedgwick, Moshe Baru, Marcia Sellos-Moura, Jeanie Price, Patrick Horn, and Niranjanan Nirmalananthan
- Subjects
mitochondrial neurogastrointestinal encephalomyopathy ,MNGIE ,TYMP ,enzyme replacement ,erythrocyte encapsulated thymidine phosphorylase ,thymidine phosphorylase ,mitochondrial disease ,rare disease ,orphan disease ,Phase II ,multiple dose ,Medicine - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.
- Published
- 2019
- Full Text
- View/download PDF
3. Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy
- Author
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Michelle Levene, Murray D. Bain, Nicholas F. Moran, Niranjanan Nirmalananthan, Joanna Poulton, Mauro Scarpelli, Massimiliano Filosto, Hanna Mandel, Andrew D. MacKinnon, Lynette Fairbanks, Dario Pacitti, and Bridget E Bax
- Subjects
Mitochondrial neurogastrointestinal encephalomyopathy ,Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) ,nuclear thymidine phosphorylase gene (TYMP) ,enzyme replacement ,thymidine phosphorylase ,mitochondrial disease ,rare disease ,orphan disease ,Medicine - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.
- Published
- 2019
- Full Text
- View/download PDF
4. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE-MTDPS1)
- Author
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Massimiliano Filosto, Stefano Cotti Piccinelli, Filomena Caria, Serena Gallo Cassarino, Enrico Baldelli, Anna Galvagni, Irene Volonghi, Mauro Scarpelli, and Alessandro Padovani
- Subjects
MNGIE ,MTDPS1 ,mitochondrial diseases ,mitochondrial therapy ,mitochondrial neurogastrointestinal encephalopathy ,Medicine - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause a loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues, and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy, and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Other two MNGIE-type phenotypes have been described so far, which are linked to mutations in POLG and RRM2B genes. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped thymidine phosphorylase therapy) and newer, promising therapies are expected in the near future. Since successful treatment is strictly related to early diagnosis, it is essential that clinicians be warned about the clinical features and diagnostic procedures useful to suspect diagnosis of MNGIE-MTDPS1. The aim of this review is to promote the knowledge of the disease as well as the involved mechanisms and the diagnostic processes in order to reach an early diagnosis.
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- 2018
- Full Text
- View/download PDF
5. Poor Outcome in a Mitochondrial Neurogastrointestinal Encephalomyopathy Patient with a Novel TYMP Mutation: The Need for Early Diagnosis
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Mauro Scarpelli, Anna Russignan, Melinda Zombor, Csaba Bereczki, Francesca Zappini, Romina Buono, Bridget E. Bax, Alessandro Padovani, Paola Tonin, and Massimiliano Filosto
- Subjects
Mitochondrial neurogastrointestinal encephalomyopathy ,Thymidine phosphorylase ,TYMP ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped TP therapy) and newer, promising therapies are expected in the near future. However, successful treatment is strictly related to early diagnosis. We report on an incomplete MNGIE phenotype in a young man harboring the novel heterozygote c.199 C>T (Q67X) mutation in exon 2, and the previously reported c.866 A>C (E289A) mutation in exon 7 in TYMP. The correct diagnosis was achieved many years after the onset of symptoms and unfortunately, the patient died soon after diagnosis because of multiorgan failure due to severe malnutrition and cachexia before any therapeutic option could be tried. To date, early diagnosis is essential to ensure that patients have the opportunity to be treated. MNGIE should be suspected in all patients who present with both gastrointestinal and nervous system involvement, even if the classical complete phenotype is lacking.
- Published
- 2012
- Full Text
- View/download PDF
6. Liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical long-term follow-up and pathogenic implications
- Author
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Giulia Amore, Luca Vizioli, Luca Fasano, Caterina Tonon, Rita Rinaldi, Manuela Contin, Maria Teresa Dotti, Elisa Boschetti, Valentina Papa, Mauro Scarpelli, Alessia Pugliese, Susan Mohamed, Matteo Cescon, Roberto De Giorgio, Antonio Daniele Pinna, Leonardo Caporali, Lara Pisani, Massimiliano Filosto, Laura Ludovica Gramegna, Raffaele Lodi, Mariantonietta Capristo, Carlo Casali, Giovanna Cenacchi, Loris Pironi, Valerio Carelli, Maria Cristina Morelli, Francesco Sicurelli, Roberto D'Angelo, Roberta Costa, D'Angelo R., Boschetti E., Amore G., Costa R., Pugliese A., Caporali L., Gramegna L.L., Papa V., Vizioli L., Capristo M., Contin M., Mohamed S., Cenacchi G., Lodi R., Morelli M.C., Fasano L., Pisani L., Cescon M., Tonon C., Pinna A.D., Dotti M.T., Sicurelli F., Scarpelli M., Filosto M., Casali C., Pironi L., Carelli V., De Giorgio R., and Rinaldi R.
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Adult ,medicine.medical_specialty ,Neurology ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Liver transplantation ,Gastroenterology ,Ophthalmoparesis ,Leukoencephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Mitochondrial Encephalomyopathies ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Thymidine phosphorylase ,Gastrointestinal dysmotility ,Ophthalmoplegia ,business.industry ,medicine.disease ,Allogenic hematopoietic stem cell transplantation ,Mitochondrial neurogastrointestinal encephalomyopathy ,Neurology (clinical) ,medicine.symptom ,business ,Nucleoside ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy. Conversely, other features of MNGIE, as gastrointestinal dysmotility, low weight, ophthalmoparesis, and leukoencephalopathy were essentially unchanged. A similar picture characterized two patients treated with allogenic hematopoietic stem cell transplantation (AHSCT). In conclusion, LT promptly and stably normalizes nucleoside imbalance in MNGIE, stabilizing or improving some clinical parameters with marginal periprocedural mortality rate as compared to AHSCT. Nevertheless, restoring thymidine phosphorylase (TP) activity, achieved by both LT and AHSCT, does not allow a full clinical recovery, probably due to consolidated cellular damage and/or incomplete enzymatic tissue replacement.
- Published
- 2020
7. Identification and characterization of the novel m.8305C>T MTTK and m.4440G>A MTTM gene mutations causing mitochondrial myopathies
- Author
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Lidia Carreño-Gago, Alessandra Ariatti, Paola Tonin, Grazia Devigili, Noemi de Luna, Tomàs Pinós, Clara Carnicer-Cáceres, Elena García-Arumí, Lorenzo Verriello, Anna Russignan, and Mauro Scarpelli
- Subjects
Adult ,Male ,0301 basic medicine ,Mitochondrial DNA ,RNA, Transfer, Met ,Myopathy ,Mitochondrial diseases ,Biology ,Gene mutation ,medicine.disease_cause ,DNA, Mitochondrial ,03 medical and health sciences ,0302 clinical medicine ,Mitochondrial myopathy ,medicine ,Humans ,Point Mutation ,Muscle, Skeletal ,Gene ,Genetics (clinical) ,Genetics ,mitochondrial diseases ,Mutation ,mtDNA ,Mitochondrial Myopathies ,Middle Aged ,medicine.disease ,Phenotype ,Heteroplasmy ,Genes, Mitochondrial ,030104 developmental biology ,Neurology ,myopathy ,PEO ,Pediatrics, Perinatology and Child Health ,RNA, Transfer, Lys ,Female ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults. (C) 2017 Elsevier B.V. All rights reserved.
- Published
- 2018
8. Safety and efficacy of erythrocyte encapsulated thymidine phosphorylase in mitochondrial neurogastrointestinal encephalomyopathy
- Author
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Andrew D. Mackinnon, Niranjanan Nirmalananthan, Mauro Scarpelli, Joanna Poulton, Nicholas Moran, Bridget E. Bax, Dario Pacitti, Murray D. Bain, Hanna Mandel, Lynette D. Fairbanks, Michelle Levene, and Massimiliano Filosto
- Subjects
Mitochondrial disease ,lcsh:Medicine ,rare disease ,Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) ,Pharmacology ,thymidine phosphorylase ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,orphan disease ,Thymidine phosphorylase ,Adverse effect ,030304 developmental biology ,0303 health sciences ,business.industry ,lcsh:R ,General Medicine ,Enzyme replacement therapy ,medicine.disease ,Deoxyuridine ,nuclear thymidine phosphorylase gene (TYMP) ,Enzyme replacement ,Mitochondrial neurogastrointestinal encephalomyopathy ,Nuclear thymidine phosphorylase gene (TYMP) ,Orphan disease ,Rare disease ,Discontinuation ,mitochondrial disease ,Tolerability ,chemistry ,enzyme replacement ,business ,Thymidine ,030217 neurology & neurosurgery - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP, dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients, these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.
