RESUMEN
Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.
Asunto(s)
Algoritmos , Ataxia Cerebelosa/genética , Heterogeneidad Genética , Técnicas de Diagnóstico Molecular/métodos , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Argentina/epidemiología , Ataxia Cerebelosa/clasificación , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/epidemiología , Niño , Preescolar , Enfermedad Crónica , Progresión de la Enfermedad , Genes Dominantes , Genes Recesivos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Nistagmo Patológico/genética , Estudios Prospectivos , Adulto JovenRESUMEN
The role of genetics and its technological development have been fundamental in advancing the field of movement disorders, opening the door to precision medicine. Starting from the revolutionary discovery of the locus of the Huntington's disease gene, we review the milestones of genetic discoveries in movement disorders and their impact on clinical practice and research efforts. Before the 1980s, early techniques did not allow the identification of genetic alteration in complex diseases. Further advances increasingly defined a large number of pathogenic genetic alterations. Moreover, these techniques allowed epigenomic, transcriptomic and microbiome analyses. In the 2020s, these new technologies are poised to displace phenotype-based classifications towards a nosology based on genetic/biological data. Advances in genetic technologies are engineering a reversal of the phenotype-to-genotype order of nosology development, replacing convergent clinicopathological disease models with the genotypic divergence required for future precision medicine applications.
Asunto(s)
Trastornos del Movimiento , Genotipo , Humanos , Enfermedad de Huntington , Trastornos del Movimiento/genética , Fenotipo , TecnologíaAsunto(s)
Distonía/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Trastornos Mentales/genética , Mutación , Receptores de Ácido Kaínico/genética , Adulto , Consanguinidad , Distonía/diagnóstico , Epilepsia/diagnóstico , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Trastornos Mentales/diagnóstico , Linaje , Fenotipo , Receptor de Ácido Kaínico GluK2RESUMEN
OBJECTIVE: To describe clinical features of epilepsy secondary to Malformation of Cortical Development (MCD) in a series of adult patients. MATERIALS AND METHODS: We searched our database for all cases with confirmed epilepsy and MCD and included in the study only those with complete data. Mean age, sex, age at seizure onset (ASO), seizure types, abnormal neurological exam (ANE), mental retardation, family history, gestational or perinatal insults (G-PI), interictal EEG and response to treatment were analyzed. Cases were classified into the 3 main groups (G) according to the Barkovich classification (BC) and then compared: (G1) "malformations due to abnormal cell proliferation", (G2) "malformations due to abnormal migration" and (G3) "malformations due to abnormal cortical organization". RESULTS: We identified 152 (5.06%) patients with MCD from a total of 3000 with epilepsy. In total, 138 patients with complete medical data were included in this study. The mean age of patients was 36.2 years, 52.2% were female, the mean ASO was 12.3 years, 5.1% of cases had a positive family history and 21% had G-PI. An ANE was observed in 21% and mental retardation in 31.9%. Most of the patients (84.8%) had refractory epilepsy. The distribution of cases according to the BC was: 51.4% in G1, 28.9% in G2 and 19.6% in G3. Comparing the 3 groups, we found that an ANE was statistically more frequent in G3 and was present in 70.4% of cases. CONCLUSION: Our series of adult patients with epilepsy and MCD suggests that MCD are identified as commonly in a developing country as in previous "first world" series. Neurological deficits were more common in the subgroup of patients with polymicrogyria and schizencephaly (BC Group 3).
