217 results on '"Legati, A."'
Search Results
2. Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY‐associated diseases
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Chiara Cavestro, Francesca Morra, Andrea Legati, Marco D'Amato, Alessia Nasca, Arcangela Iuso, Naomi Lubarr, Jennifer L. Morrison, Patricia G. Wheeler, Clara Serra‐Juhé, Benjamín Rodríguez‐Santiago, Eulalia Turón‐Viñas, Clement Prouteau, Magalie Barth, Susan J. Hayflick, Daniele Ghezzi, Valeria Tiranti, and Ivano Di Meo
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein‐associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY‐related disorders. Methods Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. Results We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY‐related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4′‐phosphopantetheinylated proteins were significantly reduced in COASY patients. Interpretation These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY‐associated diseases.
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- 2024
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3. A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies
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Daniele Sala, Silvia Marchet, Lorenzo Nanetti, Andrea Legati, Caterina Mariotti, Eleonora Lamantea, Daniele Ghezzi, Alessia Catania, and Costanza Lamperti
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MT-ATP6 ,Ataxia ,ATP synthase ,Mitochondria ,OXPHOS ,Complex V ,Medicine - Abstract
Abstract Background MT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias. Methods We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients’ primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential. Results In both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes. Conclusions We describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.
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- 2024
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4. Generation of iPSCs from identical twin, one affected by LHON and one unaffected, both carrying a combination of two mitochondrial variants: m.14484 T>C and m.10680G>A
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Camille Peron, Andrea Cavaliere, Chiara Fasano, Angelo Iannielli, Manuela Spagnolo, Andrea Legati, Maria Nicol Colombo, Ambra Rizzo, Francesca L. Sciacca, Valerio Carelli, Vania Broccoli, Costanza Lamperti, and Valeria Tiranti
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Biology (General) ,QH301-705.5 - Abstract
Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial illness, causing retinal ganglion cell degeneration and central vision loss. It stems from point mutations in mitochondrial DNA (mtDNA), with key mutations being m.3460G > A, m.11778G > A, and m.14484 T > C. Fibroblasts from identical twins, sharing m.14484 T > C and m.10680G > A variants each with 70 % heteroplasmy, were used to generate iPSC lines. Remarkably, one twin, a LHON patient, displayed symptoms, while the other, a carrier, remained asymptomatic. These iPSCs offer a valuable tool for studying factors influencing disease penetrance and unravelling the role of m.10680G > A, which is still debated.
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- 2024
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5. De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting
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Beatrice Berti, Daniela Verrigni, Alessia Nasca, Michela Di Nottia, Daniela Leone, Alessandra Torraco, Teresa Rizza, Emanuele Bellacchio, Andrea Legati, Concetta Palermo, Silvia Marchet, Costanza Lamperti, Antonio Novelli, Eugenio Maria Mercuri, Enrico Silvio Bertini, Marika Pane, Daniele Ghezzi, and Rosalba Carrozzo
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DNM1L ,cardiomyopathy ,mitochondrial disorders ,paroxysmal vomiting ,mitochondrial dynamics ,mitochondrial fission ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic–dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.
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- 2024
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6. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia
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Yap, Zheng Yie, Efthymiou, Stephanie, Seiffert, Simone, Parra, Karen Vargas, Lee, Sukyeong, Nasca, Alessia, Maroofian, Reza, Schrauwen, Isabelle, Pendziwiat, Manuela, Jung, Sunhee, Bhoj, Elizabeth, Striano, Pasquale, Mankad, Kshitij, Vona, Barbara, Cuddapah, Sanmati, Wagner, Anja, Alvi, Javeria Raza, Davoudi-Dehaghani, Elham, Fallah, Mohammad-Sadegh, Gannavarapu, Srinitya, Lamperti, Costanza, Legati, Andrea, Murtaza, Bibi Nazia, Nadeem, Muhammad Shahid, Rehman, Mujaddad Ur, Saeidi, Kolsoum, Salpietro, Vincenzo, von Spiczak, Sarah, Sandoval, Abigail, Zeinali, Sirous, Zeviani, Massimo, Reich, Adi, Group, SYNaPS Study, Genomics, University of Washington Center for Mendelian, Jang, Cholsoon, Helbig, Ingo, Barakat, Tahsin Stefan, Ghezzi, Daniele, Leal, Suzanne M, Weber, Yvonne, Houlden, Henry, and Yoon, Wan Hee
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Genetics ,Clinical Research ,Brain Disorders ,Neurosciences ,Neurodegenerative ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Alleles ,Animals ,Ataxia ,Cells ,Cultured ,Child ,Cohort Studies ,DNA Mutational Analysis ,Drosophila melanogaster ,Epilepsy ,Family Health ,Female ,Fibroblasts ,Hearing Loss ,Humans ,Ketoglutarate Dehydrogenase Complex ,Male ,Mutation ,Neurodevelopmental Disorders ,RNA Splicing ,Vision Disorders ,SYNaPS Study Group ,University of Washington Center for Mendelian Genomics ,CRISPR-Cas9 gene editing ,DEE ,Drosophila ,OGDHL ,bi-allelic ,developmental and epileptic encephalopathy ,exome sequencing ,mitochondria ,neurodevelopmental disease ,α-ketoglutarate ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.
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- 2021
7. Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions
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Chiara Frascarelli, Nadia Zanetti, Alessia Nasca, Rossella Izzo, Costanza Lamperti, Eleonora Lamantea, Andrea Legati, and Daniele Ghezzi
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mtDNA ,long reads ,oxford nanopore ,MinION ,macrodeletion ,multiple deletions ,Genetics ,QH426-470 - Abstract
Primary mitochondrial diseases are progressive genetic disorders affecting multiple organs and characterized by mitochondrial dysfunction. These disorders can be caused by mutations in nuclear genes coding proteins with mitochondrial localization or by genetic defects in the mitochondrial genome (mtDNA). The latter include point pathogenic variants and large-scale deletions/rearrangements. MtDNA molecules with the wild type or a variant sequence can exist together in a single cell, a condition known as mtDNA heteroplasmy. MtDNA single point mutations are typically detected by means of Next-Generation Sequencing (NGS) based on short reads which, however, are limited for the identification of structural mtDNA alterations. Recently, new NGS technologies based on long reads have been released, allowing to obtain sequences of several kilobases in length; this approach is suitable for detection of structural alterations affecting the mitochondrial genome. In the present work we illustrate the optimization of two sequencing protocols based on long-read Oxford Nanopore Technology to detect mtDNA structural alterations. This approach presents strong advantages in the analysis of mtDNA compared to both short-read NGS and traditional techniques, potentially becoming the method of choice for genetic studies on mtDNA.
