Seguridad y eficacia de ataluren en pacientes con diagnóstico de distrofia muscular de duchenne portadores de una mutación sin sentido en el gen de distrofina / Safety and efficacy of ataluren in patients diagnosed with duchenne muscular dystrophy who carry a nonsense mutation in the dystrophin gene

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación ha recibido la solicitud de evaluar el uso de Ataluren para su uso en Pacientes ambulantes mayores de 5 años con diagnóstico de distrofia muscular de Duchenne debida a una mutación sin sentido en el gen de la distrofina dentro del sistema de EsSalud, indicación actualmente no contemplada en el petitorio de medicamentos. Esta acción sigue lo estipulado en la Directiva N° 002-IETSI-ESSALUD-2015 y el objetivo final es determinar el estado del arte sobre la eficacia y seguridad de ataluren. Tecnología Sanitaria de Interés: Ataluren: La PTC124 (3-(5-(2-fluorofeni)-1, 2,4-oxadiazol-3-y1)-ácido benzoico), también conocida como Ataluren (TranslarnaTM) es una molécula pequeña de oxadiazol cuyo mecanismo de acción consiste en cominuar la traducción de ARNm sobre los codones de terminación prematuros causados por la mutación sin sentido, permitiendo la síntesis de distrofina completa y funcional. METODOLOGIA: Estrategia de Busqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de Ataluren para el tratamiento de la DMD en las bases de datos de MEDLINE, EMBASE, CENTRAL, DARE y TRIPDATABASE. Se hizo una búsqueda adicional en www.clinicaltrials.gov, para poder identificar ensayos clínicos aún en elaboración o que no hayan sido publicados. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales oncológicas y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS:Sinopses de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica que sustente el uso de ataluren en DMD según la pregunta PICO establecida. Para el presente documento se seleccionó el siguiente cuerpo de evidencia que es resumido a continuación: Guías Clínicas: Se identificó una única guía práctica realizada en Colombia que hizo mención a este tratamiento. Evaluaciones de tecnología sanitaria: Se identificó una ETS del Reino Unido. Revisiones sistemáticas: No se identificaron revisiones sistemáticas. Estudios de calidad de vida: No se identificaron estudios que evaluaran calidad de vida. Ensayos clínicos: Se identificaron dos ECAs correspondientes a las fases 2a y fase 2 b. Ensayos clínicos en curso: se identificó el registro correspondiente a un estudio de fase III pendiente de publicar sus resultados. CONCLUSIONES: se evidencia que ataluren es un medicamento aún en estudio que no ha demostrado al momento ser diferente a placebo en el tratamiento de la DMD con mutación sin sentido. De hecho, la evidencia disponible que el ataluren no es mejor que el placebo en mejorar indicadores clínicos importantes en el manejo de esta enfermedad, como la DC6M, considerada como desenlace principal en enfermedades raras con compromiso neuromuscular. Ataluren tampoco mostró ser diferente al placebo en mejorar la calidad de vida de los pacientes, ni disminuye los tiempos para realizar tareas motoras como subir o bajar escalones, correr o caminar 10 metros y levantarse desde la posición supina. El Instituto de Evaluación de Tecnología en Salud e investigación ­ IETSI, no aprueba el uso de ataluren para el tratamiento de la DMD con mutación sin sentido del gen de la distrofina.

[Association study of dysbindin genotypes with bipolar I disorder by multiple allele-specific PCR]

Bipolar I disorder is a common disorder with a complex etiology. A genetic approach is gaining increasing importance in this disorder. The dysbindin gene, located at 6p22.3 is considered a susceptibility gene for schizophrenia. Certain genotypes of dysbindin are thought to be associated with other psychoses such as bipolar disorders. This study intends to assess the association in previously implicated dysbindin genotypes and haplotypes with bipolar I disorder in an Iranian population. We genotyped four previously reported SNPs: rs2619522, rs1018381, 2743852 and rs2619538. Their haplotypes were analyzed in a population of 124 patients that consisted of 44 confirmed bipolar I disorder patients and 80 control subjects. We used multiple allele-specific PCR method for genotyping, which was verified by direct sequencing. In concordance with previous reports in other populations our findings showed no association between the single SNPs and bipolar I disorder. Furthermore, none of the alleles showed a significant association with the disorder. In contrast to previous reports, haplotype analysis did not reveal any statistically significant associations with bipolar I disorder. Considering reports of previous studies regarding the implication of these dysbindin genotypes in bipolar I disorder, it is probable that allelic heterogeneity along with lack of an established causal variant in the dysbindin gene can be main factors for this discordance. With regards to ethnicities in other studies, population variation can also be considered an important factor in the observed variation

