[Linkage analysis of the 15q25-15q22 region in an extended multigenerational family segregating for idiopathic epilepsy]. / Análisis de ligamiento a la región 15Q25-15Q22 de una familia multigeneracional extendida segregando epilepsia idiopática.

INTRODUCTION: Linkage analyses provide strong evidence of how genetic factors influence epilepsy, due to the fact that they involve the determination of the cosegregation of specific marker alleles with epilepsy within families. AIMS: Our aim was to determine whether there was some kind of propensity to develop generalised idiopathic epilepsy (GIE) in the 15q22.1-q25.1 region in an extended multigenerational family from the Paisa de Antioquia community, which is a genetic isolate located in Colombia that segregates for GIE and has a strong capacity to detect linkage. PATIENTS AND METHODS: We selected a family containing a number of individuals suffering from epilepsy who visited the Antioquia Neurological Institute. Each affected individual had to have been diagnosed by a neurologist as suffering from non-myoclonic idiopathic epilepsy or from partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise seizures electroencephalographically. RESULTS: Of the 106 individuals in this family who were included in the family tree, 76 were genotyped; 15 of them suffered from generalised clonic tonic seizures and six were considered as being possibly affected. Lod score results were significantly negative for all the markers in relation to each of the models under consideration. CONCLUSIONS: The possibility of the genes that code for the a-3, a-5 and b-4 subunits of the neuronal nicotinic acetylcholine receptor (CHRNA3, CHRNA5 and CHRNB4) situated in the 15q region being responsible for the familial aggregation of GIE in this family, as has been suggested in previous studies in other families, was ruled out.

[Linkage analysis in an extended multigenerational family segregating for idiopathic epilepsy]. / Análisis de ligamiento en una familia multigeneracional extendida que segrega para epilepsia idiopática.

INTRODUCTION: Linkage analyses enable us to identify the loci that bestow susceptibility to certain diseases which are assumed to have a genetic aetiology by determining the cosegregation of alleles of specific markers within families. AIMS: The aim of this study was to determine whether there is generalised idiopathic epilepsy (GIE) susceptibility in the 8q22.1 -q24.23, 16p13.3 and 21q22.3 regions within an extended multigenerational family belonging to the Paisa community in Antioquia, a genetic isolate located in Colombia segregating for GIE with a strong capacity for detecting linkage. PATIENTS AND METHODS: A family with a number of individuals affected by idiopathic epilepsy who visited the Instituto Neurológico de Antioquia was selected for study. An affected individual was required to have been diagnosed by a neurologist as suffering from non-myoclonic idiopathic epilepsy or partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise the seizures electroencephalographically. RESULTS: Of the 106 individuals in this family that were included in the family tree, 76 were genotyped, 15 of whom were affected by generalised clonic tonic seizures and six were considered to be possibly affected. Results of the lod score were significantly negative for all the markers in relation to each model that was considered. CONCLUSIONS: The possibility of the genes located in the 8q22.1 -q24.23, 16p13.3 and 21q22.3 regions being responsible for the familial aggregation of GIE in this family was ruled out, which is in accordance with claims made in previous studies conducted on other families.

Análisis de ligamiento en una familia multigeneracional extendida que segrega para epilepsia idiopática / Linkage analysis in an extended multigenerational family segregating for idiopathic epilepsy

Introducción. Los análisis de ligamiento permiten identificar loci que confieren susceptibilidad a diversas enfermedades de las que se presume una etiología genética, mediante la determinación de la cosegregación de alelos de marcadores específicos dentro de las familias. Objetivo. Determinar si existe susceptibilidad para desarrollar epilepsia idiopática generalizada (EIG) en las regiones 8q22.1 -q24.23, 16p13.3 y 21q22.3 en una familia multigeneracional extendida perteneciente a la comunidad Paisa de Antioquia, una población aislada genéticamente localizada en Colombia que segrega para EIG y con una gran potencialidad para detectar ligamiento. Pacientes y métodos. Se selecciona una familia con múltiples individuos afectados de epilepsia idiopática que consultaron al Instituto Neurológico de Antioquia. El individuo afectado debía tener un diagnóstico realizado por un neurólogo de epilepsia idiopática no mioclónica o de epilepsia idiopática parcial. Se realizó una videomonitorización a todos los pacientes con sospecha de epilepsia idiopática, con el fin de caracterizar electroencefalográficamente las crisis. Resultados. De los 106 individuos en esta familia incluidos en la genealogía, se genotipificaron 76, de los que 15 estaban afectados de crisis tonicoclónicas generalizadas y seis se consideraron posiblemente afectados. Los resultados de lod score son significativamente negativos para todos los marcadores con relación a cada modelo considerado. Conclusiones. Se descarta que los genes localizados en las regiones 8q22.1 -q24.23, 16p13.3 y 21q22.3 sean los responsables de la agregación familiar de la EIG en esta familia, como lo han sugerido estudios anteriores en otras familias (AU)