- Published
- 2019
9. Erythrocyte Encapsulated Thymidine Phosphorylase for the Treatment of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy: Study Protocol for a Multi-Centre, Multiple Dose, Open Label Trial
- Author
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Cornelia Kornblum, Sema Kalkan Uçar, Moshe Baru, Agathe Roubertie, Murray D. Bain, Jeanie Price, Marcia Sellos-Moura, Shamima Rahman, Patrick Horn, Philip Sedgwick, Mauro Scarpelli, Lynette D. Fairbanks, Thomas Klopstock, Massimiliano Filosto, Bridget E. Bax, Hanna Mandel, Michelle Levene, Niranjanan Nirmalananthan, and Ege Üniversitesi
- Subjects
TYMP ,Mitochondrial disease ,lcsh:Medicine ,rare disease ,Pharmacology ,thymidine phosphorylase ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,erythrocyte encapsulated thymidine phosphorylase ,0302 clinical medicine ,medicine ,ddc:610 ,orphan disease ,Thymidine phosphorylase ,030304 developmental biology ,0303 health sciences ,mitochondrial neurogastrointestinal encephalomyopathy ,business.industry ,lcsh:R ,General Medicine ,Enzyme replacement therapy ,medicine.disease ,Deoxyuridine ,Phase II ,Clinical trial ,Enzyme replacement ,Erythrocyte encapsulated thymidine phosphorylase ,Mitochondrial neurogastrointestinal encephalomyopathy ,MNGIE ,Multiple dose ,Orphan disease ,Rare disease ,mitochondrial disease ,chemistry ,Tolerability ,Pharmacodynamics ,enzyme replacement ,multiple dose ,Thymidine ,business ,030217 neurology & neurosurgery - Abstract
WOS: 000483737700026, PubMed ID: 31344955, Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments., Medical Research CouncilMedical Research Council UK (MRC) [K025406]; Orphan Technologies, This study is funded by the Medical Research Council (K025406) and Orphan Technologies.
- Published
- 2019
10. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1)
- Author
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Stefano Cotti Piccinelli, Alessandro Padovani, Serena Gallo Cassarino, Enrico Baldelli, Anna Galvagni, Filomena Caria, Massimiliano Filosto, Mauro Scarpelli, and Irene Volonghi
- Subjects
0301 basic medicine ,medicine.medical_treatment ,MTDPS1 ,lcsh:Medicine ,Mitochondrial diseases ,Review ,Disease ,Hematopoietic stem cell transplantation ,Bioinformatics ,Cachexia ,Ophthalmoparesis ,03 medical and health sciences ,Mitochondrial neurogastrointestinal encephalopathy ,Mitochondrial therapy ,MNGIE ,0302 clinical medicine ,Ptosis ,medicine ,Thymidine phosphorylase ,Gastrointestinal dysmotility ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,030104 developmental biology ,Peripheral neuropathy ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause a loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues, and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy, and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Other two MNGIE-type phenotypes have been described so far, which are linked to mutations in POLG and RRM2B genes. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped thymidine phosphorylase therapy) and newer, promising therapies are expected in the near future. Since successful treatment is strictly related to early diagnosis, it is essential that clinicians be warned about the clinical features and diagnostic procedures useful to suspect diagnosis of MNGIE-MTDPS1. The aim of this review is to promote the knowledge of the disease as well as the involved mechanisms and the diagnostic processes in order to reach an early diagnosis.
- Published
- 2018
11. Molecular Genetics of Limb‐Girdle Muscular Dystrophies
- Author
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Massimiliano Filosto, Alessandro Padovani, and Mauro Scarpelli
- Subjects
Genetics ,medicine.medical_specialty ,Weakness ,Muscle biopsy ,medicine.diagnostic_test ,Genetic heterogeneity ,Skeletal muscle ,Biology ,medicine.disease ,medicine.anatomical_structure ,Molecular genetics ,medicine ,Dystroglycan ,biology.protein ,Muscular dystrophy ,medicine.symptom ,Myopathy - Abstract
The limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous neuromuscular disorders caused by specific protein defects in muscle fibres and characterised by predominant weakness and wasting in proximal limb and axial muscles. Most of these diseases present with wide clinical heterogeneity and the limb-girdle phenotype should be regarded as one of the possible phenotypic expressions of a specific protein defect. Therefore, a precise clinical evaluation is often difficult, and an appropriate diagnostic approach using clinical, pathological, biochemical and genetic resources is essential to achieve the correct diagnosis. The current classification of LGMDs is based on inheritance pattern. Dominant forms are classified as type 1 (LGMD1), whereas the recessive forms are classified as type 2 (LGMD2). A progressive alphabetical letter identifies the different involved genes and indicates the order of identification. This review reports a comprehensive update on the genetic bases and the main clinical aspects of these groups of diseases according to protein defect and transmission modality. Key Concepts The limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of hereditary neuromuscular disorders caused by specific protein defects in muscle fibres and characterised by predominant weakness and wasting in proximal limb and axial muscles. The current classification of LGMDs is based on inheritance pattern. Dominant forms are classified as type 1 (LGMD1), whereas the recessive forms are classified as type 2 (LGMD2). A progressive alphabetical letter identifies the different involved genes and indicates the order of identification. LGMDs are diseases having wide inter- and intra-familial phenotypic heterogeneity and therefore the limb-girdle phenotype is often the only one of the possible phenotypic expressions of a specific protein defect. Four recessive LGMDs are caused by mutations in the genes encoding the four members of the skeletal muscle sarcoglycan complex which is a part of the large macromolecular complex of proteins named the dystrophin-associated protein complex (DAPC) which is thought to have structural functions in providing membrane stability, maintaining the integrity of sarcolemma and in ensuring transduction during muscle contraction. Eight genes have been found to be responsible for an LGMD-dystroglycanopathy until now. Mutations in these genes reduce dystroglycan glycosylation and cause different phenotypes ranging from mild to dramatic conditions. Limb-girdle muscular dystrophies should to be considered the mildest expression of the phenotypic spectrum of dystroglycanopathies. Keywords: LGMD; autosomal-dominant limb-girdle muscular dystrophy; autosomal-recessive limb-girdle muscular dystrophy; muscle biopsy; myopathy
- Published
- 2015
12. Redefining phenotypes associated with mitochondrial DNA single deletion
- Author
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Carlo Minetti, Enrico Bertini, Elena Cardaioli, Elena Pegoraro, Filippo M. Santorelli, Liliana Vercelli, Donato Sauchelli, Michelangelo Mancuso, Paola Da Pozzo, Giacomo P. Comi, Maurizio Moggio, Daniele Orsucci, Mauro Scarpelli, Valerio Carelli, M. Sciacco, Serenella Servidei, Elena Caldarazzo Ienco, Corrado Angelini, Massimiliano Filosto, Paola Tonin, Isabella Moroni, Massimo Zeviani, Gabriele Siciliano, Claudio Bruno, Maria Lucia Valentino, Costanza Lamperti, Tiziana Mongini, Maria Alice Donati, Michela Catteruccia, Dario Ronchi, Luca Bello, Antonio Toscano, Olimpia Musumeci, Antonio Federico, Mancuso, M., Orsucci, D., Angelini, C., Bertini, E., Carelli, V., Comi, G.P., Donati, M.A., Federico, A., Minetti, C., Moggio, M., Mongini, T., Santorelli, F.M., Servidei, S., Tonin, P., Toscano, A., Bruno, C., Bello, L., Caldarazzo Ienco, E., Cardaioli, E., Catteruccia, M., Da Pozzo, P., Filosto, M., Lamperti, C., Moroni, I., Musumeci, O., Pegoraro, E., Ronchi, D., Sauchelli, D., Scarpelli, M., Sciacco, M., Valentino, M.L., Vercelli, L., Zeviani, M., and Siciliano, G.
