المؤلفون: Rogac M, Neubauer D, Leonardis L, Pecaric N, Meznaric M, Maver A, Sperl W, Garavaglia BM, Lamantea E, Peterlin B

المصدر: Balkan Journal of Medical Genetics, Vol 24, Iss 2, Pp 5-14 (2022)

مصطلحات موضوعية: exome-sequencing, magnetic resonance imaging (mri), mitochondrial disease (md), nijmegen mitochondrial disease criteria (mdc), muscle biopsy, Genetics, QH426-470

الوصف: The goal of the study was to retrospectively evaluate a cohort of children and adults with mitochondrial diseases (MDs) in a single-center experience. Neurological clinical examination, brain magnetic resonance imaging (MRI) and spectroscopy, muscle biopsy, metabolic and molecular-genetic analysis were evaluated in 26 children and 36 adult patients with MD in Slovenia from 2004 to 2018. Nijmegen MD criteria (MDC) were applied to all patients and the need for a muscle biopsy was estimated. Exome-sequencing was used in half of the patients. Twenty children (77.0%) and 12 adults (35.0%) scored a total of ≥8 on MDC, a result that is compatible with the diagnosis of definite MD. Yield of exome-sequencing was 7/22 (31.0%), but the method was not applied systematically in all patients from the beginning of diagnostics. Brain MRI morphological changes, which can be an imaging clue for the diagnosis of MD, were found in 17/24 children (71.0%). In 7/26 (29.0%) children, and in 20/30 (67.0%) adults, abnormal mitochondria were found on electron microscopy (EM) and ragged-red fibers were found in 16/30 (53.0%) adults. Respiratory chain enzymes (RCEs) and/or pyruvate dehydrogenase complex (PDHc) activities were abnormal in all the children and six adult cases. First, our data revealed that MDC was useful in the clinical diagnosis of MD, and second, until the use of NGS methods, extensive, laborious and invasive diagnostic procedures were performed to reach a final diagnosis. In patients with suspected MD, there is a need to prioritize molecular diagnosis with the more modern next-generation sequencing (NGS) method.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1311-0160Test

الوصول الحر: https://doaj.org/article/285c4e26ee0b411688311fb7e252d1ceTest

المؤلفون: Ardissone A., Ferrera G., Lamperti C., Tiranti V., Ghezzi D., Moroni I., Lamantea E.

المساهمون: A. Ardissone, G. Ferrera, C. Lamperti, V. Tiranti, D. Ghezzi, I. Moroni, E. Lamantea

مصطلحات موضوعية: mitochondrial disorder, mitochondrial DNA, pediatric, phenotype, Settore MED/03 - Genetica Medica, Settore MED/26 - Neurologia

الوصف: Background and purpose: Mitochondrial diseases (MDs) are heterogeneous disorders caused by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) associated with specific syndromes. However, especially in childhood, patients often display heterogeneity. Several reports on the biochemical and molecular profiles in children have been published, but studies tend not to differentiate between mtDNA- and nDNA-associated diseases, and focus is often on a specific phenotype. Thus, large cohort studies specifically focusing on mtDNA defects in the pediatric population are lacking. Methods: We reviewed the clinical, metabolic, biochemical, and neuroimaging data of 150 patients with MDs due to mtDNA alterations collected at our neurological institute over the past 20 years. Results: mtDNA impairment is less frequent than nDNA impairment in pediatric MDs. Ocular involvement is extremely frequent in our cohort, as is classical Leber hereditary optic neuropathy, especially with onset before 12 years of age. Extraneurological manifestations and isolated myopathy appear to be rare, unlike adult phenotypes. Deep gray matter involvement, early disease onset, and specific phenotypes, such as Pearson syndrome and Leigh syndrome, represent unfavorable prognostic factors. Phenotypes related to single large scale mtDNA deletions appear to be very frequent in the pediatric population. Furthermore, we report for the first time an mtDNA pathogenic variant associated with cavitating leukodystrophy. Conclusions: We report on a large cohort of pediatric patients with mtDNA defects, adding new data on the phenotypical characterization of mtDNA defects and suggestions for diagnostic workup and therapeutic approach.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37038312; info:eu-repo/semantics/altIdentifier/wos/WOS:000979070900001; volume:30; issue:7; firstpage:2079; lastpage:2091; numberofpages:13; journal:EUROPEAN JOURNAL OF NEUROLOGY; https://hdl.handle.net/2434/993969Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85153621155

الإتاحة: https://doi.org/10.1111/ene.15814Test
https://hdl.handle.net/2434/993969Test

المؤلفون: Zambon A. A., Ghezzi D., Baldoli C., Cutillo G., Fontana K., Sofia V., Patricelli M. G., Nasca A., Vinci S., Spiga I., Lamantea E., Fanelli G. F., Sora M. G. N., Rovelli R., Poloniato A., Carrera P., Filippi M., Barera G.