Asunto(s)
Encéfalo/patología , Epilepsia/complicaciones , Epilepsia/patología , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/epidemiología , Adolescente , Adulto , Edad de Inicio , Anciano , Encéfalo/anomalías , Electroencefalografía , Epilepsia/clasificación , Epilepsia/cirugía , Femenino , Humanos , Discapacidad Intelectual , Imagen por Resonancia Magnética , Masculino , Malformaciones del Desarrollo Cortical/clasificación , Malformaciones del Desarrollo Cortical/diagnóstico , Persona de Mediana Edad , Adulto JovenRESUMEN
In order to determine whether Blastoferon®, a biosimilar interferon (IFN)- beta 1a formulation, shares epitopes with other known IFN-beta products, a series of neutralization bioassays were performed with a set of well-characterized anti-IFN- beta monoclonal antibodies and human sera (World Health Organization Reference Reagents). The bioassay was the interferon-induced inhibition of virus cytopathic effect on human cells in culture (EMC virus and A-549 cells). Computer-calculated results were reported as Tenfold Reduction Units (TRU)/ml. To further assess Blastoferon® immunogenicity, in vivo production of anti-IFN beta antibodies was determined in sera of patients included in the pharmacovigilance plan of Blastoferon® by the level of IFN- beta 1a binding antibodies (by enzyme immunoassay -EIA) and neutralizing antibodies (in the Wish-VSV system). The highly characterized neutralizing monoclonal antibodies A1 and A5 that bind to specific regions of the IFN- beta molecule reacted positively with the three beta 1a IFNs: Blastoferon®, Rebif®, and the IFN- beta WHO Second International Standard 00/572. As expected, the non-neutralizing monoclonal antibodies B4 and B7 did not neutralize any of the IFN- beta preparations. The commercially available monoclonal antibody B-02 reacted essentially equally with Rebif® and Blastoferon®. The WHO Reference Reagent human serum anti-IFN- beta polyclonal antibody neutralized all the IFN- beta products, whereas the WHO Reference Reagent human serum anti-IFN-alpha polyclonal antibody G037-501-572 appropriately failed to react with any of the IFN- beta products. On the basis of in vitro reactivity with known, well-characterized monoclonal and polyclonal antibody preparations, Blastoferon® shares immunological determinants with other human interferon- beta products, especially IFN- beta 1a. In vivo antibodies were detected by EIA in 72.9% of 37 chronically treated multiple sclerosis patients, whereas neutralizing antibodies were found in 8.1% of them. Blastoferon® appears to have immunological characteristics comparable to other IFN- beta 1a products.
Asunto(s)
Adyuvantes Inmunológicos , Epítopos , Interferón beta/inmunología , Anticuerpos Monoclonales , Anticuerpos Neutralizantes/sangre , Línea Celular Tumoral , Efecto Citopatogénico Viral/efectos de los fármacos , Virus de la Encefalomiocarditis/efectos de los fármacos , Virus de la Encefalomiocarditis/patogenicidad , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Humanos , Interferón beta-1a , Interferon beta-1b , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Pruebas de NeutralizaciónRESUMEN
OBJECTIVES: To characterize the IFNbeta1a-regulated gene expression on leukocytes of Multiple Sclerosis (MS) patients using microarrays with whole human genome representation. METHODS: Genes differentially expressed by interferon-beta were identified by a microarray in vitro study performed in leukocytes obtained from 5 MS relapsing-remitting patients. RESULTS: Following the culture of peripheral blood mononuclear cells from MS relapsing-remitting patients for 24 hs with IFNbeta1a, the expression of 868 genes was modified: 545 increased (including CXCL11, CCL8, INDO, IFI27, CFB, CXCL10 and IFIT1) and 323 diminished (including RBP7, SEPT5, RNF8, ADORA2B and FOS). CONCLUSIONS: Since many of them were previously recognized as involved in MS pathogenesis, the IFNbeta1a mechanism of action could imply a compensatory regulation of systems deregulated in MS.
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Adyuvantes Inmunológicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Interferón beta/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adolescente , Adulto , Femenino , Perfilación de la Expresión Génica/métodos , Genoma Humano , Humanos , Técnicas In Vitro , Interferón beta-1a , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
AIM: We describe the clinical features, treatment and prognosis in a series of patients with epilepsy secondary to hypothalamic hamarthomas (HH) in a developing country. MATERIALS AND METHODS: Eight patients with epilepsy and HH were included between 1997 and 2006. We analyzed gender, age, age at seizure onset (ASO), seizure types (ST), mental retardation (MR), precocious puberty (PP), electroencephalogram (EEG)-magnetic resonance imaging (MRI) features and response to treatment. RESULTS: Mean age 25.1 years, 2/6 female/male, none had PP, ASO 4.5 years. Complex partial seizure were the most frequent (100%), mean similar to those seen in temporal (62.5%) or frontal lobe epilepsy (37.5%). Exactly 87.5% developed gelastic seizures (GS). Half of the patients showed MR. Mild-to-severe MR was associated with the presence of multiple ST including atonic and complex partial seizures with frontal semiology. Interictal EEG was abnormal in 87.5% patients. Video EEG was performed in three cases with unspecific findings. HH were small and sessile in seven patients whereas large and pedunculated in one. All patients were refractory to medical treatment. In five, an additional procedure was performed without any significant improvement. CONCLUSION: These series show the heterogeneous spectrum of this entity and the difficulties in its treatment in a developing country.