- Subjects
Male ,Ophthalmoplegia, Chronic Progressive External ,Mitochondrial Diseases ,Databases, Factual ,Kearns-Sayre Syndrome ,mitochondrial DNA ,Disease ,CPEO ,KSS ,Mitochondrial disorders ,mtDNA ,Pearson syndrome ,Single deletion ,Neurology (clinical) ,Neurology ,Bioinformatics ,Acyl-CoA Dehydrogenase ,Kearns–Sayre syndrome ,Congenital Bone Marrow Failure Syndromes ,Genetics ,Ophthalmoplegia ,Inborn Errors ,Medicine (all) ,Acyl-CoA Dehydrogenase, Long-Chain ,Middle Aged ,Heteroplasmy ,Mitochondrial ,Settore MED/26 - NEUROLOGIA ,Phenotype ,Female ,Cohort study ,Adult ,musculoskeletal diseases ,Mitochondrial DNA ,Mitochondrial disease ,Biology ,DNA, Mitochondrial ,Lipid Metabolism, Inborn Errors ,Databases ,Young Adult ,Muscular Diseases ,medicine ,Humans ,Factual ,Retrospective Studies ,Retrospective cohort study ,DNA ,Lipid Metabolism ,medicine.disease ,progressive external ophthalmoplegia ,PEO ,Chronic Progressive External ,Long-Chain ,Gene Deletion - Abstract
Progressive external ophthalmoplegia (PEO), Kearns–Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”. In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and “KSS spectrum” (a category of which classic KSS represents the most severe extreme). The criteria for “KSS spectrum” include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials. © 2015, Springer-Verlag Berlin Heidelberg.
- Published
- 2015
13. Strategies for treating mitochondrial disorders: An update
- Author
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Alessandro Padovani, Mauro Scarpelli, Silvia Rota, Alice Todeschini, Massimiliano Filosto, and Fabrizio Rinaldi
- Subjects
Mitochondrial DNA ,Mitochondrial Turnover ,Endocrinology, Diabetes and Metabolism ,Mitochondrial disease ,respiratory chain ,Respiratory chain ,mitochondrial DNA ,Biology ,Mitochondrion ,Bioinformatics ,DNA, Mitochondrial ,Biochemistry ,Electron Transport ,Endocrinology ,Genetics ,medicine ,Homeostasis ,Humans ,Molecular Biology ,chemistry.chemical_classification ,mitochondrial diseases ,therapy ,Reactive oxygen species ,Translation (biology) ,medicine.disease ,Mitochondria ,chemistry ,Calcium ,Reactive Oxygen Species ,Mitochondrial diseases ,Therapy ,Function (biology) - Abstract
Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases.
- Published
- 2014
14. Short stature and high serum transaminase levels: growth hormone deficiency in a child with Becker muscular dystrophy
- Author
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Claudia Banzato, Claudia Piona, Evelina Maines, Franco Antoniazzi, Rossella Gaudino, Paola Tonin, Mauro Scarpelli, Grazia Morandi, and Paolo Cavarzere
- Subjects
Male ,medicine.medical_specialty ,Human Growth Hormone ,business.industry ,High serum ,medicine.disease ,Short stature ,Body Height ,Transaminase ,Growth hormone deficiency ,short stature ,Muscular Dystrophy, Duchenne ,Endocrinology ,Becker muscular dystrophy ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,child ,medicine.symptom ,Muscular dystrophy ,Child ,business ,Transaminases - Published
- 2017
15. Mitochondrial diseases: advances and issues
- Author
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Alice Todeschini, Alessandro Padovani, Mauro Scarpelli, Massimiliano Filosto, and Irene Volonghi
- Subjects
0301 basic medicine ,Mitochondrial DNA ,lcsh:QH426-470 ,medicine.medical_treatment ,Mitochondrial diseases ,MNGIE ,Therapy ,Hematopoietic stem cell transplantation ,Review ,Bioinformatics ,DNA sequencing ,Deep sequencing ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Thymidine phosphorylase ,Genetics (clinical) ,Exome sequencing ,lcsh:R5-920 ,mitochondrial diseases ,therapy ,business.industry ,Clinical trial ,lcsh:Genetics ,030104 developmental biology ,Mitochondrial respiratory chain ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery - Abstract
Mauro Scarpelli,1 Alice Todeschini,2 Irene Volonghi,2 Alessandro Padovani,2 Massimiliano Filosto2 1Department of Neuroscience, Unit of Neurology, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; 2Center for Neuromuscular Diseases and Neuropathies, Unit of Neurology, ASST “Spedali Civili”, University of Brescia, Brescia, Italy Abstract: Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders. Keywords: mitochondrial diseases, therapy, MNGIE
- Published
- 2017
16. Myopathic Involvement and Mitochondrial Pathology in Kennedy Disease and in Other Motor Neuron Diseases
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Michelangelo Mancuso, Annalisa LoGerfo, Greta Alì, Cecilia Carlesi, Ubaldo Bonuccelli, Lucia Petrozzi, Massimiliano Filosto, Anna Rocchi, E. Caldarazzo Ienco, Gabriele Siciliano, Mauro Scarpelli, and Daniele Orsucci
- Subjects
Bulbo-Spinal Atrophy ,Mitochondrial DNA ,Pathology ,medicine.medical_specialty ,MtDNA ,Multiple deletions ,Bulbo-Spinal Atrophy, X-Linked ,Exercise intolerance ,Disease ,Mitochondrion ,Biology ,Bioinformatics ,DNA, Mitochondrial ,Biochemistry ,Androgen ,SBMA ,Receptors ,medicine ,Animals ,Humans ,ALS ,AR ,Kennedy's disease ,Motoneuron disease ,SMA ,Motor Neuron Disease ,Amyotrophic lateral sclerosis ,Molecular Biology ,Muscle biopsy ,medicine.diagnostic_test ,DNA ,General Medicine ,Spinal muscular atrophy ,X-Linked ,medicine.disease ,Mitochondrial ,Mitochondria ,Spinal and bulbar muscular atrophy ,Receptors, Androgen ,Molecular Medicine ,medicine.symptom - Abstract
Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.
- Published
- 2014
17. Myoclonus in mitochondrial disorders
- Author
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Filippo M. Santorelli, Mauro Scarpelli, Giacomo P. Comi, Maria Lucia Valentino, Serenella Servidei, Claudio Bruno, Corrado Angelini, Paola Tonin, Isabella Moroni, Tiziana Mongini, Michelangelo Mancuso, Costanza Lamperti, Elena Caldarazzo Ienco, Massimo Zeviani, Gabriele Siciliano, Liliana Vercelli, Graziella Uziel, Maurizio Moggio, Carlo Minetti, Daniele Orsucci, Enrico Bertini, Claudia Nesti, Elena Pegoraro, Guido Primiano, Michela Catteruccia, Olimpia Musumeci, Massimiliano Filosto, Antonio Toscano, and Valerio Carelli
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Mitochondrial DNA ,Pathology ,Neurology ,Ataxia ,Cerebellar ataxia ,business.industry ,Mitochondrial disease ,medicine.disease ,nervous system diseases ,Epilepsy ,medicine ,Myoclonic epilepsy ,Neurology (clinical) ,medicine.symptom ,business ,Myoclonus - Abstract
Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading.
- Published
- 2014
18. Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up
- Author
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Alessandro Salviati, Giuliano Tomelleri, Laura Bertolasi, and Mauro Scarpelli
- Subjects
Pediatrics ,medicine.medical_specialty ,Activities of daily living ,Short Communication ,Hexosaminidase deficiency ,Disease ,Sandhoff disease ,Gangliosidosis ,hexosaminidase deficiency ,motor neuron disease ,Lower motor neuron ,Endocrinology ,Genetics ,medicine ,Motor neuron disease ,lcsh:QH301-705.5 ,Molecular Biology ,lcsh:R5-920 ,business.industry ,Muscle weakness ,Motor neuron ,medicine.disease ,Natural history ,medicine.anatomical_structure ,lcsh:Biology (General) ,Physical therapy ,medicine.symptom ,lcsh:Medicine (General) ,business - Abstract
An adult with Sandhoff disease presented with pure lower motor neuron phenotype. Twenty years later, he showed signs of upper motor neuron involvement. 25 years from the onset, his muscle weakness slightly worsened but he was fully independent in activities of daily living. GM2-gangliosidosis can manifest as a motor neuron disease with a slowly progressive course. The correct knowledge of the natural history can be really important to achieve the diagnosis, design new therapies and evaluate clinical trials.