المساهمون: A.A. Zambon, D. Ghezzi, C. Baldoli, G. Cutillo, K. Fontana, V. Sofia, M.G. Patricelli, A. Nasca, S. Vinci, I. Spiga, E. Lamantea, G.F. Fanelli, M.G.N. Sora, R. Rovelli, A. Poloniato, P. Carrera, M. Filippi, G. Barera

مصطلحات موضوعية: Settore MED/03 - Genetica Medica, Settore MED/26 - Neurologia

الوصف: Objectives: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. Methods: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. Results: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. Interpretation: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37644805; info:eu-repo/semantics/altIdentifier/wos/WOS:001063877200001; volume:10; issue:10; firstpage:1844; lastpage:1853; numberofpages:10; journal:ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY; https://hdl.handle.net/2434/1027828Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85169163105

الإتاحة: https://doi.org/10.1002/acn3.51876Test
https://hdl.handle.net/2434/1027828Test

المؤلفون: Frascarelli C., Zanetti N., Nasca A., Izzo R., Lamperti C., Lamantea E., Legati A., Ghezzi D.

المساهمون: C. Frascarelli, N. Zanetti, A. Nasca, R. Izzo, C. Lamperti, E. Lamantea, A. Legati, D. Ghezzi

مصطلحات موضوعية: MinION, complex-rearrangement, long read, macrodeletion, mtDNA, multiple deletion, oxford nanopore, structural variants, Settore MED/03 - Genetica Medica, Settore BIO/18 - Genetica

الوصف: 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.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37456669; info:eu-repo/semantics/altIdentifier/wos/WOS:001029313700001; volume:14; firstpage:1; lastpage:17; numberofpages:17; journal:FRONTIERS IN GENETICS; https://hdl.handle.net/2434/993816Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85165061839

الإتاحة: https://doi.org/10.3389/fgene.2023.1089956Test
https://hdl.handle.net/2434/993816Test

المؤلفون: Invernizzi F., Izzo R., Colangelo I., Legati A., Zanetti N., Garavaglia B., Lamantea E., Peverelli L., Ardissone A., Moroni I., Maggi L., Bonanno S., Fiori L., Velardo D., Magri F., Comi G. P., Ronchi D., Ghezzi D., Lamperti C.

المساهمون: F. Invernizzi, R. Izzo, I. Colangelo, A. Legati, N. Zanetti, B. Garavaglia, E. Lamantea, L. Peverelli, A. Ardissone, I. Moroni, L. Maggi, S. Bonanno, L. Fiori, D. Velardo, F. Magri, G.P. Comi, D. Ronchi, D. Ghezzi, C. Lamperti

مصطلحات موضوعية: creatine kinase, hyperCKemia, myoglobinuria, Next Generation Sequencing (NGS), rhabdomyolysi, skeletal muscle damage, Settore MED/03 - Genetica Medica, Settore MED/26 - Neurologia

الوصف: 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.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37510298; info:eu-repo/semantics/altIdentifier/wos/WOS:001036056200001; volume:14; issue:7; firstpage:1; lastpage:18; numberofpages:18; journal:GENES; https://hdl.handle.net/2434/993814Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85165879611

الإتاحة: https://doi.org/10.3390/genes14071393Test
https://hdl.handle.net/2434/993814Test

المؤلفون: Lenzini, L., Carecchio, M., Iori, E., Legati, A., Lamantea, E., Avogaro, A., Vitturi, N.

المساهمون: Università degli Studi di Padova, Ministero della Salute

المصدر: Molecular Genetics and Metabolism Reports ; volume 30, page 100830 ; ISSN 2214-4269

مصطلحات موضوعية: Endocrinology, Genetics, Molecular Biology

الإتاحة: https://doi.org/10.1016/j.ymgmr.2021.100830Test
https://api.elsevier.com/content/article/PII:S2214426921001257?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2214426921001257?httpAccept=text/plainTest

المؤلفون: Peverelli L., Catania A., Marchet S., Ciasca P., Cammarata G., Melzi L., Bellino A., Fancellu R., Lamantea E., Capristo M., Caporali L., La Morgia C., Carelli V., Ghezzi D., Bianchi Marzoli S., Lamperti C.

المساهمون: Peverelli L., Catania A., Marchet S., Ciasca P., Cammarata G., Melzi L., Bellino A., Fancellu R., Lamantea E., Capristo M., Caporali L., La Morgia C., Carelli V., Ghezzi D., Bianchi Marzoli S., Lamperti C.

مصطلحات موضوعية: complex I, Leber optic atrophy, LHON, mitochondrial respiratory chain, transmitochondrial cybrids

الوصف: Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34177762; info:eu-repo/semantics/altIdentifier/wos/WOS:000664512900001; volume:12; firstpage:657317; lastpage:657317; numberofpages:8; journal:FRONTIERS IN NEUROLOGY; info:eu-repo/grantAgreement/EC/H2020/825575; http://hdl.handle.net/11585/864626Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85108421550; https://doi.org/10.3389/fneur.2021.657317Test

الإتاحة: https://doi.org/10.3389/fneur.2021.657317Test
http://hdl.handle.net/11585/864626Test

المؤلفون: Bugiardini E., Bottani E., Marchet S., Poole O. V., Beninca C., Horga A., Woodward C., Lam A., Hargreaves I., Chalasani A., Valerio A., Lamantea E., Venner K., Holton J. L., Zeviani M., Houlden H., Quinlivan R., Lamperti C., Hanna M. G., Pitceathly R. D. S.