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- 2023
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8. Generation of iPSCs from identical twin, one affected by LHON and one unaffected, both carrying a combination of two mitochondrial variants: m.14484 T>C and m.10680G>A
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Peron, Camille, primary, Cavaliere, Andrea, additional, Fasano, Chiara, additional, Iannielli, Angelo, additional, Spagnolo, Manuela, additional, Legati, Andrea, additional, Nicol Colombo, Maria, additional, Rizzo, Ambra, additional, Sciacca, Francesca L., additional, Carelli, Valerio, additional, Broccoli, Vania, additional, Lamperti, Costanza, additional, and Tiranti, Valeria, additional
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- 2024
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9. Primary brain calcification: an international study reporting novel variants and associated phenotypes.
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Ramos, Eliana Marisa, Carecchio, Miryam, Lemos, Roberta, Ferreira, Joana, Legati, Andrea, Sears, Renee Louise, Hsu, Sandy Chan, Panteghini, Celeste, Magistrelli, Luca, Salsano, Ettore, Esposito, Silvia, Taroni, Franco, Richard, Anne-Claire, Tranchant, Christine, Anheim, Mathieu, Ayrignac, Xavier, Goizet, Cyril, Vidailhet, Marie, Maltete, David, Wallon, David, Frebourg, Thierry, Pimentel, Lylyan, Geschwind, Daniel H, Vanakker, Olivier, Galasko, Douglas, Fogel, Brent L, Innes, A Micheil, Ross, Alison, Dobyns, William B, Alcantara, Diana, O'Driscoll, Mark, Hannequin, Didier, Campion, Dominique, French PFBC study group, Oliveira, João R, Garavaglia, Barbara, Coppola, Giovanni, and Nicolas, Gaël
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French PFBC study group ,Humans ,Brain Diseases ,Calcinosis ,Receptor ,Platelet-Derived Growth Factor beta ,Proto-Oncogene Proteins c-sis ,Receptors ,G-Protein-Coupled ,Receptors ,Virus ,Pedigree ,Heterozygote ,Phenotype ,Mutation ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Child ,Female ,Male ,Sodium-Phosphate Cotransporter Proteins ,Type III ,Genetic Variation ,Young Adult ,Cognitive Dysfunction ,Receptor ,Platelet-Derived Growth Factor beta ,Receptors ,G-Protein-Coupled ,Virus ,and over ,Sodium-Phosphate Cotransporter Proteins ,Type III ,Genetics ,Genetics & Heredity ,Clinical Sciences - Abstract
Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
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- 2018
10. De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting.
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Berti, Beatrice, Verrigni, Daniela, Nasca, Alessia, Di Nottia, Michela, Leone, Daniela, Torraco, Alessandra, Rizza, Teresa, Bellacchio, Emanuele, Legati, Andrea, Palermo, Concetta, Marchet, Silvia, Lamperti, Costanza, Novelli, Antonio, Mercuri, Eugenio Maria, Bertini, Enrico Silvio, Pane, Marika, Ghezzi, Daniele, and Carrozzo, Rosalba
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MITOCHONDRIAL dynamics ,CELL respiration ,BRAIN diseases ,GENETIC variation ,CARDIOMYOPATHIES ,FAMILIAL spastic paraplegia ,RESPIRATION in plants ,HEART ,SUDDEN death - Abstract
Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic–dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
11. NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia
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Federica Invernizzi, Rossella Izzo, Isabel Colangelo, Andrea Legati, Nadia Zanetti, Barbara Garavaglia, Eleonora Lamantea, Lorenzo Peverelli, Anna Ardissone, Isabella Moroni, Lorenzo Maggi, Silvia Bonanno, Laura Fiori, Daniele Velardo, Francesca Magri, Giacomo P. Comi, Dario Ronchi, Daniele Ghezzi, and Costanza Lamperti
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hyperCKemia ,creatine kinase ,rhabdomyolysis ,skeletal muscle damage ,Next Generation Sequencing (NGS) ,myoglobinuria ,Genetics ,QH426-470 - Abstract
Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors.
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- 2023
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12. Brain calcifications and PCDH12 variants.
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Nicolas, Gaël, Sanchez-Contreras, Monica, Ramos, Eliana Marisa, Lemos, Roberta R, Ferreira, Joana, Moura, Denis, Sobrido, Maria J, Richard, Anne-Claire, Lopez, Alma Rosa, Legati, Andrea, Deleuze, Jean-François, Boland, Anne, Quenez, Olivier, Krystkowiak, Pierre, Favrole, Pascal, Geschwind, Daniel H, Aran, Adi, Segel, Reeval, Levy-Lahad, Ephrat, Dickson, Dennis W, Coppola, Giovanni, Rademakers, Rosa, and de Oliveira, João RM
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Neurosciences ,Stem Cell Research ,Brain Disorders ,Stem Cell Research - Nonembryonic - Non-Human ,Clinical Research ,Genetics ,2.1 Biological and endogenous factors ,Neurological - Abstract
ObjectiveTo assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications.MethodsWe performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC).ResultsWe identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency
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- 2017
13. Genetic Prion Disease Caused by PRNP Q160X Mutation Presenting with an Orbitofrontal Syndrome, Cyclic Diarrhea, and Peripheral Neuropathy
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Fong, Jamie C, Rojas, Julio C, Bang, Jee, Legati, Andrea, Rankin, Katherine P, Forner, Sven, Miller, Zachary A, Karydas, Anna M, Coppola, Giovanni, Grouse, Carrie K, Ralph, Jeffrey, Miller, Bruce L, and Geschwind, Michael D
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Brain Disorders ,Acquired Cognitive Impairment ,Rare Diseases ,Clinical Research ,Peripheral Neuropathy ,Dementia ,Neurodegenerative ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Brain ,Codon ,Nonsense ,Disease Progression ,Follow-Up Studies ,Humans ,Longitudinal Studies ,Male ,Pedigree ,Peripheral Nerves ,Phenotype ,Prion Diseases ,Prion Proteins ,Amyloidosis ,DNA sequencing ,dysautonomia ,exome ,mutation ,peripheral neuropathy ,prion dementia ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences ,Biological psychology - Abstract
Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.