- Published
- 2014
19. Modified Yarham and Smith scores for pathogenicity assessment of mtDNA tRNA variants – Response
- Author
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Lidia Carreño-Gago, Tomàs Pinós, Paola Tonin, Noemi de Luna, Elena García-Arumí, Mauro Scarpelli, Grazia Devigili Verriello, Clara Carnicer-Cáceres, Lorenzo Alessandra Ariatti, and Anna Russignan
- Subjects
Genetics ,Mitochondrial DNA ,Virulence ,Mitochondrial Myopathies ,RNA ,Biology ,Pathogenicity ,medicine.disease ,DNA, Mitochondrial ,chemistry.chemical_compound ,RNA, Transfer ,Neurology ,chemistry ,Mitochondrial myopathy ,Mutation ,Pediatrics, Perinatology and Child Health ,Transfer RNA ,Mutation (genetic algorithm) ,medicine ,Humans ,Neurology (clinical) ,Genetics (clinical) ,DNA - Published
- 2018
20. Phenotypic heterogeneity of the 8344A>G mtDNA 'MERRF' mutation
- Author
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Elena Caldarazzo Ienco, Claudio Bruno, Massimiliano Filosto, Graziella Uziel, Maurizio Moggio, Daniele Orsucci, Enrico Bertini, Isabella Moroni, Gabriele Siciliano, Corrado Angelini, Paola Tonin, Mauro Scarpelli, Massimo Zeviani, Elena Pegoraro, Marco Spinazzi, M. Sciacco, Serenella Servidei, Liliana Vercelli, Diego Martinelli, Maria Lucia Valentino, Valerio Carelli, Carlo Minetti, Michelangelo Mancuso, Filippo M. Santorelli, Donato Sauchelli, Costanza Lamperti, Giacomo P. Comi, Tiziana Mongini, Dario Ronchi, Olimpia Musumeci, Antonio Toscano, M. Mancuso, D. Orsucci, C. Angelini, E. Bertini, V. Carelli, G. P. Comi, C. Minetti, M. Moggio, T. Mongini, S. Servidei, P. Tonin, A. Toscano, G. Uziel, C. Bruno, E. C. Ienco, M. Filosto, C. Lamperti, D. Martinelli, I. Moroni, O. Musumeci, E. Pegoraro, D. Ronchi, F. M. Santorelli, D. Sauchelli, M. Scarpelli, M. Sciacco, M. Spinazzi, M. L. Valentino, L. Vercelli, M. Zeviani, and G. Siciliano
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Pathology ,Ataxia ,Lipomatosis ,genetics/pathology/physiopathology, Magnetic Resonance Imaging, Male, Middle Aged, Mutation ,Genetic, Disease Progression, Female, Humans, MERRF Syndrome ,Adult, Age of Onset, DNA ,DNA, Mitochondrial ,patients ,Ophthalmoparesis ,Ptosis ,Myoclonic epilepsy with ragged-red fibers (MERRF) ,G+mitochondrial+DNA+mutation%22">8344A>G mitochondrial DNA mutation ,MERRF syndrome ,epilepsy ,ataxia ,Databases, Genetic ,medicine ,Humans ,Age of Onset ,genetics, Phenotype, Retrospective Studies ,genetics, Database ,Retrospective Studies ,business.industry ,Muscle weakness ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Mitochondrial ,Settore MED/26 - NEUROLOGIA ,Phenotype ,Mutation ,Disease Progression ,Myoclonic epilepsy ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Myoclonus - Abstract
Objectives: Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with the 8344A>G mutation. The secondary aim was revision of the previously published data. Methods: Retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) and systematic revision. Results: Forty-two patients carrying the mutation were identified. The great majority did not have full-blown MERRF syndrome. Myoclonus was present in 1 of 5 patients, whereas myopathic signs and symptoms, generalized seizures, hearing loss, eyelid ptosis, and multiple lipomatosis represented the most common clinical features. Some asymptomatic mutation carriers have also been observed. Myoclonus was more strictly associated with ataxia than generalized seizures in adult 8344A>G subjects. Considering all of the 321 patients so far available, including our dataset and previously published cases, at the mean age of approximately 35 years, the clinical picture was characterized by the following signs/symptoms, in descending order: myoclonus, muscle weakness, ataxia (35%–45% of patients); generalized seizures, hearing loss (25%–34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%–24.9%); and increased creatine kinase levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, migraine (5%–14.9%). Conclusions: Our results showed higher clinical heterogeneity than commonly thought. Moreover, MERRF could be better defined as a myoclonic ataxia rather than a myoclonic epilepsy.
- Published
- 2013
21. Poor Outcome in a Mitochondrial Neurogastrointestinal Encephalomyopathy Patient with a Novel TYMP Mutation: The Need for Early Diagnosis
- Author
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Alessandro Padovani, Bridget E. Bax, Romina Buono, Csaba Bereczki, Anna Russignan, Melinda Zombor, Francesca Zappini, Massimiliano Filosto, Paola Tonin, and Mauro Scarpelli
- Subjects
medicine.medical_specialty ,Pathology ,medicine.medical_treatment ,TYMP ,Published online: December, 2012 ,Hematopoietic stem cell transplantation ,Gastroenterology ,lcsh:RC346-429 ,Cachexia ,Ophthalmoparesis ,Ptosis ,Internal medicine ,medicine ,Thymidine phosphorylase ,Gastrointestinal dysmotility ,lcsh:Neurology. Diseases of the nervous system ,business.industry ,Heterozygote advantage ,medicine.disease ,Peripheral neuropathy ,Mitochondrial neurogastrointestinal encephalomyopathy ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped TP therapy) and newer, promising therapies are expected in the near future. However, successful treatment is strictly related to early diagnosis. We report on an incomplete MNGIE phenotype in a young man harboring the novel heterozygote c.199 C>T (Q67X) mutation in exon 2, and the previously reported c.866 A>C (E289A) mutation in exon 7 in TYMP. The correct diagnosis was achieved many years after the onset of symptoms and unfortunately, the patient died soon after diagnosis because of multiorgan failure due to severe malnutrition and cachexia before any therapeutic option could be tried. To date, early diagnosis is essential to ensure that patients have the opportunity to be treated. MNGIE should be suspected in all patients who present with both gastrointestinal and nervous system involvement, even if the classical complete phenotype is lacking.
- Published
- 2012
22. Mitochondrial DNA haplogroups may influence Fabry disease phenotype
- Author
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Ubaldo Bonuccelli, Gabriele Siciliano, Anna Zampetti, W Boadu, Lucia Chico, Daniele Orsucci, Mauro Scarpelli, Maria Gnarra, GianPietro Sechi, Claudio Feliciani, Alessandro Salviati, Costanza Simoncini, Laura Fancellu, Michelangelo Mancuso, Daniela Concolino, and Simona Sestito
- Subjects
0301 basic medicine ,Adult ,Male ,Mitochondrial DNA ,Genotype ,Disease ,Biology ,DNA, Mitochondrial ,Haplogroup ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,oxidative stress ,Humans ,Genetics ,Fabry ,haplogroups ,mitochondrial genotype ,mtDNA ,Polymorphism, Genetic ,General Neuroscience ,Haplogroups ,Mitochondrial genotype ,Oxidative stress ,Middle Aged ,medicine.disease ,Phenotype ,Fabry disease ,030104 developmental biology ,Haplotypes ,Italy ,Fabry Disease ,Female ,Age of onset ,030217 neurology & neurosurgery ,Human mitochondrial DNA haplogroup - Abstract
While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.