المساهمون: Bugiardini, E., Bottani, E., Marchet, S., Poole, O. V., Beninca, C., Horga, A., Woodward, C., Lam, A., Hargreaves, I., Chalasani, A., Valerio, A., Lamantea, E., Venner, K., Holton, J. L., Zeviani, M., Houlden, H., Quinlivan, R., Lamperti, C., Hanna, M. G., Pitceathly, R. D. S.

الوصف: ObjectiveTo describe the clinical and functional consequences of 1 novel and 1 previously reported truncating MT-ATP6 mutation.MethodsThree unrelated probands with mitochondrial encephalomyopathy harboring truncating MT-ATP6 mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity of 1 novel variant, and the effects of all 3 mutations on ATPase 6 and complex V structure and function were investigated.ResultsPatient 1 presented with adult-onset cerebellar ataxia, chronic kidney disease, and diabetes, whereas patient 2 had myoclonic epilepsy and cerebellar ataxia; both harbored the novel m.8782G>A; p.(Gly86) mutation. Patient 3 exhibited cognitive decline, with posterior white matter abnormalities on brain MRI, and severely impaired renal function requiring transplantation. The m.8618dup; p.(Thr33Hisfs32) mutation, previously associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa, was identified. All 3 probands demonstrated a broad range of heteroplasmy across different tissue types. Blue-native gel electrophoresis of cultured fibroblasts and skeletal muscle tissue confirmed multiple bands, suggestive of impaired complex V assembly. Microscale oxygraphy showed reduced basal respiration and adenosine triphosphate synthesis, while reactive oxygen species generation was increased. Transmitochondrial cybrid cell lines studies confirmed the deleterious effects of the novel m.8782 G>A; p.(Gly86) mutation.ConclusionsWe expand the clinical and molecular spectrum of MT-ATP6-related mitochondrial disorders to include leukodystrophy, renal disease, and myoclonic epilepsy with cerebellar ataxia. Truncating MT-ATP6 mutations may exhibit highly variable mutant levels across different tissue types, an important consideration during genetic counseling.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32042910; info:eu-repo/semantics/altIdentifier/wos/WOS:000530284200001; volume:6; issue:1; firstpage:e381; journal:NEUROLOGY. GENETICS; http://hdl.handle.net/11379/532260Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85081922177; https://ng.neurology.org/content/6/1/e381Test

الإتاحة: https://doi.org/10.1212/NXG.0000000000000381Test
http://hdl.handle.net/11379/532260Test
https://ng.neurology.org/content/6/1/e381Test

المؤلفون: 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., Taroni F.

المساهمون: 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., Taroni F.

مصطلحات موضوعية: AFG3L2, OPA1, DOA, optic neuropathy, SCA28

الوصف: 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.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32219868; info:eu-repo/semantics/altIdentifier/wos/WOS:000527023600001; volume:88; firstpage:18; lastpage:32; numberofpages:15; journal:ANNALS OF NEUROLOGY; http://hdl.handle.net/11585/794138Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85083678159

الإتاحة: https://doi.org/10.1002/ana.25723Test
http://hdl.handle.net/11585/794138Test

المؤلفون: Ardissone A., Bruno C., Diodato D., Donati A., Ghezzi D., Lamantea E., Lamperti C., Mancuso M., Martinelli D., Primiano G., Procopio E., Rubegni A., Santorelli F., Schiaffino M. C., Servidei S., Tubili F., Bertini E., Moroni I.

المساهمون: A. Ardissone, C. Bruno, D. Diodato, A. Donati, D. Ghezzi, E. Lamantea, C. Lamperti, M. Mancuso, D. Martinelli, G. Primiano, E. Procopio, A. Rubegni, F. Santorelli, M.C. Schiaffino, S. Servidei, F. Tubili, E. Bertini, I. Moroni

مصطلحات موضوعية: Basal ganglia, Childhood, Leigh syndrome, Mitochondrial disease, Human, Italy, Membrane Protein, Mitochondrial Protein, Mutation, Leigh Disease, Mitochondrial Diseases, Settore MED/03 - Genetica Medica, Settore MED/26 - Neurologia

الوصف: Background: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database. Results: Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date. Conclusion: We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34627336; info:eu-repo/semantics/altIdentifier/wos/WOS:000705208700006; volume:16; issue:1; firstpage:1; lastpage:12; numberofpages:12; journal:ORPHANET JOURNAL OF RARE DISEASES; http://hdl.handle.net/2434/902710Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85116630941

الإتاحة: https://doi.org/10.1186/s13023-021-02029-3Test
http://hdl.handle.net/2434/902710Test