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INTRODUCTION: Parkinson's disease (PD) has a complex genetic background involving both rare and common genetic variants. Although a small percentage of cases show a clear Mendelian inheritance pattern, it is much more relevant to identify patients who present with a complex genetic profile of risk variants with different severity. The ß-glucocerebrosidase coding gene (GBA1) is recognized as the most frequent genetic risk factor for PD and Lewy body dementia, irrespective of reduction of the enzyme activity due to genetic variants. METHODS: In a selected cohort of 190 Hungarian patients with clinical signs of PD and suspected genetic risk, we performed the genetic testing of the GBA1 gene. As other genetic hits can modify clinical features, we also screened for additional rare variants in other neurodegenerative genes and assessed the APOE-ε genotype of the patients. RESULTS: In our cohort, we identified 29 GBA1 rare variant (RV) carriers. Out of the six different detected RVs, the highly debated E365K and T408M variants are composed of the majority of them (22 out of 32). Three patients carried two GBA1 variants, and an additional three patients carried rare variants in other neurodegenerative genes (SMPD1, SPG11, and SNCA). We did not observe differences in age at onset or other clinical features of the patients carrying two GBA1 variants or patients carrying heterozygous APOE-ε4 allele. CONCLUSION: We need further studies to better understand the drivers of clinical differences in these patients, as this could have important therapeutic implications.
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Glucosilceramidasa , Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Enfermedad de Parkinson/genética , Hungría , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios de Cohortes , Predisposición Genética a la Enfermedad/genética , Anciano de 80 o más AñosRESUMEN
BACKGROUND AND PURPOSE: Clinical outcome information on patients with neuromuscular diseases (NMDs) who have been infected with SARS-CoV-2 is limited. The aim of this study was to determine factors associated with the severity of COVID-19 outcomes in people with NMDs. METHODS: Cases of NMD, of any age, and confirmed/presumptive COVID-19, submitted to the International Neuromuscular COVID-19 Registry up to 31 December 2021, were included. A mutually exclusive ordinal COVID-19 severity scale was defined as follows: (1) no hospitalization; (2) hospitalization without oxygenation; (3) hospitalization with ventilation/oxygenation; and (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs) for severe outcome, adjusting for age, sex, race/ethnicity, NMD, comorbidities, baseline functional status (modified Rankin scale [mRS]), use of immunosuppressive/immunomodulatory medication, and pandemic calendar period. RESULTS: Of 315 patients from 13 countries (mean age 50.3 [±17.7] years, 154 [48.9%] female), 175 (55.5%) were not hospitalized, 27 (8.6%) were hospitalized without supplemental oxygen, 91 (28.9%) were hospitalized with ventilation/supplemental oxygen, and 22 (7%) died. Higher odds of severe COVID-19 outcomes were observed for: age ≥50 years (50-64 years: OR 2.4, 95% confidence interval [CI] 1.33-4.31; >64 years: OR 4.16, 95% CI 2.12-8.15; both vs. <50 years); non-White race/ethnicity (OR 1.81, 95% CI 1.07-3.06; vs. White); mRS moderately severe/severe disability (OR 3.02, 95% CI 1.6-5.69; vs. no/slight/moderate disability); history of respiratory dysfunction (OR 3.16, 95% CI 1.79-5.58); obesity (OR 2.24, 95% CI 1.18-4.25); ≥3 comorbidities (OR 3.2, 95% CI 1.76-5.83; vs. ≤2; if comorbidity count used instead of specific comorbidities); glucocorticoid treatment (OR 2.33, 95% CI 1.14-4.78); and Guillain-Barré syndrome (OR 3.1, 95% CI 1.35-7.13; vs. mitochondrial disease). CONCLUSIONS: Among people with NMDs, there is a differential risk of COVID-19 outcomes according to demographic and clinical characteristics. These findings could be used to develop tailored management strategies and evidence-based recommendations for NMD patients.