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- 2017
14. Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY‐associated diseases.
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Cavestro, Chiara, Morra, Francesca, Legati, Andrea, D'Amato, Marco, Nasca, Alessia, Iuso, Arcangela, Lubarr, Naomi, Morrison, Jennifer L., Wheeler, Patricia G., Serra‐Juhé, Clara, Rodríguez‐Santiago, Benjamín, Turón‐Viñas, Eulalia, Prouteau, Clement, Barth, Magalie, Hayflick, Susan J., Ghezzi, Daniele, Tiranti, Valeria, and Di Meo, Ivano
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PHENOTYPES ,EPILEPSY ,CELL communication ,COENZYME A ,AUTISM spectrum disorders ,TRANSCRIPTOMES - Abstract
Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein‐associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY‐related disorders. Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY‐related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4′‐phosphopantetheinylated proteins were significantly reduced in COASY patients. Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY‐associated diseases. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
15. A novel MRPS34 gene mutation with combined OXPHOS deficiency in an adult patient with Leigh syndrome
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L. Lenzini, M. Carecchio, E. Iori, A. Legati, E. Lamantea, A. Avogaro, and N. Vitturi
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
We report a novel pathogenic variant (c.223G > C; p.Gly75Arg) in the gene encoding the small mitoribosomal subunit protein mS34 in a long-surviving patient with Leigh Syndrome who was genetically diagnosed at age 34 years.The patient presented with delayed motor milestones and a stepwise motor deterioration during life, along with brain MRI alterations involving the subcortical white matter, deep grey nuclei and in particular the internal globi pallidi, that appeared calcified on CT scan. The novel variant is associated with a reduction of mS34 protein levels and of the OXPHOS complex I and IV subunits in peripheral blood mononuclear cells of the case.This study expands the number of variants that, by affecting the stability of the mitoribosome, may cause an OXPHOS deficiency in Leigh Syndrome and reports, for the first time, an unusual long survival in a patient with a homozygous MRPS34 pathogenic variant.
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- 2022
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16. A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques
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Moreno, Fermin, Rabinovici, Gil D, Karydas, Anna, Miller, Zachary, Hsu, Sandy Chan, Legati, Andrea, Fong, Jamie, Schonhaut, Daniel, Esselmann, Hermann, Watson, Christa, Stephens, Melanie L, Kramer, Joel, Wiltfang, Jens, Seeley, William W, Miller, Bruce L, Coppola, Giovanni, and Grinberg, Lea Tenenholz
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Biochemistry and Cell Biology ,Biological Sciences ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Rare Diseases ,Genetics ,Neurodegenerative ,Dementia ,Aging ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease Related Dementias (ADRD) ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Brain ,DNA-Binding Proteins ,Female ,Frontotemporal Lobar Degeneration ,Humans ,Inclusion Bodies ,Male ,Middle Aged ,Motor Neuron Disease ,Mutation ,Parkinsonian Disorders ,Pedigree ,Plaque ,Amyloid ,Siblings ,Clinical Sciences ,Biochemistry and cell biology - Abstract
IntroductionAlthough TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.ResultsWe describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance.ConclusionsTARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.
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- 2015
17. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export.
- Author
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Legati, Andrea, Giovannini, Donatella, Nicolas, Gaël, López-Sánchez, Uriel, Quintáns, Beatriz, Oliveira, João RM, Sears, Renee L, Ramos, Eliana Marisa, Spiteri, Elizabeth, Sobrido, María-Jesús, Carracedo, Ángel, Castro-Fernández, Cristina, Cubizolle, Stéphanie, Fogel, Brent L, Goizet, Cyril, Jen, Joanna C, Kirdlarp, Suppachok, Lang, Anthony E, Miedzybrodzka, Zosia, Mitarnun, Witoon, Paucar, Martin, Paulson, Henry, Pariente, Jérémie, Richard, Anne-Claire, Salins, Naomi S, Simpson, Sheila A, Striano, Pasquale, Svenningsson, Per, Tison, François, Unni, Vivek K, Vanakker, Olivier, Wessels, Marja W, Wetchaphanphesat, Suppachok, Yang, Michele, Boller, Francois, Campion, Dominique, Hannequin, Didier, Sitbon, Marc, Geschwind, Daniel H, Battini, Jean-Luc, and Coppola, Giovanni
- Subjects
Humans ,Brain Diseases ,Metabolic ,Inborn ,Neurodegenerative Diseases ,Calcinosis ,Genetic Predisposition to Disease ,Receptors ,G-Protein-Coupled ,Receptors ,Virus ,Pedigree ,DNA Mutational Analysis ,Lod Score ,Mutation ,Missense ,Middle Aged ,Female ,Male ,Genetic Association Studies ,HEK293 Cells ,Xenotropic and Polytropic Retrovirus Receptor ,Neurosciences ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.
- Published
- 2015
18. Editorial: Application of Omics Approaches to the Diagnosis of Genetic Neurological Disorders
- Author
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Andrea Legati, Edoardo Giacopuzzi, Marco Spinazzi, and Monkol Lek
- Subjects
omics ,neurological disorder ,genetics ,next generation sequencing ,metabolomics (omics) ,transcriptomics ,Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2021
- Full Text
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19. Benign hereditary chorea and deletions outside NKX2-1: What's the role of MBIP?