- Published
- 2016
23. Aortic and Mitral Valve Involvement in Maroteaux-Lamy Syndrome VI: Surgical Implications in the Enzyme Replacement Therapy Era
- Author
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Salvatore Torre, Giovanni Battista Luciani, Mauro Scarpelli, Alessandro Salviati, Ebba Buffone, and Giuseppe Faggian
- Subjects
Pulmonary and Respiratory Medicine ,Aortic valve ,Adult ,mitral valve ,medicine.medical_specialty ,Mucopolysaccharidosis ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,surgery ,03 medical and health sciences ,0302 clinical medicine ,Valve replacement ,Aortic valve replacement ,Mitral valve ,Internal medicine ,medicine ,Humans ,Mitral Valve Stenosis ,In patient ,Enzyme Replacement Therapy ,030212 general & internal medicine ,Mucopolysaccharidosis VI ,business.industry ,Enzyme replacement therapy ,Aortic Valve Stenosis ,medicine.disease ,aortic valve ,Surgery ,Maroteaux–Lamy syndrome ,medicine.anatomical_structure ,Mucopolysaccharidoses (MPS) type VI ,cardiovascular system ,Cardiology ,Maroteaux-Lamy syndrome ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Open-heart operations in patients with mucopolysaccharidoses are exceedingly rare and pose distinct clinical challenges. Few reports exist of valve replacement in type VI mucopolysaccharidosis, mostly entailing combined mitral and aortic valve replacement. Here reported is the case of a young woman with mitral and aortic valve disease, in whom the surgical procedure was confined to the aortic valve. The rationale behind this strategy, particularly in light of the benefits offered by specific enzyme replacement therapy of type VI mucopolysaccharidosis, is discussed.
- Published
- 2016
24. A two part, multi-centre, multiple dose study of Erythrocyte Encapsulated Thymidine Phosphorylase (EETP) in patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
- Author
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Agathe Roubertie, Mauro Scarpelli, M. Filosto, Cornelia Kornblum, M. Levene, Thomas Klopstock, Hanna Mandel, Niranjanan Nirmalananthan, Bridget E. Bax, and S Rahman
- Subjects
Neurology ,Biochemistry ,business.industry ,Pediatrics, Perinatology and Child Health ,Medicine ,In patient ,Neurology (clinical) ,Pharmacology ,Thymidine phosphorylase ,Multi centre ,business ,Multiple dose ,Genetics (clinical) - Published
- 2017
25. The role of mitochondria in neurodegenerative diseases
- Author
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Alessandro Padovani, Giuliano Tomelleri, Alice Todeschini, Valeria Gregorelli, Maria Cotelli, Mauro Scarpelli, Massimiliano Filosto, Valentina Vielmi, and Paola Tonin
- Subjects
medicine.medical_specialty ,Mitochondrial DNA ,Parkinson's disease ,Neurology ,Cell ,Alzheimer's disease ,Amyotrophic lateral sclerosis ,Huntington disease ,Inclusion body myopathy ,Mitochondria ,mtDNA ,Neurodegenerative disorders ,Mitochondrion ,Pathogenesis ,medicine ,Animals ,Humans ,Alzheimer’s disease ,Parkinson’s disease ,business.industry ,Neurodegenerative Diseases ,medicine.disease ,medicine.anatomical_structure ,Apoptosis ,Neurology (clinical) ,business ,Neuroscience - Abstract
Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field.
- Published
- 2011
26. A high-dose bortezomib neuropathy with sensory ataxia and myelin involvement
- Author
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Laura Broglio, Anna Maria Pelizzari, Alessandro Padovani, Michelangelo Mancuso, Massimiliano Filosto, Mauro Scarpelli, Giuseppe Rossi, M. Rinaldi, Marta Tentorio, and Serena Buzio
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Ataxia ,Neural Conduction ,Neurological disorder ,Bortezomib ,Central nervous system disease ,Myelin ,Sensory ataxia ,A high-dose bortezomib neuropathy with sensory ataxia and myelin involvement ,immune system diseases ,hemic and lymphatic diseases ,Reaction Time ,medicine ,Humans ,Protease Inhibitors ,Myelin Sheath ,Multiple myeloma ,Aged ,Dose-Response Relationship, Drug ,business.industry ,medicine.disease ,Boronic Acids ,Surgery ,medicine.anatomical_structure ,nervous system ,Neurology ,Pyrazines ,Proteasome inhibitor ,Neurology (clinical) ,medicine.symptom ,business ,medicine.drug - Abstract
Bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, is known to induce an axonal, dose-dependent neuropathy clinically characterized by pain, paresthesias, burning dysesthesias and numbness. In this study, we describe a patient treated with high-dose bortezomib whose main clinical feature was severe sensory ataxia. Electrodiagnostic studies showed, other than axonal changes, myelin involvement.
- Published
- 2007
27. Prevalence of asymptomatic vertebral fractures in late-onset Pompe disease
- Author
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Corrado Angelini, Paola Tonin, Massimiliano Filosto, Maurizio Moggio, Valeria Lucchini, Mauro Scarpelli, Sabrina Ravaglia, Alice Todeschini, Martina Brigo, Sofia Cotelli, Francesca Zappini, Serena Pancheri, Francesco Bertoldo, and Claudio Semplicini
- Subjects
Male ,Pediatrics ,Cross-sectional study ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Osteoporosis ,Disease ,Comorbidity ,Bone fragility ,Pompe disease ,bone mass impairment ,asymptomatic vertebral fractures ,patients ,Biochemistry ,Endocrinology ,Bone Density ,Glycogen storage disease type II ,Prevalence ,Glycogen Storage Disease Type II ,Middle Aged ,Neurology ,Spinal Fractures ,Female ,medicine.symptom ,Semi quantitative ,Bone mass ,Adult ,medicine.medical_specialty ,Adolescent ,Late onset ,Context (language use) ,Asymptomatic ,Young Adult ,Proximal myopathy ,Internal medicine ,medicine ,Humans ,Myopathy ,Aged ,business.industry ,Biochemistry (medical) ,medicine.disease ,Surgery ,Osteopenia ,Radiography ,Cross-Sectional Studies ,Neurology (clinical) ,business - Abstract
Bone fragility and low bone mass have been reported in small case series of patients with Pompe disease with severely reduced muscle strength or immobilization.Our objective was to determine the prevalence of morphometric vertebral fractures and to evaluate bone mass in adults with late-onset Pompe disease.We conducted a multicenter cross-sectional observational study from August 2012 to December 2013.All subjects were outpatients referred to University Referral Centers.PATIENTS included 22 late-onset Pompe disease patients with progressive proximal myopathy and minimal respiratory involvement without other diseases affecting bone mass.The prevalence of morphometric vertebral fractures was systematically assessed by semiquantitative analysis of lateral spine x-rays (T4-L5).A high prevalence of morphometric vertebral fractures was found. At least 1 vertebral fracture was present in 17 of 22 patients (77%). All vertebral fractures were asymptomatic. Bone mineral density was normal in 36.5% of the patients, whereas 36.5% were osteopenic and 27% were osteoporotic in at least 1 site. Fracture prevalence was independent of muscular and respiratory functional parameters and of genotype.Our data show for the first time that asymptomatic and atraumatic vertebral fractures occur frequently in late-onset Pompe disease patients without a significant impairment of bone mass. Screening for asymptomatic vertebral fractures should be routinely performed in Pompe disease irrespective of the disease severity. Fracture risk should be confirmed in longitudinal studies.
- Published
- 2014
28. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?
- Author
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Olimpia Musumeci, Dario Ronchi, Graziella Uziel, Tiziana Mongini, Elena Caldarazzo Ienco, Enrico Bertini, Alice Donati, Corrado Angelini, Michela Catteruccia, Antonio Toscano, Paola Tonin, Filippo M. Santorelli, Massimo Zeviani, Mauro Scarpelli, Elena Pegoraro, Gabriele Siciliano, Valerio Carelli, Daniele Orsucci, Maurizio Moggio, M. Sciacco, Serenella Servidei, Giacomo P. Comi, Massimiliano Filosto, Donato Sauchelli, Costanza Lamperti, Liliana Vercelli, Michelangelo Mancuso, Maria Lucia Valentino, Carlo Minetti, Isabella Moroni, Claudio Bruno, Mancuso, M., Orsucci, D., Angelini, C., Bertini, E., Carelli, V., Comi, G.P., Donati, A., Minetti, C., Moggio, M., Mongini, T., Servidei, S., Tonin, P., Toscano, A., Uziel, G., Bruno, C., Ienco, E.C., Filosto, M., Lamperti, C., Catteruccia, M., Moroni, I., Musumeci, O., Pegoraro, E., Ronchi, D., Santorelli, F.M., Sauchelli, D., Scarpelli, M., Sciacco, M., Valentino, M.L., Vercelli, L., Zeviani, M., and Siciliano, G.