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COVID-19 , Enfermedades Neuromusculares , Humanos , Femenino , Persona de Mediana Edad , Masculino , SARS-CoV-2 , Enfermedades Neuromusculares/epidemiología , Sistema de Registros , OxígenoRESUMEN
Mitochondrial disorders represent a major challenge in medicine. Most of the mitochondrial proteins are encoded by the nuclear DNA (nDNA), whereas a very small fraction is encoded by the mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction. The disease usually affects multiple organs in varying locations and severity; however, there are some forms which affect a single organ. The diagnosis of mitochondrial disorders is based on clinical examination, biochemical and histopathologic examinations, functional studies, and molecular genetic testing. Neuropathologic alterations of the muscle are variable and can range from striking abnormalities, such as cytochrome oxidase-negative and ragged red fibers, to nonspecific or minimal changes. Neuropathologic alterations in the brain show common features in disorders with different genetic background. These are characterized by various degrees of vacuolation in the white and gray matter, regional neurodegeneration with reactive astrogliosis, loss of oligodendrocytes, presence of macrophages and microgliosis, capillary proliferation, and mineralization of vessel walls. The advent of molecular genetics, the discovery of biomarkers and new sequencing platforms to perform targeted exome and whole-genome sequencing have changed traditional approaches to diagnose mitochondrial diseases.
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ADN Mitocondrial/genética , Mitocondrias , Enfermedades Mitocondriales , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Mutación/genéticaRESUMEN
Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 ß-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.
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Succinato-CoA Ligasas/metabolismo , Alelos , Animales , Western Blotting , Carnitina/análogos & derivados , Carnitina/metabolismo , Células Cultivadas , ADN Mitocondrial/genética , Heterocigoto , Humanos , Técnicas In Vitro , Potencial de la Membrana Mitocondrial/genética , Potencial de la Membrana Mitocondrial/fisiología , Ratones , Ratones Noqueados , Ratones Mutantes , Mitocondrias/genética , Fosforilación/genética , Fosforilación/fisiología , ARN Mensajero/genética , Succinato-CoA Ligasas/genéticaRESUMEN
BACKGROUND: In case of orphan drugs applicability of the standard health technology assessment (HTA) process is limited due to scarcity of good clinical and health economic evidence. Financing these premium priced drugs is more controversial in the Central and Eastern European (CEE) region where the public funding resources are more restricted, and health economic justification should be an even more important aspect of policy decisions than in higher income European countries. OBJECTIVES: To explore and summarize the recent scientific evidence on value drivers related to the health technology assessment of ODs with a special focus on the perspective of third party payers in CEE countries. The review aims to list all potentially relevant value drivers in the reimbursement process of orphan drugs. METHODS: A systematic literature review was performed; PubMed and Scopus databases were systematically searched for relevant publications until April 2015. Extracted data were summarized along key HTA elements. RESULTS: From the 2664 identified publications, 87 contained relevant information on the evaluation criteria of orphan drugs, but only 5 had direct information from the CEE region. The presentation of good clinical evidence seems to play a key role especially since this should be the basis of cost-effectiveness analyses, which have more importance in resource-constrained economies. Due to external price referencing of pharmaceuticals, the relative budget impact of orphan drugs is expected to be higher in CEE than in Western European (WE) countries unless accessibility of patients remains more limited in poorer European regions. Equity principles based on disease prevalence and non-availability of alternative treatment options may increase the price premium, however, societies must have some control on prices and a rationale based on multiple criteria in reimbursement decisions. CONCLUSIONS: The evaluation of orphan medicines should include multiple criteria to appropriately measure the clinical added value of orphan drugs. The search found only a small number of studies coming from CEE, therefore European policies on orphan drugs may be based largely on experiences in WE countries. More research should be done in the future in CEE because financing high-priced orphan drugs involves a greater burden for these countries.
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Producción de Medicamentos sin Interés Comercial/economía , Enfermedades Raras/tratamiento farmacológico , Evaluación de la Tecnología Biomédica/métodos , Análisis Costo-Beneficio , Costos de los Medicamentos , Europa (Continente) , HumanosRESUMEN
The probability of mitochondrial permeability transition (mPT) pore opening is inversely related to the magnitude of the proton electrochemical gradient. The module conferring sensitivity of the pore to this gradient has not been identified. We investigated mPT's voltage-sensing properties elicited by calcimycin or H2O2 in human fibroblasts exhibiting partial or complete lack of ANT1 and in C2C12 myotubes with knocked-down ANT1 expression. mPT onset was assessed by measuring in situ mitochondrial volume using the 'thinness ratio' and the 'cobalt-calcein' technique. De-energization hastened calcimycin-induced swelling in control and partially-expressing ANT1 fibroblasts, but not in cells lacking ANT1, despite greater losses of mitochondrial membrane potential. Matrix Ca(2+) levels measured by X-rhod-1 or mitochondrially-targeted ratiometric biosensor 4mtD3cpv, or ADP-ATP exchange rates did not differ among cell types. ANT1-null fibroblasts were also resistant to H2O2-induced mitochondrial swelling. Permeabilized C2C12 myotubes with knocked-down ANT1 exhibited higher calcium uptake capacity and voltage-thresholds of mPT opening inferred from cytochrome c release, but intact cells showed no differences in calcimycin-induced onset of mPT, irrespective of energization and ANT1 expression, albeit the number of cells undergoing mPT increased less significantly upon chemically-induced hypoxia than control cells. We conclude that ANT1 confers sensitivity of the pore to the electrochemical gradient.