- Author
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Invernizzi, Federica, Zorzi, Giovanna, Legati, Andrea, Coppola, Giovanni, D'Adamo, Pio, Nardocci, Nardo, Garavaglia, Barbara, and Ghezzi, Daniele
- Published
- 2018
- Full Text
- View/download PDF
20. NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia
- Author
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Invernizzi, Federica, primary, Izzo, Rossella, additional, Colangelo, Isabel, additional, Legati, Andrea, additional, Zanetti, Nadia, additional, Garavaglia, Barbara, additional, Lamantea, Eleonora, additional, Peverelli, Lorenzo, additional, Ardissone, Anna, additional, Moroni, Isabella, additional, Maggi, Lorenzo, additional, Bonanno, Silvia, additional, Fiori, Laura, additional, Velardo, Daniele, additional, Magri, Francesca, additional, Comi, Giacomo P., additional, Ronchi, Dario, additional, Ghezzi, Daniele, additional, and Lamperti, Costanza, additional
- Published
- 2023
- Full Text
- View/download PDF
21. Laura DI FABIO, Due democrazie, una sorveglianza comune. Italia e Repubblica Federale Tedesca nella lotta al terrorismo interno e internazionale (1967-1986), Firenze, Le Monnier – Mondadori Education, 2018, 223 pp.
- Author
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Alessandro STOPPOLONI (Roma, 1989) ha completato nel luglio del 2015 il percorso per ottenere il doppio titolo nell’ambito del corso integrato italo-tedesco organizzato dall’Università di Bologna e da quella di Bielefeld discutendo una tesi dal titolo Fra teoria e pratica: la psicologia politica di Peter Brückner (1966-1978). In precedenza ha studiato presso le Università Roma Tre e Paris X (come studente Erasmus). In questo momento si sta occupando di temi legati alla storia della psichiatria.
- Subjects
History (General) ,D1-2009 ,Modern history, 1453- ,D204-475 - Published
- 2018
22. Generation of two human iPSC lines, FINCBi002-A and FINCBi003-A, carrying heteroplasmic macrodeletion of mitochondrial DNA causing Pearson’s syndrome
- Author
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Camille Peron, Roberta Mauceri, Angelo Iannielli, Andrea Cavaliere, Andrea Legati, Ambra Rizzo, Francesca L. Sciacca, Vania Broccoli, and Valeria Tiranti
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Pearson marrow pancreas syndrome (PMPS) is a sporadic mitochondrial disease, resulting from the clonal expansion of a mutated mitochondrial DNA (mtDNA) molecule bearing a macro-deletion, and therefore missing essential genetic information. PMPS is characterized by the presence of deleted (Δ) mtDNA that co-exist with the presence of a variable amount of wild-type mtDNA, a condition termed heteroplasmy. All tissues of the affected individual, including the haemopoietic system and the post-mitotic, highly specialized tissues (brain, skeletal muscle, and heart) contain the large-scale mtDNA deletion in variable amount. We generated human induced pluripotent stem cells (hiPSCs) from two PMPS patients, carrying different type of large-scale deletion.
- Published
- 2021
- Full Text
- View/download PDF
23. Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I
- Author
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Ahmad Alahmad, Alessia Nasca, Juliana Heidler, Kyle Thompson, Monika Oláhová, Andrea Legati, Eleonora Lamantea, Jana Meisterknecht, Manuela Spagnolo, Langping He, Seham Alameer, Fahad Hakami, Abeer Almehdar, Anna Ardissone, Charlotte L Alston, Robert McFarland, Ilka Wittig, Daniele Ghezzi, and Robert W Taylor
- Subjects
complex I ,Leigh syndrome ,mitochondrial disease ,NDUFC2 ,OXPHOS ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects’ fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects’ fibroblasts with wild‐type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.
- Published
- 2020
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- View/download PDF
24. Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions
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Alessia Nasca, Andrea Legati, Megi Meneri, Melisa Emel Ermert, Chiara Frascarelli, Nadia Zanetti, Manuela Garbellini, Giacomo Pietro Comi, Alessia Catania, Costanza Lamperti, Dario Ronchi, and Daniele Ghezzi
- Subjects
endonuclease G ,ENDOG ,mitochondrial DNA ,mitochondrial myopathy ,multiple mtDNA deletions ,Cytology ,QH573-671 - Abstract
Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient’s muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient’s clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient’s fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.
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- 2022
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25. NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia
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Lamperti, Federica Invernizzi, Rossella Izzo, Isabel Colangelo, Andrea Legati, Nadia Zanetti, Barbara Garavaglia, Eleonora Lamantea, Lorenzo Peverelli, Anna Ardissone, Isabella Moroni, Lorenzo Maggi, Silvia Bonanno, Laura Fiori, Daniele Velardo, Francesca Magri, Giacomo P. Comi, Dario Ronchi, Daniele Ghezzi, and Costanza
- Subjects
hyperCKemia ,creatine kinase ,rhabdomyolysis ,skeletal muscle damage ,Next Generation Sequencing (NGS) ,myoglobinuria - Abstract
Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors.
- Published
- 2023
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26. RECENSIONE: Oscar GRECO, I demoni del mezzogiorno. Follia, pregiudizio e marginalità nel manicomio di Girifalco (1881-1921), Soveria Mannelli, Rubbettino, 2018, 256 pp.
- Author
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Alessandro STOPPOLONI (Roma, 1989) ha completato nel luglio del 2015 il percorso per ottenere il doppio titolo nell’ambito del corso integrato italo-tedesco organizzato dall’Università di Bologna e da quella di Bielefeld discutendo una tesi dal titolo Fra teoria e pratica: la psicologia politica di Peter Brückner (1966-1978). In precedenza ha studiato presso le Università Roma Tre e Paris X (come studente Erasmus). In questo momento si sta occupando di temi legati alla storia della psichiatria.
- Subjects
History (General) ,D1-2009 ,Modern history, 1453- ,D204-475 - Published
- 2018
27. RECENSIONE: Giovanni PIETRANGELI, La più grossa fabbrica di Roma. Dirigenti, tecnici e operaie alla Voxson, Venezia, Edizioni Ca’ Foscari, 2017, 160 pp.
- Author
-
Alessandro STOPPOLONI (Roma, 1989) ha completato nel luglio del 2015 il percorso per ottenere il doppio titolo nell’ambito del corso integrato italo-tedesco organizzato dall’Università di Bologna e da quella di Bielefeld discutendo una tesi dal titolo Fra teoria e pratica: la psicologia politica di Peter Brückner (1966-1978). In precedenza ha studiato presso le Università Roma Tre e Paris X (come studente Erasmus). In questo momento si sta occupando di temi legati alla storia della psichiatria.