- Subjects
Male ,MELAS syndrome ,Bioinformatics ,G+mutation%22">mitochondrial m.3243A>G mutation ,MIDD ,Genotype ,Databases, Genetic ,MELAS Syndrome ,Child ,Genetics ,mtDNA ,Medicine (all) ,Stroke-like episodes ,Middle Aged ,Mitochondrial DNA ,Mitochondrial ,Settore MED/26 - NEUROLOGIA ,A3243G ,mitochondrial DNA ,PEO ,stroke-like episodes ,Phenotype ,phenotypic ,Italy ,Neurology ,Lactic acidosis ,Child, Preschool ,Mutation (genetic algorithm) ,MELAS ,Female ,medicine.symptom ,Adult ,mitochondrial encephalopathy with lactic acidosis and stroke-like episode ,Heterozygote ,G+"MELAS%22">m.3243A>G "MELAS ,Adolescent ,Hearing loss ,Mitochondrial disease ,Biology ,DNA, Mitochondrial ,Databases ,Young Adult ,Sex Factors ,Genetic ,Mitochondrial Encephalomyopathies ,medicine ,Humans ,Aged ,Infant ,Mutation ,Retrospective Studies ,Neurology (clinical) ,Preschool ,DNA ,medicine.disease - Abstract
The m.3243A>G "MELAS" (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study ("Nation-wide Italian Collaborative Network of Mitochondrial Diseases"). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. "MIDD" (maternally-inherited diabetes and deafness) and "PEO" (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The "MELAS" acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises. © 2013 Springer-Verlag Berlin Heidelberg.
- Published
- 2014
29. Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome
- Author
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Ramon Martí, Yolanda Cámara, Michio Hirano, Javier Torres-Torronteras, Emiliano González-Vioque, Mauro Scarpelli, and Andrea Caballero
- Subjects
Male ,Mitochondrial DNA ,DNA Copy Number Variations ,Purine nucleoside phosphorylase ,Deoxyribonucleosides ,deoxyribonucleosides ,catabolism inhibition ,mitochondrial DNA depletion syndrome ,pharmacological approach ,Mitochondrion ,Biology ,DNA, Mitochondrial ,chemistry.chemical_compound ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Genetics ,medicine ,Deoxyguanosine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Cells, Cultured ,Mice, Knockout ,Ophthalmoplegia ,Catabolism ,Intestinal Pseudo-Obstruction ,General Medicine ,Cytidine deaminase ,Articles ,medicine.disease ,Molecular biology ,Mitochondria ,Deoxyribonucleoside ,chemistry ,Mitochondrial DNA depletion syndrome - Abstract
Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several deoxyribonucleoside triphosphates (dNTPs), and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of deoxyguanosine kinase-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides (dNs) involved in each biochemical defect (deoxyguanosine or deoxycytidine, dCtd) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of dN catabolism using tetrahydrouridine (THU; inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using an MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of dCtd or THU. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. We propose increasing cellular availability of the deficient dNTP precursor by direct administration of the dN or inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism.
- Published
- 2013
30. Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement
- Author
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Murray D. Bain, Mauro Scarpelli, Bridget E. Bax, Paola Tonin, Massimiliano Filosto, and Nicholas Moran
- Subjects
Intestinal pseudo-obstruction ,Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Biology ,Gastroenterology ,Cachexia ,Leukoencephalopathy ,Blood Transfusion, Autologous ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Internal medicine ,medicine ,Escherichia coli ,Humans ,Thymidine phosphorylase ,Clinical/Scientific Notes ,Gastrointestinal dysmotility ,Genetics ,therapy ,Thymidine Phosphorylase ,Ophthalmoplegia ,Metabolic disorder ,Intestinal Pseudo-Obstruction ,medicine.disease ,Treatment Outcome ,Allogeneic hematopoietic stem cell transplantation ,patient ,Neurology (clinical) ,Mitochondrial neurogastrointestinal encephalomyopathy - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive metabolic disorder caused by a deficiency of thymidine phosphorylase (TP, EC2.4.2.4) due to mutations in the nuclear gene TYMP. TP deficiency leads to plasma and tissue accumulations of thymidine and deoxyuridine which generate imbalances within the mitochondrial nucleotide pools, ultimately leading to mitochondrial dysfunction.1 MNGIE is characterized clinically by leukoencephalopathy, external ophthalmoplegia, peripheral polyneuropathy, cachexia, and enteric neuromyopathy manifesting as gastrointestinal dysmotility. The condition is relentlessly progressive, with patients usually dying from a combination of nutritional and neuromuscular failure at an average age of 37 years.2 Allogeneic hematopoietic stem cell transplantation (AHSCT) offers a permanent cure. Clinical and biochemical improvements following AHSCT have been reported but it carries a high mortality risk and is limited by matched donor availability.3 A consensus proposal for standardizing AHSCT recommends treatment of patients without irreversible end-stage disease and with an optimally matched donor; a majority of patients are ineligible and thus there is a critical requirement for an alternative treatment.4
- Published
- 2013
31. Disulfiram neuropathy: Two cases of distal axonopathy
- Author
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Anna Choub, Clara Lazzarini, Laura Broglio, Serena Buzio, Alessandro Padovani, Massimiliano Filosto, Maria Pia Pasolini, Maria Cotelli, Michelangelo Mancuso, Mauro Scarpelli, and Marta Tentorio
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Disulfiram ,Toxic neuropathy ,Toxicology ,medicine ,Humans ,Peripheral Nerves ,Pathological ,Withholding Treatment ,business.industry ,Peripheral Nervous System Diseases ,Recovery of Function ,General Medicine ,medicine.disease ,Axons ,Surgery ,Peripheral neuropathy ,Toxicity ,Female ,business ,Axonal degeneration ,Alcohol Deterrents ,medicine.drug - Abstract
Disulfiram may cause a peripheral neuropathy that is considered dose- and duration-of-exposure-related. Axonal degeneration has been described as a pathological hallmark of disulfiram toxicity, but experiments have reported a primary toxic effect of the molecule on Schwann cells and myelin.Case 1: At the end of two months of treatment with disulfiram 250 mg/day, a 31-year-old woman complained of weakness in distal segments of the lower limbs associated with burning dysesthesias, numbness and pain in the soles of the feet and the legs below the knees; bilateral walking steppage, reduction in foot strength, absence of ankle jerk and knee tendon reflexes, and tactile stocking pin-pick and vibratory sensory impairment in the lower limbs below the knee. Disulfiram was discontinued and she recovered partially over three months. Case 2: After one month of treatment with disulfiram 1600 mg/day, a 27-year-old man reported walking impairment, distal lower limb weakness and paresthesias. He had unsteady gait with bilateral steppage and foot drop, absence of ankle jerks and overall sensation impairment below the knee. Disulfiram was discontinued and nine months later there was almost complete recovery of motor deficits, only minor motor weakness in distal leg muscles, and no dysesthesia, sensation deficits or areflexia. In both of them clinical and neurophysiological patterns were indicative of a distal axonopathy. DISCUSSION The mechanisms by which disulfiram cause injury in human nerves are unclear, though may involve carbon disulfide. The discrepancy between experimental and clinical observations is still unexplained.We report two cases of disulfiram axonal toxicity and the partial response following discontinuation of the drug.
- Published
- 2008
32. Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA
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Ramon Martí, Javier Torres-Torronteras, Emiliano González-Vioque, Mauro Scarpelli, and Yolanda Cámara
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deoxyribonucleoside ,Mitochondrial DNA ,Deoxyribonucleosides ,Mitochondrial Diseases ,Somatic cell ,Mitochondrial disease ,Biology ,DNA, Mitochondrial ,catabolism inhibition ,chemistry.chemical_compound ,mitochondrial disorders ,therapeutic strategy ,Drug Discovery ,medicine ,Animals ,Humans ,Gene ,Nucleotide salvage ,Pharmacology ,Genetics ,Point mutation ,Genetic Therapy ,medicine.disease ,chemistry ,DNA ,Gene Deletion - Abstract
Mutations in an increasing number of nuclear genes involved in deoxyribonucleotide homeostasis cause disorders associated with somatic mitochondrial DNA (mtDNA) abnormalities. Dysfunction of the products of these genes leads to limited availability of substrates for mtDNA replication and results in mtDNA depletion, multiple deletions or point mutations; mtDNA depletion is the molecular feature linked to greatest clinical severity. In this review, we discuss recent results demonstrating that enhancement of the salvage pathways by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion. Hence, we propose administration of selected deoxyribonucleosides and/or inhibitors of their catabolism as a pharmacological strategy to treat these diseases.