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Translocador 1 del Nucleótido Adenina/deficiencia , Fibroblastos/metabolismo , Potencial de la Membrana Mitocondrial , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Membranas Mitocondriales/metabolismo , Calcimicina/farmacología , Células Cultivadas , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Peróxido de Hidrógeno/farmacología , Masculino , Proteínas de Transporte de Membrana Mitocondrial/genética , Poro de Transición de la Permeabilidad MitocondrialRESUMEN
Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (ß-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aß mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aß spectrum from Aß40 to Aß39 and Aß37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.
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Precursor de Proteína beta-Amiloide/genética , Variación Genética/genética , Enfermedad de Parkinson/genética , Anciano , Enfermedad de Alzheimer/genética , Línea Celular , Proteínas de Unión al ADN/genética , Demencia/genética , Femenino , Frecuencia de los Genes/genética , Genotipo , Células HEK293 , Humanos , Masculino , Enfermedades Neurodegenerativas/genéticaRESUMEN
We have recently shown that the ATP-forming SUCLA2 subunit of succinyl-CoA ligase, an enzyme of the citric acid cycle, is exclusively expressed in neurons of the human cerebral cortex; GFAP- and S100-positive astroglial cells did not exhibit immunohistoreactivity or in situ hybridization reactivity for either SUCLA2 or the GTP-forming SUCLG2. However, Western blotting of post mortem samples revealed a minor SUCLG2 immunoreactivity. In the present work we sought to identify the cell type(s) harboring SUCLG2 in paraformaldehyde-fixed, free-floating surgical human cortical tissue samples. Specificity of SUCLG2 antiserum was supported by co-localization with mitotracker orange staining of paraformaldehyde-fixed human fibroblast cultures, delineating the mitochondrial network. In human cortical tissue samples, microglia and oligodendroglia were identified by antibodies directed against Iba1 and myelin basic protein, respectively. Double immunofluorescence for SUCLG2 and Iba1 or myelin basic protein exhibited no co-staining; instead, SUCLG2 appeared to outline the cerebral microvasculature. In accordance to our previous work there was no co-localization of SUCLA2 immunoreactivity with either Iba1 or myelin basic protein. We conclude that SUCLG2 exist only in cells forming the vasculature or its contents in the human brain. The absence of SUCLA2 and SUCLG2 in human glia is in compliance with the presence of alternative pathways occurring in these cells, namely the GABA shunt and ketone body metabolism which do not require succinyl CoA ligase activity, and glutamate dehydrogenase 1, an enzyme exhibiting exquisite sensitivity to inhibition by GTP.
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Corteza Cerebral/enzimología , Neuroglía/enzimología , Succinato-CoA Ligasas/metabolismo , Anciano , Proteínas de Unión al Calcio , Proteínas de Unión al ADN/metabolismo , Femenino , Fibroblastos/enzimología , Humanos , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Proteína Básica de Mielina/metabolismo , Fosforilación/fisiologíaRESUMEN
SUCLA2 encodes the ATP-forming ß subunit (A-SUCL-ß) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-ß in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-ß immunoreactivity co-localized >99 % with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL-ß antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL-ß immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming ß subunit (G-SUCL-ß) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-ß immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.
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Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Neuronas/metabolismo , Succinato-CoA Ligasas/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Succinato-CoA Ligasas/genéticaRESUMEN
Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
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Variación Genética , Enfermedad de Parkinson/genética , Penetrancia , Receptores de Superficie Celular/genética , Estudios de Casos y Controles , Familia , Femenino , Ligamiento Genético , Humanos , MasculinoRESUMEN
Recently, mutations in eukaryotic translation initiation factor 4G1 (EIF4G1) were reported as a rare cause of familial Parkinson's disease (PD). We screened the 33 exons of EIF4G1 by high-resolution melting curve analysis for variants in our Central European cohort of 376 PD cases. Variant frequency was assessed in a total of 975 PD cases and 1,014 general population controls. Eight novel nonsynonymous and four synonymous variants were identified. In our cohort, novel and previously identified nonsynonymous variants were very rare. Although it is possible that our general population controls also comprise individuals who have or could develop PD in the future, the presence of the original mutation (EIF4G1 p.Arg1205 His) in three controls only, raises questions about the causality of this variant with regard to PD.