- Subjects
History (General) ,D1-2009 ,Modern history, 1453- ,D204-475 - Published
- 2018
28. KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature
- Author
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Anna Ardissone, Davide Tonduti, Andrea Legati, Eleonora Lamantea, Rita Barone, Imen Dorboz, Odile Boespflug-Tanguy, Gabriella Nebbia, Marco Maggioni, Barbara Garavaglia, Isabella Moroni, Laura Farina, Anna Pichiecchio, Simona Orcesi, Luisa Chiapparini, and Daniele Ghezzi
- Subjects
Mitochondrial disease ,KARS ,Leukoencephalopathy ,Calcifications ,Medicine - Abstract
Abstract Background KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. Results Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. Conclusions With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.
- Published
- 2018
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29. Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions
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Frascarelli, Chiara, primary, Zanetti, Nadia, additional, Nasca, Alessia, additional, Izzo, Rossella, additional, Lamperti, Costanza, additional, Lamantea, Eleonora, additional, Legati, Andrea, additional, and Ghezzi, Daniele, additional
- Published
- 2023
- Full Text
- View/download PDF
30. Multiple Genetic Rare Variants in Autism Spectrum Disorders: A Single-Center Targeted NGS Study
- Author
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Chiara Reale, Valeria Tessarollo, Sara Bulgheroni, Silvia Annunziata, Andrea Legati, Daria Riva, Chiara Pantaleoni, Barbara Garavaglia, and Stefano D’Arrigo
- Subjects
autism spectrum disorder ,targeted gene panel ,rare inherited variants ,family segregation ,genetic makeup ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Many studies based on chromosomal microarray and next-generation sequencing (NGS) have identified hundreds of genes associated with autism spectrum disorder (ASD) risk, demonstrating that there are several complex genetic factors that contribute to ASD risk. We performed targeted NGS gene panels for 120 selected genes, in a clinical population of 40 children with well-characterized ASD. The variants identified were annotated and filtered, focusing on rare variants with a minimum allele frequency MET and SLIT3 and the potentially stronger involvement of FAT1 and VPS13B in ASD. Taken together, our findings reinforce the importance of using gene panels to understand the contribution of the different genes already associated with ASD in the pathogenesis of the disease.
- Published
- 2021
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31. Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis
- Author
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Catania, Alessia, Ardissone, Anna, Verrigni, Daniela, Legati, Andrea, Reyes, Aurelio, Lamantea, Eleonora, Diodato, Daria, Tonduti, Davide, Imperatore, Valentina, Pinto, Anna Maria, Moroni, Isabella, Bertini, Enrico, Robinson, Alan, Carrozzo, Rosalba, Zeviani, Massimo, and Ghezzi, Daniele
- Published
- 2018
- Full Text
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32. Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations
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Alessia Nasca, Teresa Rizza, Mara Doimo, Andrea Legati, Andrea Ciolfi, Daria Diodato, Cristina Calderan, Gianfranco Carrara, Eleonora Lamantea, Chiara Aiello, Michela Di Nottia, Marcello Niceta, Costanza Lamperti, Anna Ardissone, Stefania Bianchi-Marzoli, Giancarlo Iarossi, Enrico Bertini, Isabella Moroni, Marco Tartaglia, Leonardo Salviati, Rosalba Carrozzo, and Daniele Ghezzi
- Subjects
OPA1 ,Optic atrophy ,Mitochondrial disorder ,Encephalopathy ,Recessive trait ,Targeted resequencing ,Medicine - Abstract
Abstract Background Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients’ biological samples, and a clearly fragmented mitochondrial network was observed in patients’ fibroblasts. Conclusions This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature.
- Published
- 2017
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33. Variants in ATP5F1B are associated with dominantly inherited dystonia
- Author
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Nasca, Alessia, primary, Mencacci, Niccolò E, additional, Invernizzi, Federica, additional, Zech, Michael, additional, Sarmiento, Ignacio J Keller, additional, Legati, Andrea, additional, Frascarelli, Chiara, additional, Bustos, Bernabe I, additional, Romito, Luigi M, additional, Krainc, Dimitri, additional, Winkelmann, Juliane, additional, Carecchio, Miryam, additional, Nardocci, Nardo, additional, Zorzi, Giovanna, additional, Prokisch, Holger, additional, Lubbe, Steven J, additional, Garavaglia, Barbara, additional, and Ghezzi, Daniele, additional
- Published
- 2023
- Full Text
- View/download PDF
34. CPEO and Mitochondrial Myopathy in a Patient with DGUOK Compound Heterozygous Pathogenetic Variant and mtDNA Multiple Deletions
- Author
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V. Montano, C. Simoncini, Cassi L. Calì, A. Legati, G. Siciliano, and M. Mancuso
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The classic features of deoxyguanosine kinase (DGUOK) deficiency are infantile onset hepatic failure with nystagmus and hypotonia; mitochondrial DNA studies on affected tissue reveal mitochondrial DNA depletion. Later, it has been shown that the mutations in the same gene may present with adult-onset mitochondrial myopathy and mitochondrial DNA multiple deletions in skeletal muscle. Here we report the case of a 42-year-old Italian woman presenting with a chronic progressive external ophthalmoplegia and myopathy with mtDNA multiple deletions and the compound heterozygous c.462T>A (p.Asn154Lys) and c.707+2T>G pathogenic variants in DGUOK.
- Published
- 2019
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35. Clinical and Biochemical Features in a Patient With Mitochondrial Fission Factor Gene Alteration
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Alessia Nasca, Francesca Nardecchia, Anna Commone, Michela Semeraro, Andrea Legati, Barbara Garavaglia, Daniele Ghezzi, and Vincenzo Leuzzi
- Subjects
mitochondrial fission factor ,MFF ,epileptic encephalopathy ,leigh syndrome ,mitochondrial disorders ,mitochondria ,Genetics ,QH426-470 - Abstract
Mitochondrial Fission Factor (MFF) is part of a protein complex that promotes mitochondria and peroxisome fission. Hitherto, only 5 patients have been reported harboring mutations in MFF, all of them with the clinical features of a very early onset Leigh-like encephalopathy. We report on an 11-year-old boy with epileptic encephalopathy. He presented with neurological regression, epileptic myoclonic seizures, severe intellectual disability, microcephaly, tetraparesis, optic atrophy, and ophthalmoplegia. Brain MRI pattern was compatible with Leigh syndrome. NGS-based analysis of a gene panel for mitochondrial disorders revealed a homozygous c.892C>T (p. Arg298*) in the MFF gene. Fluorescence staining detected abnormal morphology of mitochondria and peroxisomes in fibroblasts from the patient; a strong reduction in MFF protein levels and the presence of truncated forms were observed. No biochemical alterations denoting peroxisomal disorders were found. As reported in other disorders affecting the dynamics of intracellular organelles, our patient showed clinical features suggesting both mitochondrial and peroxisomal impairment. High levels of lactate in our case suggested an involvement of the energetic metabolism but without clear respiratory chain deficiency, while biomarkers of peroxisomal dysfunction were normal. We confirm that MFF mutations are associated with epileptic encephalopathy with Leigh-like MRI pattern.