- Published
- 2013
33. Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy
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Francesco Canonico, Alice Todeschini, Alessandro Padovani, Giovanna Lucchini, Fabio Pavan, F Santus, Rossella Parini, Massimiliano Filosto, Giuliano Tomelleri, Attilio Rovelli, Valentina Vielmi, Mauro Scarpelli, Paola Tonin, Maria Alice Donati, and Maria Cotelli
- Subjects
Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,PRES ,Young Adult ,Fatal Outcome ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Internal medicine ,Medicine ,Humans ,Transplantation, Homologous ,Thymidine phosphorylase ,Ophthalmoplegia ,Respiratory distress ,business.industry ,Septic shock ,Intestinal Pseudo-Obstruction ,Hematopoietic Stem Cell Transplantation ,Disease Management ,Posterior reversible encephalopathy syndrome ,Allogeneic hematopoietic stem cell transplantation ,HSCT ,Mitochondrial neurogastrointestinal encephalomyopathy ,MNGIE ,medicine.disease ,Surgery ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Neurology ,Female ,Neurology (clinical) ,Bone marrow ,business - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us to answer the questions of if, how and when MNGIE patients require HSCT treatment.
- Published
- 2012
34. Mitochondrial Sensorineural Hearing Loss: A Retrospective Study and a Description of Cochlear Implantation in a MELAS Patient
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Francesca Zappini, Massimiliano Filosto, Paola Tonin, Giuliano Tomelleri, Anna Russignan, and Mauro Scarpelli
- Subjects
medicine.medical_specialty ,lcsh:QH426-470 ,Article Subject ,Mitochondrial disease ,mitochondrial disorders ,Hearing impairment ,sensorineural hearing loss ,MELAS syndrome ,cochlear implantation ,Disease ,Audiology ,Quality of life ,Genetics ,otorhinolaryngologic diseases ,Medicine ,Cochlear implantation ,Molecular Biology ,Genetics (clinical) ,business.industry ,Retrospective cohort study ,medicine.disease ,lcsh:Genetics ,Clinical Study ,Sensorineural hearing loss ,Age of onset ,business - Abstract
Hearing impairment is common in patients with mitochondrial disorders, affecting over half of all cases at some time in the course of the disease. In some patients, deafness is only part of a multisystem disorder. By contrast, there are also a number of “pure” mitochondrial deafness disorders, the most common probably being maternally inherited. We retrospectively analyzed the last 60 genetically confirmed mitochondrial disorders diagnosed in our Department: 28 had bilateral sensorineural hearing loss, whereas 32 didn't present ear's abnormalities, without difference about sex and age of onset between each single group of diseases. We reported also a case of MELAS patient with sensorineural hearing loss, in which cochlear implantation greatly contributed to the patient's quality of life. Our study suggests that sensorineural hearing loss is an important feature in mitochondrial disorders and indicated that cochlear implantation can be recommended for patients with MELAS syndrome and others mitochondrial disorders.
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- 2012
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35. Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy
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Mauro Scarpelli, Andrea Salvi, Paola Tonin, Gian Maria Fabrizi, Alessandro Padovani, Silvia Testi, Massimiliano Filosto, Mara Rossi, Alberto Grottolo, Alice Todeschini, Giuliano Tomelleri, Valentina Vielmi, and Maria Cotelli
- Subjects
Intestinal pseudo-obstruction ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Pathology ,Exercise intolerance ,Ophthalmoparesis ,Leukoencephalopathy ,Diagnosis, Differential ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Genetics ,medicine ,MNGIE early diagnosis ,Humans ,Genetics (clinical) ,MNGIE atypical onset ,Thymidine Phosphorylase ,Ophthalmoplegia ,business.industry ,Intestinal Pseudo-Obstruction ,medicine.disease ,Abdominal Pain ,Transplantation ,Mitochondrial neurogastrointestinal encephalomyopathy ,Mutation ,Female ,medicine.symptom ,Differential diagnosis ,business ,Polyneuropathy - Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase and is characterized by external ophthalmoparesis, gastrointestinal dysmotility, leukoencephalopathy, and neuropathy. The availability of new therapeutic options (peritoneal dialysis, allogeneic stem cell transplantation, enzyme replacement) makes it necessary to diagnose the disease early, which is not always achieved due to the difficulty in recognizing this disorder, especially in case of atypical presentation. We describe three MNGIE patients with atypical onset of the disease. In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance and muscle cramps, and the third patient had a CIDP-like polyneuropathy. This study stresses the insidious heterogeneous clinical onset of some cases of MNGIE, expands the spectrum of the phenotype, and suggests considering MNGIE in the differential diagnosis of enteropathic arthritis, isolated exercise intolerance, and inflammatory polyneuropathies not responsive to the usual treatment. A better understanding of the clinical heterogeneity of MNGIE is necessary in order to diagnose atypical cases and promote early diagnosis, which is now absolutely necessary in view of the new available therapies.
- Published
- 2011
36. Current options in the treatment of mitochondrial diseases
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Mauro Scarpelli, Massimiliano Filosto, Giuliano Tomelleri, Alessandro Padovani, Michelangelo Mancuso, Carla Baronchelli, Maria Cotelli, Paola Tonin, Valentina Vielmi, Alice Todeschini, and Valeria Gregorelli
- Subjects
Mitochondrial DNA ,Genetic enhancement ,Coenzyme Q10 ,Drug therapy ,Gene therapy ,MELAS ,Mitochondrial diseases ,MNGIE ,Biology ,Mitochondrion ,Antioxidants ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,Drug Discovery ,Allotopic expression ,Animals ,Humans ,Pharmacology (medical) ,Gene ,Genetics ,Thymidine Phosphorylase ,Ophthalmoplegia ,Intestinal Pseudo-Obstruction ,Genetic Therapy ,Heteroplasmy ,Exercise Therapy ,Nuclear DNA ,Psychiatry and Mental health ,Mitochondrial respiratory chain ,Drug Design ,Acidosis, Lactic - Abstract
Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.
- Published
- 2010
37. McArdle disease and sporadic inclusion-body myositis
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Matteo Marini, Paola Tonin, Giuliano Tomelleri, Mauro Scarpelli, S. Krause, Gaetano Vattemi, and Massimiliano Filosto
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Pathology ,medicine.medical_specialty ,Histology ,MCARDLE DISEASE ,McArdle disease ,business.industry ,Sporadic Inclusion Body Myositis ,sporadic inclusion-body myositis ,vacuoles ,Pathology and Forensic Medicine ,Neurology ,Physiology (medical) ,medicine ,Neurology (clinical) ,business - Published
- 2009
38. Novel mitochondrial tRNA Leu(CUN) transition and D4Z4 partial deletion in a patient with a facioscapulohumeral phenotype
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Giuliano Tomelleri, Chiara Savio, Massimiliano Filosto, Michelangelo Mancuso, Mauro Scarpelli, Gaetano Vattemi, Nicolo' Rizzuto, Paola Tonin, Rossella Tupler, Francesca Greco, and Vittorio Govoni
- Subjects
Mitochondrial DNA ,RNA, Transfer, Leu ,Biopsy ,Molecular Sequence Data ,Biology ,DNA, Mitochondrial ,Mitochondrial myopathy ,medicine ,Facioscapulohumeral muscular dystrophy ,Humans ,FSHD ,mtDNA ,Muscle, Skeletal ,Genetics (clinical) ,Genetics ,Muscle biopsy ,medicine.diagnostic_test ,Transition (genetics) ,Base Sequence ,Point mutation ,Middle Aged ,medicine.disease ,Molecular biology ,Heteroplasmy ,Muscular Dystrophy, Facioscapulohumeral ,Phenotype ,Neurology ,Pediatrics, Perinatology and Child Health ,Transfer RNA ,Nucleic Acid Conformation ,Female ,Neurology (clinical) ,Gene Deletion ,Polymorphism, Restriction Fragment Length - Abstract
Point mutations in mtDNA-encoded tRNA genes frequently cause isolated myopathies but rarely cause the facioscapulohumeral phenotype. We report on a patient affected with chronic progressive weakness of facioscapulohumeral/peroneal muscles whose muscle biopsy showed a mitochondrial myopathy. mtDNA direct sequencing and RFLP analysis revealed a heteroplasmic transition T12313C which disrupts a conserved site in the TΨC stem of the tRNALeu(CUN) gene and fulfills the accepted criteria of pathogenicity. A partial deletion of the nuclear DNA D4Z4 region with residual repeat sizes of 25 kb was also found in the patient and in her mother. This is the first reported case of mitochondrial myopathy/facioscapulohumeral muscular dystrophy (FSHD) “double trouble”.