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Hamartoma/diagnóstico , Hamartoma/terapia , Enfermedades Hipotalámicas/diagnóstico , Enfermedades Hipotalámicas/terapia , Adolescente , Adulto , Argentina , Trastornos del Conocimiento/epidemiología , Comorbilidad , Países en Desarrollo , Electroencefalografía , Epilepsia Parcial Compleja/epidemiología , Epilepsia Parcial Compleja/fisiopatología , Femenino , Hamartoma/complicaciones , Humanos , Enfermedades Hipotalámicas/complicaciones , Hipotálamo/patología , Hipotálamo/fisiopatología , Hipotálamo/cirugía , Imagen por Resonancia Magnética , Masculino , Neurología/métodos , Neurocirugia/métodos , Procedimientos Neuroquirúrgicos , Prevalencia , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Recombinant human interferon-beta (IFN-b) is a well-established treatment for multiple sclerosis (MS). The regulatory process for marketing authorization of biosimilars is currently under debate in certain countries. In the EU, EMEA has clearly defined the process including overarching and product-specific guidelines, which includes clinical testing. Biosimilarity needs to be based on comparability criteria, including at least molecular characterization, biological activity relevant for the therapeutic effect and relative bioavailability ("bioequivalence"). In the case of such complex diseases as MS, where the effect of treatment is not so directly measurable, in vitro tools can provide additional data to support comparability. Genomic microarrays assays might be useful to compare multisource biopharmaceuticals. The aim of the present study was to compare the pharmacodynamic genomic effects (in terms of transcriptional regulation) of two recombinant human IFN-I(2)1a preparations on lymphocytes of multiple sclerosis patients using a whole genome microarray assay. METHODS: We performed an ex vivo whole genome expression profiling of the effect of two preparations of IFN-I(2)1a on non-adherent mononuclears from five relapsing-remitting MS patients analyzing microarrays (CodeLink Human Whole Genome). Patients blood was drawn, PBMCs isolated and cultured in three different conditions: culture medium (control), 1,000 U/ml of IFN-I(2)1a (BLA- (STOFERON, Bio Sidus) and 1,000 U/ml of IFN-I(2)1a (REBIF, Serono) RNA was purified from non-adherent cells (mostly lymphocytes), amplified and hybridized. Raw data were generated by CodeLink proprietary software. Data normalization, quality control and analysis of differential gene expression between treatments were done using linear model for microarray data. Functional annotation analysis of IFN-I(2)1a MS treatment transcription was done using DAVID. RESULTS: Out of the approximately 45,000 human sequences examined, no evidence of differential regulation was found when both treatments were compared (minimum adjusted p-value > 0.999). The IFN-I(2)1a effect differentially regulated the expression of 868 genes. The expression of standard markers such as GTP cyclohidrolase, MxA, and OAS isoenzymes A and B changed as a consequence of the action of IFN-I(2)1a. CONCLUSIONS: This exhaustive and highly sensitive assay did not show differences in the genomic expression profile of these two products under the assayed experimental conditions. These results suggest that this technology might be useful for the initial comparison of biosimilars, being part of a comprehensive comparability program that includes clinical testing.
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Perfilación de la Expresión Génica , Interferón beta/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Transcripción Genética/efectos de los fármacos , Análisis por Conglomerados , Biología Computacional/métodos , Composición de Medicamentos/métodos , Femenino , Genoma Humano , Humanos , Interferón beta-1a , Interferón beta/genética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The linking of amino haptens to carboxymethyldextran (CMD) requires carboxyl activation, for example, via carbodiimdes. We have discovered that substantial N-acylurea, derived from these carbodiimides, can be trapped on the CMD backbone. As an alternative, CMD can be conveniently lactonized by heating in inert solvents, and this carboxymethyldextran lactone (CLD) can be employed directly for amine conjugation.