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Factor 4G Eucariótico de Iniciación/genética , Enfermedad de Parkinson/genética , Anciano , Estudios de Cohortes , Exones , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Datos de Secuencia MolecularRESUMEN
Neurodegeneration with brain iron accumulation (NBIA) is a rare, progressive neurodegenerative disorder with extrapyramidal and cognitive clinical symptoms characterized by iron accumulation predominantly in the globus pallidus, cs well as extensive axonal spheroids in various regions of the brain. Recent studies indicate multiple genetic causes, however the illness can occur without obvious genetic background. The most frequent genetic form is the pantothene kinase associated neurodegeneration (PKAN) with mutation in the pantothenate kinase 2 (PANK2) gene. Further forms include phosphoslipase A2 (PLA2G6) gene mutation, neuroferritinopathy, and aceruloplasminaemia. To demonstrate the phenotypic variability associated with NBIA we present two patients. In the first patient iron deposition in the globus pallidus and axonal spheroids throughout the whole brain confirmed the neuropathological diagnosis of NBIA. Based on the long duration (27 years), the relatively late onset (at age of 13) of the disease, and the symmetrical hypointensity in the globus pallidus, without the eye-of-the-tiger sign in cranial MRI, this case most likely represented an idiopathic form of NBIA but atypical PKAN may be also considered. In our second patient, who is still alive after duration of 9 years, MRI revealed the typical eye-of-the-tiger phenomenon that supported the clinical diagnosis of NBIA and wcs highly suggestive of PKAN. Since NBIA shows similarities with other neurodegenerative disorders, genetic examination may be essential in the diagnosis of this disease, however, cranial MRI together with the clinical picture may be highly indicative of NBIA.
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Encéfalo/metabolismo , Encéfalo/patología , Hierro/metabolismo , Degeneración Nerviosa/diagnóstico , Enfermedades Neurodegenerativas/diagnóstico , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Adulto , Edad de Inicio , Niño , Preescolar , Femenino , Globo Pálido/metabolismo , Globo Pálido/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Degeneración Nerviosa/enzimología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Enfermedades Neurodegenerativas/enzimología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
Accumulation of cathepsin D immunoreactive lysosomes correlates with tissue pathology in sporadic Creutzfeldt-Jakob disease (CJD) brains. The C-to-T transition within exon 2 of the cathepsin D (CTSD) gene is associated with altered enzymatic activity. Possession of the TT genotype is a risk factor for variant CJD. To verify the association between the CTSD position 224T allele and the risk for and survival in sporadic and genetic CJD, we genotyped 540 sporadic, 101 genetic CJD, and 723 control individuals. Genotype data and duration of illness were compared using multiple logistic regression and Kruskal-Wallis test. Multivariate survival analysis was performed using Cox's regression model. The distribution of CTSD position 224 alleles was approximately the same in all groups. We observed a trend for shorter survival in sporadic CJD patients harboring the T allele at position 224 of the CTSD gene in particular in sporadic CJD patients with the prion protein gene position 129 MM genotype. We conclude that the CTSD position 224 polymorphism alone is not a significant risk or disease-modifying factor in sporadic or genetic CJD.
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Catepsina D/genética , Síndrome de Creutzfeldt-Jakob/genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Síndrome de Creutzfeldt-Jakob/mortalidad , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Autosomal-dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder that is characterized by accumulation of multiple mitochondrial DNA (mtDNA) deletions in postmitotic tissues. The disorder is heterogeneous, with five known nuclear disease genes that encode the proteins ANT1, Twinkle, POLG, POLG2, and OPA1. Defects in these proteins affect mtDNA maintenance, probably leading to stalled replication forks, consequent mtDNA deletion formation, and progressive respiratory chain deficiency. Here we present a large adPEO family with multiple mtDNA deletions, whose disease was not explained by mutations in any of the known adPEO loci. We mapped the disease locus in this family to chromosome 8q22.1-q23.3. The critical linkage region contained the RRM2B gene, which encodes the small subunit of the ribonucleotide reductase p53R2, which has previously been shown to be essential for the maintenance of mtDNA copy number. Mutation screening of RRM2B revealed a heterozygous nonsense mutation in exon 9 (c.979C-->T [p.R327X]) in all affected individuals that was absent in 380 control chromosomes. The same mutation was found to segregate in another adPEO family. The mutant mRNA escaped nonsense-mediated decay and resulted in a protein with truncation of 25 highly conserved C-terminal amino acids essential for the interaction with the ribonucleotide reductase subunit R1. We conclude that dominant-negative or gain-of-function mutations in RRM2B are a cause of multiple mtDNA deletions and adPEO.