- Published
- 2007
39. Chronic ophthalmoparesis in limb girdle muscular dystrophy 1C
- Author
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Alessandro Padovani, Marta Tentorio, Massimiliano Filosto, Carla Baronchelli, Gaetano Vattemi, Giuliano Tomelleri, Maria Cotelli, Paola Tonin, Laura Broglio, and Mauro Scarpelli
- Subjects
Weakness ,Proximal muscle weakness ,Exophthalmos ,business.industry ,Anatomy ,Limb girdle muscular dystrophy 1C ,ophthalmoparesis ,caveolin-3 gene ,medicine.disease ,Extraocular muscles ,Ophthalmoparesis ,Psychiatry and Mental health ,medicine.anatomical_structure ,medicine ,Surgery ,Neurology (clinical) ,medicine.symptom ,Myopathy ,business ,Muscle contracture ,Limb-girdle muscular dystrophy - Abstract
Extraocular muscle involvement, although frequently described in neuromuscular diseases, is not usually reported in muscular dystrophies, except for oculopharyngeal muscular dystrophy.1 Limb girdle muscular dystrophy 1C (LGMD1C) is caused by mutations in the caveolin-3 gene (CAV3) that codes for the muscle isoform of caveolin, which is the main component of caveolae sarcoplasmic microdomains involved in signal transduction mechanisms.2 Mutations in CAV3 cause at least three other muscle phenotypes: distal myopathy, isolated hyperCKaemia and rippling muscle disease (RMD), an autosomal dominant disorder characterised by mechanically triggered contractions of skeletal muscle.2 The clinical features of the LGMD phenotype include calf hypertrophy and mild to moderate proximal muscle weakness but not external ophthalmoparesis (EO). We report on a patient with EO and a CAV3 linked LGMD phenotype without clinical or electric features of rippling phenomenon. A 37-year-old man, healthy until age 25 years, came to our attention for progressive limb weakness causing difficulty in climbing stairs and running. Family members (parents, two maternal aunts, maternal uncle, paternal uncle and six first cousins) were reported to be healthy but refused to be examined. Neurological examination showed extraocular muscle paresis with vertical and lateral gaze limitation, bilateral exophthalmos and partial blepharoptosis, more evident …
- Published
- 2008
40. Neuropathology of mitochondrial diseases.
- Author
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Giuliano Tomelleri, Paola Tonin, Mauro Scarpelli, Gaetano Vattemi, Nicolò Rizzuto, Alessandro Padovani, and Alessandro Simonati
- Subjects
MITOCHONDRIAL pathology ,MUSCLES ,BRAIN ,CYTOCHROME oxidase - Abstract
Abstract The term “mitochondrial diseases” (MD) refers to a group of disorders related to respiratory chain dysfunction. Clinical features are usually extremely heterogeneous because MD may involve several tissues with different degrees of severity. Muscle and brain are mostly affected, probably because of their high dependence on oxidative metabolism. Muscle can be the only affected tissue or involved as a part of a multi-system disease; ragged red fibers, accumulation of structurally altered mitochondria and cytochrome-c-oxidase (COX) negative fibers are the main pathological features. In mitochondrial encephalopathies, central nervous system (CNS) structures are affected according to different patterns of distribution and severity. Characteristic lesions are neuronal loss, vasculo-necrotic changes, gliosis, demyelination and spongy degeneration. In accordance with either grey matter or white matter involvement two main groups of diseases may be distinguished. Neuronal loss and vasculo-necrotic multifocal lesions are the common features of grey matter involvement; demyelination and spongy degeneration occur when white matter is affected, often associated with less severe lesions of the grey structures. Grey matter lesions are prevalent in MERRF, MELAS, Alpers and Leigh syndromes. White matter involvement is always seen in Kearns-Sayre syndrome and was recently described in mtDNA depletion syndrome linked to dGK mutations and in the rare conditions associated with complex I and II deficiency. In this review we describe the main histopathological features of muscle and CNS lesions in mitochondrial diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2007
41. Late-onset glycogen storage disease type 2
- Author
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Alessandro Padovani, Silvia Rota, Alice Todeschini, Maria Cotelli, Valentina Vielmi, Fabrizio Rinaldi, Mauro Scarpelli, and Massimiliano Filosto
- Subjects
medicine.medical_specialty ,Lysosomal disease ,Autophagia ,Biology ,Biochemistry ,chemistry.chemical_compound ,Internal medicine ,medicine ,autophagia ,enzymatic replacement therapy ,glycogenosis II ,glycogen storage disease ,GAA ,GSDII ,lysosomal disease ,Pompe’s disease ,Glycogen storage disease ,Respiratory function ,Molecular Biology ,Alglucosidase alfa ,Glycogen ,Muscle weakness ,Enzymatic replacement therapy ,Glycogenosis II ,General Medicine ,Enzyme replacement therapy ,medicine.disease ,Endocrinology ,chemistry ,Respiratory failure ,Molecular Medicine ,Age of onset ,medicine.symptom ,medicine.drug - Abstract
Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usually appears in the first month of life, progresses rapidly and presents with severe cardiac involvement and complete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form is characterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activity may correlate with severity of phenotype but many adult patients sharing the same mutations present with a wide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a role for other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation. Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/or respiratory function. However, efficacy of ERT may be influenced by several factors including age when ERT begins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition, difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted to investigate factors determining the differences in clinical expression and therapeutic response in order to achieve better clinical and therapeutic management of these patients.
42. The role of brain MRI in mitochondrial neurogastrointestinal encephalomyopathy
- Author
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Paola Tonin, Giuseppe Ricciardi, Massimiliano Filosto, Francesca Calabria, Mauro Scarpelli, Isabella Zocca, Alberto Beltramello, Francesca Zappini, Anna Russignan, Maria Cotelli, Giuliano Tomelleri, and Alessandro Padovani
- Subjects
Adult ,Male ,MRS ,Pathology ,medicine.medical_specialty ,Mitochondrial neurogastrointestinal encephalomyopathy ,MNGIE ,magnetic resonance imaging ,magnetic resonance spectroscopy ,diffusion weighted imaging (DWI) ,DWI ,Ophthalmoparesis ,Leukoencephalopathy ,Muscular Dystrophy, Oculopharyngeal ,Mitochondrial Encephalomyopathies ,medicine ,Effective diffusion coefficient ,Humans ,Radiology, Nuclear Medicine and imaging ,Ophthalmoplegia ,medicine.diagnostic_test ,business.industry ,Intestinal Pseudo-Obstruction ,Brain ,Magnetic resonance imaging ,Posterior reversible encephalopathy syndrome ,General Medicine ,Original Articles ,medicine.disease ,Phenotype ,MRI ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Polyneuropathy ,Diffusion MRI - Abstract
Leukoencephalopathy is a hallmark of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) a devastating disorder characterized by ptosis, ophthalmoparesis, gastrointestinal dysfunction and polyneuropathy. To characterize MNGIE-associated leukoencephalopathy and to correlate it with clinical, biochemical and molecular data, four MNGIE patients with heterogeneous clinical phenotypes (enteropathic arthritis, exercise intolerance, CIDP-like phenotype and typical presentation) were studied by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps were also obtained. In two patients we also investigated the role of brain MRI in monitoring the evolution of leukoencephalopathy by performing follow-up imaging studies at an interval of one and two years. The extension and distribution of leukoencephalopathy were not clearly linked with age, phenotype or disease severity, and did not seem to be related to TYMP mutations, enzyme activity or pyrimidine levels. In the studied patients MRS revealed reduced N-acetyl-aspartate and increased choline signals. Although DWI appeared normal in all patients but one, ADC maps always showed moderate increased diffusivity. Leukoencephalopathy worsened over a two-year period in two patients, regardless of the clinical course, indicating a lack of correlation between clinical phenotype, size and progression of white matter abnormalities during this period. Brain MRI should be considered a very useful tool to diagnose both classical and atypical MNGIE. Serial MRIs in untreated and treated MNGIE patients will help to establish whether the leukoencephalopathy is a reversible condition or not.
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