DTNBP1 gene is associated with some symptom factors of schizophrenia in Chinese Han nationality / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To study the association of DTNBP1 gene with some symptom factors of schizophrenia.</p><p><b>METHODS</b>A total of 285 unrelated schizophrenic individuals were recruited from December 2004 to January 2009 for genetic analysis, and their symptom factors were assessed based on the Positive and Negative Syndrome Scale (PANSS). The quantitative trait test was performed by the UNPHASED program (version 3.0.12) to investigate the association between scored positive and negative symptoms and the single nucleotide polymorphisms (SNPs) in DTNBP1 gene.</p><p><b>RESULTS</b>The quantitative trait test showed allelic association of rs909706 with the excitement symptom of schizophrenia (P<0.05, adjusted by 10,000 permutations), while the genotype C/G of rs2619539 with a negative symptom, lack of spontaneity and flow of conversation (P<0.05, adjusted by 10,000 permutations).</p><p><b>CONCLUSION</b>DTNBP1 variations are possibly associated with some symptoms of schizophrenia, which could partly explain the relationship between the susceptibility gene DTNBP1 and that disease.</p>

Advances in the studies of the dysbindin gene in schizophrenia / 中华医学遗传学杂志

Recent reports indicate that the dysbindin gene located on chromosome 6p22.3 is a major susceptibility gene for schizophrenia. In the brain, the dysbindin gene may influence glutamatergic neurotransmission by multiple post- and pr- synaptic mechanisms. This paper reviews the research progress on the dysbindin gene in schizophrenia, including the dysbindin gene and its product, the possible pathogenic mechanisms, the association study of the dysbindin gene with schizophrenia, and the cognitive decline caused by the dysbind in variations.

Association Analysis of Polymorphisms on Dystrobrevin Binding Protein 1 (DTNBP1) Gene with Schizophrenia in the Korean Population

OBJECTIVES: This study was designed to investigate the association of schizophrenia and P1320, P1325, P1635, P1655, P1763 and SNP A polymorphisms on dystrobrevin binding protein 1(DTNBP1) gene in Korean patients. METHODS: We analyzed P1320, P1325, P1635, P1655, P1763 and SNP A polymorphisms on DTNBP1 gene from their DNAs extracted from their blood in 388 Korean schizophrenic patients (male 198, female 190) and 372 control subjects(male 247, female 125). We compared the differences of genotype and allele distributions of the six polymorphisms on DTNBP1 gene between the Korean schizophrenic patient group and the normal control group. RESULTS: There were no statistically significant differences of genotype and allele distributions of the P1320, P1325, P1635, P1655, P1763 and SNP A polymorphisms on DTNBP1 gene between the schizophrenic patient group and the normal control group. CONCLUSION: The results of this study suggest that P1320, P1325, P1635, P1655, P1763 and SNP A polymorphism on DTNBP1 gene do not have influence on the risk of the schizophnenic in the Korean population.

Advances in molecular genetics of schizophrenia / 中国医学科学院学报

Schizophrenia (MIM 181500) is a complex disorder affecting approximately 1% of the population worldwide. Epidemiologic evidences, together with recent linkage and association studies, have clearly demonstrated the high heritability of schizophrenia (up to 80%). Uncovering the genetic mechanism of schizophrenia has became one of the greatest challenges for both psychiatry and genetics. In recent years, remarkable advances in the genetics of this disorder has been achieved with the rapid growth of human genome information and experiment technologies. Several candidate genes within some of the best-supported linkage regions have been reported and, more importantly, replicated. Moreover, these genes present a significant connection in the signaling pathways implicated in the development of schizophrenia, especially NMDA receptor-mediated glutamate transmission. In this review, we summarize the recent advances in the genetics of schizophrenia, focusing particularly on linkage disequilibrium analysis and the latest understanding of the neurobiology of the disorder.