- Published
- 2018
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36. Variants in ATP5F1B are associated with dominantly inherited dystonia
- Author
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Alessia Nasca, Niccolò E Mencacci, Federica Invernizzi, Michael Zech, Ignacio J Keller Sarmiento, Andrea Legati, Chiara Frascarelli, Bernabe I Bustos, Luigi M Romito, Dimitri Krainc, Juliane Winkelmann, Miryam Carecchio, Nardo Nardocci, Giovanna Zorzi, Holger Prokisch, Steven J Lubbe, Barbara Garavaglia, and Daniele Ghezzi
- Subjects
ATP5F1B ,case report ,dystonia ,incomplete penetrance ,mitochondrial ATP synthase ,Neurology (clinical) - Abstract
ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.
- Published
- 2023
37. Challenges in the interpretation of lyric texts
- Author
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Buljan-Legati Ivana
- Subjects
lyrics ,community ,understanding ,Stage speech department ,freedom ,Arts in general ,NX1-820 - Abstract
It is possible, perhaps, to choose the right path to the answer to the questions how poetry has been disappearing over the centuries and has lost its purpose in the ever greater void of outer space and how it has turned from a common and welcome social activity into a phenomenon that will have to leave its fellow-townspeople due to enormous suspicion about the communal language, the world view of the majority and the material world, if first, (at least) a rough reconstruction of the sense and nature of continual changes in the poetic mechanism has been done (a more detailed overview would extend the paper enormously), as well as of the changes in style and the reception of poetry, since each choice of a possible linguistic system in a particular historical period soon heralded its own boundary line. From a popular, entertaining and educational genre as a transparent means of social communication, which has brought the individual into a community by generating stable certainty, and gave him the sense of control over his own destiny and meaning, lyrics will outgrow proportionally the aesthetic dimensions of its texts (which will subsequently substitute the foretoken of literacy), becoming less comparable and surmountable, in certain periods almost a nontransferable artistic view. In such circumstances, the public will start to have less understanding and tolerance for its 'weaknesses'.
- Published
- 2016
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38. 226 ECHOCARDIOGRAPHIC AND INVASIVE EVALUATION OF LEFT ATRIAL PRESSURE IN PATIENTS UNDERGOING CATHETER ABLATION FOR ATRIAL FIBRILLATION
- Author
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Bonelli, Andrea, primary, Inciardi, Riccardo Maria, additional, Cersosimo, Angelica, additional, Dell´era, Gabriele, additional, Degiovanni, Anna, additional, Spinoni, Enrico, additional, Bosco, Manuel, additional, Arabia, Gianmarco, additional, Salghetti, Francesca, additional, Bellicini, Mariagiulia, additional, Brangi, Elisa, additional, Legati, Michele, additional, Pagnesi, Matteo, additional, Lombardi, Carlo Mario, additional, Curnis, Antonio, additional, Patti, Giuseppe, additional, and Metra, Marco, additional
- Published
- 2022
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39. 226 ECHOCARDIOGRAPHIC AND INVASIVE EVALUATION OF LEFT ATRIAL PRESSURE IN PATIENTS UNDERGOING CATHETER ABLATION FOR ATRIAL FIBRILLATION
- Author
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Andrea Bonelli, Riccardo Maria Inciardi, Angelica Cersosimo, Gabriele Dell´era, Anna Degiovanni, Enrico Spinoni, Manuel Bosco, Gianmarco Arabia, Francesca Salghetti, Mariagiulia Bellicini, Elisa Brangi, Michele Legati, Matteo Pagnesi, Carlo Mario Lombardi, Antonio Curnis, Giuseppe Patti, and Marco Metra
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Aims Estimation of left ventricle (LV) filling pressure is one of the most important parameters to provide information in clinical practice. However, the challenging in investigating this parameter through invasive methods makes it difficult to be used. The study aims to investigate the association between cardiac structure and function derived by transthoracic echocardiography (TTE) and left atrial (LA) invasive pressure (LAP). Methods The study was a multi-center prospective study enrolling 73 patients (mean age 65 ± 8, 27% female) undergoing primary catheter ablation for AF. Patients were evaluated and enrolled from June 2021 to April 2022. Complete TTE assessing measures of LV, LA and right ventricle (RV) structure and function including speckle tracking echocardiography, was performed at baseline. Echocardiographic data have been assessed the same day of the invasive measurement of the LAP during AF ablative procedure. Linear regression analysis has been performed to assess the relationship between measures of cardiac structure and function and LAP. Logistic regression analysis assessed the parameters associated with elevated LAP (≥ 15mmHg). Results Baseline clinical characteristics of the study population did not differ according to elevated LAP vs. non-elevated LAP. Patients with elevated LAP showed instead abnormal measures of LV global longitudinal strain, measures of LA structure and function, except for LA maximal volume, and RV structure and function. After multivariable adjustment, including demographic factors and comorbidities, E/e`(p = 0,024), LA minimal volume (p = 0,009), LA emptying fraction (LAEF) (p = 0,012), LA Reservoir (p = 0,039), TAPSE (p = 0,010) and RV free wall strain (p = 0,028), but not LA maximal volume (p = 0,11), were significantly associated with LAP. Similarly, these measures, but nor LA maximal volume, were significant determinants of elevated LAP. Overall, LA minimal volume and LAEF showed the best diagnostic accuracy to predict elevated LAP (AUC 0.72 and 0.73, respectively). Conclusions Novel measures of LA structure and function, but not standard assessment by LA maximal volume, were significantly associated with LAP in patients affected by AF. These measures, along with measures of LV and RV function may be used in the diagnostic assessment of filling pressure in ambulatory settings.