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Proteínas de Ciclo Celular/genética , ADN Mitocondrial/genética , Eliminación de Gen , Mutación , Oftalmoplejía Externa Progresiva Crónica/genética , Ribonucleótido Reductasas/genética , Biopsia , Análisis Mutacional de ADN , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Dosificación de Gen , Ligamiento Genético , Genotipo , Heterocigoto , Humanos , Inmunohistoquímica , Escala de Lod , Masculino , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Músculo Esquelético/cirugía , Oftalmoplejía Externa Progresiva Crónica/fisiopatología , Linaje , Mutación Puntual , Análisis de Secuencia de ADN , Succinato Deshidrogenasa/metabolismoRESUMEN
TDP-43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP-43-immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.
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Corea/genética , Proteínas de Unión al ADN/genética , Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Parálisis Supranuclear Progresiva/genética , Corea/diagnóstico , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Salud de la Familia , Femenino , Demencia Frontotemporal/diagnóstico , Ácido Glutámico/genética , Humanos , Lisina/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Parálisis Supranuclear Progresiva/diagnóstico , Tomógrafos Computarizados por Rayos XRESUMEN
Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial frontotemporal dementia with tau pathology. Many of these mutations result in morphological phenotypes resembling sporadic tauopathies, although, to date, no such cases mimicking argyrophilic grain disease (AgD) have been documented. We now present a case with a novel S305I MAPT mutation and a morphological phenotype showing resemblance to AgD. At the age of 39, the patient developed behavioural and personality changes and lack of verbal fluency with later poor performance on naming tasks and rigidity in the extremities. After a short disease course of 1.5 years, the patient died. A unique neuropathological phenotype with neuronal diffuse cytoplasmic tau immunoreactivity, oligodendroglial-coiled bodies, argyrophilic grains, and non-argyrophilic, but tau-immunopositive and ubiquitin-immunonegative pre-grains were observed, whereas classical neurofibrillary tangles, Pick bodies, and neuritic plaques were absent. The tau-positive abnormal structures were composed only of 4R-tau isoforms and, ultrastructurally, straight filaments. Neuronal loss was greatest in the medial temporal cortex, hippocampus, and amygdala. These pathological features resemble AgD. The novel S305I substitution has a strong effect on MAPT exon 10 splicing, thereby causing a striking increase in 4R-tau isoforms. Our observation not only widens the phenotypic spectrum of FTLD with MAPT mutation but also underpins the notion that the predominance of similar neuropathological findings in sporadic AgD cases may be viewed as features of a distinct disease entity.
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Encéfalo/patología , Demencia/genética , Demencia/patología , Proteínas tau/genética , Adulto , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Microscopía Confocal , Microscopía Electrónica de Transmisión , Mutación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas tau/análisis , Proteínas tau/metabolismoRESUMEN
The recent development of genetic databases and biobanks in a number of countries reflects scientist's beliefs in the future health benefits to be derived from genetic research. The NEPSYBANK is a national program of the Hungarian Clinical Neurogenetic Society with comprehensive participation of the Neurology and Psychiatry Departments of Medical Universities and the National Institute of Psychiatry and Neurology. The NEPSYBANK forms a part of the national biobank project (www.biobank.hu). The goal is to establish nationwide collaboration and common biobanking standards on quality, access, and protection of integrity in the field of neurology and psychiatry. Biological materials and databases are already collected in stroke, epilepsy, multiple sclerosis, motoneuron diseases, dementia, movement disorders, schizophrenia, and alcohol addiction. In peripheral neuropathies, neuropathic pain syndromes, muscle diseases, migraine, myasthenia gravis, depression, panic disease, anxiety, autism, and software development is in progress. The resources have been expanded by continued prospective collection of samples and data and important bottlenecks in sample purification, sample retrieval, in protection of the integrity of the research participants, as well as in guaranteeing the security and confidentiality of the participant's information have been harmonized. The development of uniform consent management, comprehensive sample overview and quality standards for health care-related biobanking may provide a unique opportunity for Hungary in molecular clinically oriented research. The program is a diseased-based research biobank with comprehensive collection of phenotypic and environmental information as well as biobanking of DNA, RNA or buffy coat, plasma, and erythrocytes stored at -80 degrees C. The biobank has a neuropathological part as well: storing conventional pathology and biopsy specimens. The analytical and informational demands being created by biobanking requires a "connectivity of community" that has not traditionally been present in the life sciences. As you put more resources into something, your silos tend to become taller, and we need to avoid this. The life science and healthcare community should be ignored working in individual "silos."