Introduction. Linkage analyses enable us to identify the loci that bestow susceptibility to certain diseases which are assumed to have a genetic aetiology by determining the cosegregation of alleles of specific markers within families. Aims. The aim of this study was to determine whether there is generalised idiopathic epilepsy (GIE) susceptibility in the 8q22.1 -q24.23, 16p13.3 and 21q22.3 regions within an extended multigenerational family belonging to the Paisa community in Antioquia, a genetic isolate located in Colombia segregating for GIE with a strong capacity for detecting linkage. Patients and methods. A family with a number of individuals affected by idiopathic epilepsy who visited the Instituto Neurológico de Antioquia was selected for study. An affected individual was required to have been diagnosed by a neurologist as suffering from nonmyoclonic idiopathic epilepsy or partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise the seizures electroencephalographically. Results. Of the 106 individuals in this family that were included in the family tree, 76 were genotyped, 15 of whom were affected by generalised clonic tonic seizures and six were considered to be possibly affected. Results of the lod score were significantly negative for all the markers in relation to each model that was considered. Conclusions. The possibility of the genes located in the 8q22.1 -q24.23, 16p13.3 and 21q22.3 regions being responsible for the familial aggregation of GIE in this family was ruled out, which is in accordance with claims made in previous studies conducted on other families (AU)

[Vascular hereditary dementia CADASIL type in Colombia. III. Linkage analysis to notch3 gene]. / Demencia vascular hereditaria tipo CADASIL en Colombia. III. Análisis de ligamiento a Notch3.

OBJECTIVE: To perform linkage analysis between the Short Tandem Repeats (STR) microsatellite markers D19S923, D19S929, D19S22, which are in strong genetic linkage to Notch3 gene in order to contrast the hypothesis that the vascular hereditary dementia phenotype described in a multigenerational extended pedigree from Colombia correspond to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Even we know that using techniques as the Single Strand Conformational Polymorphisms (SSCP) could determine mutations in Notch3, the rationality of this approach is that intronic variations could not be defined and that we are interested in determine if some forms of the clinical presentation and its phenotypic variability make part of CADASIL. INTRODUCTION: The CADASIL phenotype is caused by mutations in the Notch3 gene. Clinical features of CADASIL are: 1. Recurrent cerebra-vascular episodes; 2. Migraine history; 3. History of transitory ischemic attack and, 4. Behavior changes and dementia. MATERIAL AND METHODS: By using SIMLINK we showed that the extended genealogy had the enough power to detect significant LOD (logarithm of oods) score values when Notch3 was considered the disorder cause. Linkage analysis was carried out by using parametric and non parametrical methods. The Elston-Stewart general method was used as the parametrical analysis and the sib pair method as the non-parametrical one. We perform simulations changing the affection status codification by including as affected or not including those individuals with migraine. Furthermore, in order to detect the stability of the results, we changed the penetrance values, the genetic frequencies on both, the marker loci and the affection locus. RESULTS: The maximum pair-wise LOD score was 2.04 which was detected at the marker D19S23 with q= 0.11cM. This distance correspond exactly with the Notch3 location. That is 100 times more probable that there is linkage that there is not. In other words this probability could be explained as if the phenotype correspond to CADASIL than to other vascular dementia. The non parametric results were compatibles with the parametric ones. When the migraine symptom was considered as a part of the affected status, the LOD score values showed not linkage. CONCLUSIONS: The results of the linkage analysis to these STR microsatellite markers suggest that the vascular hereditary dementia phenotype described in this family correspond to CADASIL caused by a polymorphism on the Notch3 gene. On the contrary, these same results suggest that the migraine phenotype is not a part of the progressive dementia.