ABSTRACT
Introducción: La distrofia muscular de Duchenne (DMD) es una enfermedad neuromuscular grave que afecta a uno de cada 3.500 varones nacidos y sigue un patrón de herencia ligada al cromosoma X. En esta enfermedad se observa una ausencia total de la distrofina, generalmente debida a mutaciones en el gen DMD, que altera la pauta de lectura y en torno al 80% de los casos son debidos a deleciones y duplicaciones de uno o más exones. Métodos: Se han revisado 284 casos de varones diagnosticados genéticamente de DMD entre los años 2007 y 2014. Estos pacientes provienen de 8 hospitales españoles de referencia que cubren la mayor parte del territorio español. Para la identificación de las mutaciones se realizaron las técnicas de reacción en cadena de la polimerasa multiplex, MLPA y secuenciación. Resultados: Los pacientes con DMD presentan en su mayoría grandes deleciones (46,1%) o grandes duplicaciones (19,7%) en el gen de la distrofina. El restante 34,2% corresponde al conjunto de mutaciones puntuales, destacando las sustituciones nucleotídicas tipo nonsense que aparecen en la mitad de los casos. Este estudio permitió identificar 23 nuevas mutaciones en DMD: 7 grandes deleciones y 16 mutaciones puntuales. Conclusiones: El algoritmo de diagnóstico genético aplicado por los centros participantes es el más adecuado para genotipificar a los pacientes con DMD. La especificidad genética de las distintas terapias en desarrollo pone de manifiesto la importancia de conocer la mutación de cada paciente, siendo un 38,7% de ellos susceptibles de participar en los ensayos clínicos actuales (AU)
Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. Methods: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. Results: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. Conclusions: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials (AU)
Subject(s)
Humans , Muscular Dystrophy, Duchenne/genetics , DNA Mutational Analysis/methods , Nucleic Acid Amplification Techniques/methods , Sequence Analysis, DNA/methods , Genetic Techniques , Dystrophin/geneticsABSTRACT
INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. METHODS: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. RESULTS: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. CONCLUSIONS: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials.
Subject(s)
Muscular Dystrophy, Duchenne/genetics , Adult , DNA Mutational Analysis , Dystrophin/genetics , Gene Deletion , Genotype , Humans , Male , Muscular Dystrophy, Duchenne/epidemiology , Spain/epidemiologyABSTRACT
The antibiotic anisomycin inhibits protein synthesis, which much research has suggested is required for the formation of long-term memory. The present work studied the effects of acute subcutaneous administration of anisomycin on the consolidation of memory in an inhibitory avoidance task in CD1 mice of both sexes. The animals were separated by sex and randomly distributed into three groups: two groups were injected with 150 mg/kg anisomycin, one immediately after the training phase and the other 24 h later, while the control group received saline. The interval between training and test was four days. Anisomycin administrated immediately after training produced statistically significant impairment of memory, which was not observed when the drug was administered 24 h after training. No sex differences were observed in the effects of anisomycin. These results extend to female mice the memory impairing effects of anisomycin previously observed in males and endorse the hypothesis that the establishment of long-term memory depends on protein synthesis shortly after training.
Subject(s)
Anisomycin/pharmacology , Avoidance Learning/drug effects , Neural Inhibition/drug effects , Protein Synthesis Inhibitors/pharmacology , Animals , Anisomycin/administration & dosage , Female , Male , Memory/drug effects , Mice , Protein Synthesis Inhibitors/administration & dosageABSTRACT
The antibiotic anisomycin inhibits protein synthesis, which much research has suggested is required for the formation of long-term memory. The present work studied the effects of acute subcutaneous administration of anisomycin on the consolidation of memory in an inhibitory avoidance task in CD1 mice of both sexes. The animals were separated by sex and randomly distributed into three groups: two groups were injected with 150 mg/kg anisomycin, one immediately after the training phase and the other 24 h later, while the control group received saline. The interval between training and test was four days. Anisomycin administrated immediately after training produced statistically significant impairment of memory, which was not observed when the drug was administered 24 h after training. No sex differences were observed in the effects of anisomycin. These results extend to female mice the memory impairing effects of anisomycin previously observed in males and endorse the hypothesis that the establishment of long-term memory depends on protein synthesis shortly after training (AU)
El antibiótico anisomicina inhibe la síntesis de proteínas, la cual muchos estudios indican que es necesaria para la formación de la memoria a largo plazo. En el presente trabajo se estudiaron los efectos de la administración aguda subcutánea de anisomicina sobre la consolidación de la memoria en una tarea de evitación inhibitoria en ratones CD1 de ambos sexos. Los animales fueron separados por sexo y distribuidos al azar en tres grupos: dos grupos fueron inyectados con 150 mg/kg de anisomicina, uno inmediatamente después de la fase de entrenamiento y el otro 24 h después, mientras que el grupo control recibió suero salino. El intervalo entre el entrenamiento y el test fue de cuatro días. La anisomicina administrada inmediatamente después del entrenamiento produjo un deterioro de memoria estadísticamente significativo, deterioro que no fue observado cuando el fármaco fue administrado 24 h después del entrenamiento. No se observaron diferencias de sexo en los efectos de la anisomicina. Estos resultados extienden a las hembras los efectos deteriorantes de la anisomicina sobre la memoria previamente observados en machos y respaldan la hipótesis de que el establecimiento de la memoria a largo plazo depende de la síntesis de proteínas poco después del entrenamiento (AU)
Subject(s)
Animals , Mice , Memory , Anisomycin/adverse effects , Memory Disorders/physiopathology , Protein Synthesis Inhibitors/pharmacokinetics , Case-Control Studies , Models, AnimalABSTRACT
BACKGROUND AND METHODS: In the search for new factors of cardiovascular risk associated to diabetes mellitus (DM), special attention has been paid in recent years to hyperhomocysteinaemia. Therefore, we have established the concentration of homocysteine (Hcy) and other biochemical parameters in the plasma of a group of 57 type 1 and 32 type 2 diabetic patients and 54 control subjects and studied whether plasmatic homocysteinaemia was related to macroangiopathy, nephropathy, retinopathy and neuropathy. Because of significant differences for plasma Hcy values between men and women in the control group, we distinguished between both groups throughout the study. RESULTS: Patients with DM had higher Hcy than control subjects (11.7+/-5.4 vs. 10.1+/-2.4 micromol/l, p<0.05). Fasting hyperhomocysteinaemia was considered as the mean of the plasma Hcy for control subjects+2 SD (14.9 micromol/l in total group, 15.6 micromol/l in males and 13.9 micromol/l in females). In the studied groups with complications, we found significant differences between normohomocysteinaemic type 1 diabetic patients and those considered hyperhomocysteinaemic by us. On the other hand, patients having type 1 DM and complications had higher plasmatic Hcy concentration than those with no complications. CONCLUSIONS: We have found a relationship between high Hcy levels and prevalence of macroangiopathy, retinopathy and nephropathy in the type 1 diabetic patients, which was not been observed in the type 2 diabetic patients of our study. As a result, we consider plasmatic Hcy a complication-risk indicator in type 1 DM, and we recommend its use together with already established biochemical parameters in the control of the evolution of the disease.