Asunto(s)
Enfermedades del Sistema Nervioso , Bancos de Tejidos , Bases de Datos Factuales , Femenino , Genoma Humano , Humanos , Hungría , Masculino , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Bancos de Tejidos/ética , Bancos de Tejidos/organización & administraciónRESUMEN
The basis of human prion diseases affecting the nervous system is accumulation of a disease-associated conformer (PrPSc) of the normal cellular prion protein (PrPC). Earlier studies demonstrated increased expression of PrPC in inclusion body myositis (IBM), dermato-, and polymyositis, as well as neurogenic muscle atrophy. To define the spectrum and reliability of PrPC immunoreactivity, its expression was examined systematically in a series of pathologically characterized muscular disorders by means of immunohistochemistry, confocal laser microscopy, and immunogold electron microscopy. Anti-PrPC immunolabelling of rimmed vacuoles was observed in IBM, inclusions of myofibrillary myopathy, targets, regenerating, and atrophic fibres, mononuclear cells, in addition to ragged red fibres in mitochondrial myopathies, and focal sarcolemmal immunostaining in non-diseased controls. Quantitative analysis demonstrated that, in neurogenic muscle lesions, anti-PrPC staining detects a significantly broader spectrum of fibres than anti-vimentin or anti-NCAM. In dystrophic muscle, PrPC expression was mainly restricted to regenerating fibres. In IBM, PrPC expression was not confined to rimmed vacuoles or vacuolated fibres and only a small percentage (7.1%) of rimmed vacuoles were PrPC positive. Ultrastructurally, PrPC was observed in the cytoplasm of lymphocytes, in the myofibrillar network of targets, and in rimmed vacuoles. Knowledge of disease circumstances with altered expression of PrPC is important in the setting of a potentially increased chance for extraneural PrPC-PrPSc conversion. In addition, our observations suggest that PrPC may have a general stress-response effect in various neuromuscular disorders.
Asunto(s)
Enfermedades Neuromusculares/metabolismo , Priones/análisis , Enfermedad Crónica , Dermatomiositis/inmunología , Dermatomiositis/metabolismo , Dermatomiositis/patología , Humanos , Inmunohistoquímica/métodos , Microscopía Confocal/métodos , Microscopía Electrónica/métodos , Fibras Musculares Esqueléticas/inmunología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Distrofias Musculares/inmunología , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Miositis por Cuerpos de Inclusión/inmunología , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Enfermedades Neuromusculares/inmunología , Enfermedades Neuromusculares/patología , Polimiositis/inmunología , Polimiositis/metabolismo , Polimiositis/patología , Vacuolas/patología , Vimentina/análisisRESUMEN
Intramuscular injection of plasmid is a potential alternative to viral vectors for the transfer of therapeutic genes into skeletal muscle fibers. The low efficiency of plasmid-based gene transfer can be enhanced by electroporation (EP) coupled with the intramuscular application of hyaluronidase. We have investigated several factors that can influence the efficiency of plasmid-based gene transfer. These factors include electrical parameters of EP, optimal use of hyaluronidase, age and strain of the host, and plasmid size. Muscles of very young and mature normal, mdx, and immunodeficient mice were injected with plasmids expressing beta-galactosidase, microdystrophin, full-length dystrophin, or full-length utrophin. Transfection efficiency, muscle fiber damage, and duration of transgene expression were analyzed. The best transfection level with the least collateral damage was attained at 175-200 V/cm. Pretreatment with hyaluronidase markedly increased transfection, which was also influenced by the plasmid size and the strain and the age of the mice. Even in immunodeficient mice, there was a significant late decline in transgene expression and plasmid DNA copies, although both still remained relatively high after 1 year. Thus, properly optimized EP-assisted plasmid-based gene transfer is a feasible, efficient, and safe method of gene replacement therapy for dystrophin deficiency of muscle but readministration may be necessary.