- Published
- 2022
40. ATPase Domain <scp> AFG3L2 </scp> Mutations Alter <scp>OPA1</scp> Processing and Cause Optic Neuropathy
- Author
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Maria Lucia Valentino, Stefania Magri, Matthis Synofzik, Lorenzo Peverelli, Mingyan Fang, Alessia Nasca, Piero Barboni, Andrea Legati, Anna Ardissone, Stefania Bianchi Marzoli, Francesca Tagliavini, Eleonora Lamantea, Silvia Baratta, Daniele Ghezzi, Costanza Lamperti, Valerio Carelli, Chiara La Morgia, Rebecca Schüle, Mariantonietta Capristo, Gabriella Cammarata, Leonardo Caporali, Francesca Balistreri, Valentina Del Dotto, Davide Pareyson, Massimo Zeviani, L Melzi, Ludger Schöls, Michele Carbonelli, Franco Taroni, Maria Lucia Cascavilla, Alessandra Maresca, Caporali L., Magri S., Legati A., Del Dotto V., Tagliavini F., Balistreri F., Nasca A., La Morgia C., Carbonelli M., Valentino M.L., Lamantea E., Baratta S., Schols L., Schule R., Barboni P., Cascavilla M.L., Maresca A., Capristo M., Ardissone A., Pareyson D., Cammarata G., Melzi L., Zeviani M., Peverelli L., Lamperti C., Marzoli S.B., Fang M., Synofzik M., Ghezzi D., Carelli V., and Taroni F.
- Subjects
Male ,0301 basic medicine ,DOA ,Gene mutation ,medicine.disease_cause ,ATP-Dependent Proteases ,ATPases Associated with Diverse Cellular Activities ,Adolescent ,Adult ,Aged ,Child ,Female ,GTP Phosphohydrolases ,Genetic Testing ,High-Throughput Nucleotide Sequencing ,Humans ,Middle Aged ,Mutation ,Optic Atrophy ,Optic Nerve Diseases ,Pedigree ,Whole Exome Sequencing ,Young Adult ,OPA1 ,genetics [Optic Atrophy] ,Optic neuropathy ,0302 clinical medicine ,genetics [ATPases Associated with Diverse Cellular Activities] ,Research Articles ,Exome sequencing ,Genetics ,genetics [Optic Nerve Diseases] ,Neurology ,Spinocerebellar ataxia ,medicine.symptom ,Research Article ,genetics [GTP Phosphohydrolases] ,Spastic gait ,Ataxia ,Biology ,SCA28 ,03 medical and health sciences ,Atrophy ,Exome Sequencing ,medicine ,ddc:610 ,AFG3L2 ,medicine.disease ,eye diseases ,optic neuropathy ,030104 developmental biology ,genetics [ATP-Dependent Proteases] ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.
- Published
- 2020
41. A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy
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Legati, Andrea, Reyes, Aurelio, Ceccatelli Berti, Camilla, Stehling, Oliver, Marchet, Silvia, Lamperti, Costanza, Ferrari, Alberto, Robinson, Alan J, Mühlenhoff, Ulrich, Lill, Roland, Zeviani, Massimo, Goffrini, Paola, and Ghezzi, Daniele
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- 2017
- Full Text
- View/download PDF
42. KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature
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Ardissone, Anna, Tonduti, Davide, Legati, Andrea, Lamantea, Eleonora, Barone, Rita, Dorboz, Imen, Boespflug-Tanguy, Odile, Nebbia, Gabriella, Maggioni, Marco, Garavaglia, Barbara, Moroni, Isabella, Farina, Laura, Pichiecchio, Anna, Orcesi, Simona, Chiapparini, Luisa, and Ghezzi, Daniele
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- 2018
- Full Text
- View/download PDF
43. Biallelic Variants in
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Alessia, Nasca, Andrea, Legati, Megi, Meneri, Melisa Emel, Ermert, Chiara, Frascarelli, Nadia, Zanetti, Manuela, Garbellini, Giacomo Pietro, Comi, Alessia, Catania, Costanza, Lamperti, Dario, Ronchi, and Daniele, Ghezzi
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Endodeoxyribonucleases ,Humans ,Mitochondrial Myopathies ,Endonucleases ,DNA, Mitochondrial ,Mitochondria - Abstract
Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date
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- 2022
44. A novel MRPS34 gene mutation with combined OXPHOS deficiency in an adult patient with Leigh syndrome
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Lenzini, L., Carecchio, M., Iori, E., Legati, A., Lamantea, E., Avogaro, A., and Vitturi, N.
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Medicine (General) ,Endocrinology ,R5-920 ,QH301-705.5 ,Genetics ,Biology (General) ,Molecular Biology ,Article - Abstract
We report a novel pathogenic variant (c.223G > C; p.Gly75Arg) in the gene encoding the small mitoribosomal subunit protein mS34 in a long-surviving patient with Leigh Syndrome who was genetically diagnosed at age 34 years. The patient presented with delayed motor milestones and a stepwise motor deterioration during life, along with brain MRI alterations involving the subcortical white matter, deep grey nuclei and in particular the internal globi pallidi, that appeared calcified on CT scan. The novel variant is associated with a reduction of mS34 protein levels and of the OXPHOS complex I and IV subunits in peripheral blood mononuclear cells of the case. This study expands the number of variants that, by affecting the stability of the mitoribosome, may cause an OXPHOS deficiency in Leigh Syndrome and reports, for the first time, an unusual long survival in a patient with a homozygous MRPS34 pathogenic variant.
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- 2022
45. Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions
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Nasca, Alessia, primary, Legati, Andrea, additional, Meneri, Megi, additional, Ermert, Melisa Emel, additional, Frascarelli, Chiara, additional, Zanetti, Nadia, additional, Garbellini, Manuela, additional, Comi, Giacomo Pietro, additional, Catania, Alessia, additional, Lamperti, Costanza, additional, Ronchi, Dario, additional, and Ghezzi, Daniele, additional
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- 2022
- Full Text
- View/download PDF
46. A novel MRPS34 gene mutation with combined OXPHOS deficiency in an adult patient with Leigh syndrome
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Lenzini, L., primary, Carecchio, M., additional, Iori, E., additional, Legati, A., additional, Lamantea, E., additional, Avogaro, A., additional, and Vitturi, N., additional
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- 2022
- Full Text
- View/download PDF
47. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia
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Yvonne G. Weber, Mujaddad Ur Rehman, Massimo Zeviani, Srinitya Gannavarapu, Sirous Zeinali, Sanmati Cuddapah, Zheng Yie Yap, Sukyeong Lee, Javeria Raza Alvi, Adi Reich, Wan Hee Yoon, Isabelle Schrauwen, Tahsin Stefan Barakat, Pasquale Striano, Andrea Legati, Ingo Helbig, Sarah von Spiczak, Vincenzo Salpietro, Henry Houlden, Kolsoum Saeidi, Cholsoon Jang, Mohammad-Sadegh Fallah, Alessia Nasca, Abigail Sandoval, Elham Davoudi-Dehaghani, Karen Vargas Parra, Kshitij Mankad, Stephanie Efthymiou, Anja Wagner, Sunhee Jung, Suzanne M. Leal, Manuela Pendziwiat, Bibi Nazia Murtaza, Daniele Ghezzi, Muhammad Nadeem, Elizabeth J. Bhoj, Costanza Lamperti, Reza Maroofian, Simone Seiffert, Barbara Vona, and Clinical Genetics
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Male ,Microcephaly ,DNA Mutational Analysis ,Compound heterozygosity ,Cohort Studies ,Exon ,Missense mutation ,Child ,Cells, Cultured ,Genetics (clinical) ,Exome sequencing ,Genetics ,CRISPR-Cas9 gene editing ,Cultured ,mitochondria ,Drosophila melanogaster ,Drosophila ,Female ,medicine.symptom ,Ataxia ,Cells ,RNA Splicing ,Vision Disorders ,Biology ,bi-allelic ,Article ,Frameshift mutation ,SDG 3 - Good Health and Well-being ,medicine ,Animals ,Humans ,Ketoglutarate Dehydrogenase Complex ,Allele ,developmental and epileptic encephalopathy ,Hearing Loss ,Alleles ,DEE ,Family Health ,Epilepsy ,Fibroblasts ,medicine.disease ,OGDHL ,neurodevelopmental disease ,α-ketoglutarate ,exome sequencing ,Neurodevelopmental Disorders ,Mutation - Abstract
The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.
- Published
- 2021
48. Paola FAORLIN, Maria PUCCIO, In viaggio con Garibaldi. La Storia in scena – Un laboratorio fra identità nazionale e multiculturalità, Genova, Erga Edizioni, 2011, 121 pp.
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Piera ANCARANI, insegnante di scuola primaria, lavora nel tempo pieno dal 1979. Ha svolto attività di coordinamento del plesso e di supporto ai Dirigenti nei circoli didattici di appartenenza. Da quando lavora in un Istituto Comprensivo, ha rivestito incarichi di Funzione Strumentale per la promozione di percorsi sulle Pari Opportunità e per l’innalzamento del successo scolastico. Attualmente è docente referente di progetti legati alla “Cultura della Memoria”. È coautrice di un saggio sull’integrazione degli alunni autistici (Il mondo di Alessandro, Roma, Il Minotauro, 2001) e di libri di testo e di sussidi parascolastici. L’ultima pubblicazione propone un percorso di “Didattica della Storia personale” nella scuola elementare.
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History (General) ,D1-2009 ,Modern history, 1453- ,D204-475 - Published
- 2011
49. Multiple Genetic Rare Variants in Autism Spectrum Disorders: A Single-Center Targeted NGS Study
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Andrea Legati, Sara Bulgheroni, Barbara Garavaglia, Valeria Tessarollo, Chiara Pantaleoni, Daria Riva, Silvia Annunziata, Stefano D'Arrigo, and Chiara Reale
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Technology ,targeted gene panel ,QH301-705.5 ,QC1-999 ,Population ,autism spectrum disorder ,Biology ,behavioral disciplines and activities ,mental disorders ,medicine ,General Materials Science ,Allele ,Biology (General) ,education ,Instrumentation ,Allele frequency ,Gene ,QD1-999 ,Fluid Flow and Transfer Processes ,Genetics ,education.field_of_study ,Process Chemistry and Technology ,Physics ,General Engineering ,rare inherited variants ,medicine.disease ,Engineering (General). Civil engineering (General) ,Computer Science Applications ,VPS13B ,Chemistry ,family segregation ,Autism spectrum disorder ,genetic makeup ,Population study ,Autism ,TA1-2040 - Abstract
Many studies based on chromosomal microarray and next-generation sequencing (NGS) have identified hundreds of genes associated with autism spectrum disorder (ASD) risk, demonstrating that there are several complex genetic factors that contribute to ASD risk. We performed targeted NGS gene panels for 120 selected genes, in a clinical population of 40 children with well-characterized ASD. The variants identified were annotated and filtered, focusing on rare variants with a minimum allele frequency <, 1% in GnomAD. We found 147 variants in 39 of the 40 patients. It was possible to perform family segregation analysis in 28 of the 40 patients. We found 4 de novo and 101 inherited variants. For the inherited variants, we observed that all the variants identified in the patients came equally from the paternal and maternal genetic makeup. We identified 9 genes that are more frequently mutated than the others, and upon comparing the mutational frequency of these 9 genes in our cohort and the mutational frequency in the GnomAD population, we found significantly increased frequencies of rare variants in our study population. This study supports the hypothesis that ASD is the result of a combination of rare deleterious variants (low contribution) and many low-risk alleles (genetic background), highlighting the importance of MET and SLIT3 and the potentially stronger involvement of FAT1 and VPS13B in ASD. Taken together, our findings reinforce the importance of using gene panels to understand the contribution of the different genes already associated with ASD in the pathogenesis of the disease.
- Published
- 2021
50. Editorial: Application of Omics Approaches to the Diagnosis of Genetic Neurological Disorders
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Legati, Andrea, Giacopuzzi, Edoardo, Spinazzi, Marco, and Lek, Monkol
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next generation sequencing ,transcriptomics ,Editorial ,Neurology ,diagnosis ,genomics ,genetics ,neurological disorder ,metabolomics (omics) ,omics - Published
- 2021
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