Phenotypic correlations in a large single center cohort of patients with BSCL2 nerve disorders: a clinical, neurophysiological and muscle MRI study

Background: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMN). We present a series of BSCL2 patients and correlate clinical, neurophysiological and muscle-MRI findings. Methods: 26 patients from 5 families carrying the p.N88S mutation were ascertained. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth/CMT, spastic paraplegia), physical examination, disability measured as modified Rankin score (mRS) and neurophysiological findings were collected. A whole body muscle-MRI had been performed in 18 patients. We analyzed the pattern of muscle involvement on T1-weighted and STIR sequences. Hierarchical analysis using heatmaps and a MRI Composite Score (MRI CS) were generated. Statistical analysis was carried out with STATA SE v.15. Results Mean age was 51.54+/-19.94 years and 14 patients were males. dHMN was the most common phenotype (50%) and 5 patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (mRS=1.34+/-1.13) although median time since onset of disease was 32 years (range=10-47). CMT-like patients were more disabled and disability correlated with age. On muscle-MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI CS was strongly correlated with disability. Conclusion: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle-MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials

Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Background: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of alpha-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. Methods: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. Results: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. Conclusions: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.Peer reviewe

Epilepsia eta Genetika

El aislamiento de determinados genes que intervienen en el origen de la epilepsia idiopática ha permitido una mejor clasi cación de la epilepsia. En el presente trabajo se da cuenta del examen clínico de dos familias con síndrome epiléptico. La primera muestra una epilepsia nocturna asociada al cromosoma 20q, que presenta una mutación en el gen (CHRNA4) de la subunidad 4 del receptor nicotínico de la acetilcolina. La segunda muestra una epilepsia lateral temporal autosómica dominante asociada al cromosoma 10q.Epilepsia idiopatikoen sorreran parte hartzen duten zenbait geneen isolaketak epilepsiaren sailkapena hobetzea baimendu du. Lan honetan sindrome epileptikoa duten bi sendiren ikerketa kliniko eta genetikoa aurkezten da. Lehenak, 20q kromosomari loturiko gau epilepsia frontala agertzen du, azetil kolinaren errezeptore nikotinikoaren 4 azpiunitatearen genean (CHRNA4) mutazio bat agertzen duelarik. Bigarrenak, 10q kromosomari loturiko autosomiko gainartzailea den epilepsia albo-tenporala agertzen du.L'isolement de certains gènes qui interviennent dans l'origine de l'épilepsie idiopathique a permis une meilleure classi cation de l'épilepsie. Dans ce travail on rend compte de l'examen clinique de deux familles qui souffrent du syndrome épileptique. La première montre une épilepsie nocturne associée au chromosome 20q, qui présente une mutation dans le gène (CHRNA4) de la sous-unité 4 du récepteur nicotinique de l'acétylcholine. La seconde montre une épilepsie latérale temporelle autosomique dominante associée au chromosome 10q.The isolating of certain genes that intervene in the origin of idiopathic epilepsy has allowed for a better classification of epilepsy as a whole. This work is about the clinical analysis of two families with an epileptic syndrome. The first family displays a nocturnal epilepsy associated to chromosome 20q, which has a mutation in gen (CHRNA4) of sub-unit á4 of the acetylcoline nicotinic receptor. The second family displays a dominant lateral temporal lobe and autosomal epilepsy associated to chromosome 10q

Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Background: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of alpha-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration

Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.status: publishe

ENGIU: Encuentro Nacional de Grupos de Investigación de UNIMINUTO.

El desarrollo del prototipo para el sistema de detección de Mina Antipersona (MAP), inicia desde el semillero ADSSOF perteneciente al programa de Administración en Seguridad y Salud en el trabajo de la UNIMINUTO, se realiza a partir de un detector de metales que emite una señal audible, que el usuario puede interpretar como aviso de presencia de un objeto metálico, en este caso una MAP. La señal audible se interpreta como un dato, como ese dato no es perceptible a 5 metros de distancia, se implementa el transmisor de Frecuencia Modulada FM por la facilidad de modulación y la escogencia de frecuencia de transmisión de acuerdo con las normas y resolución del Ministerio de Comunicaciones; de manera que esta sea la plataforma base para enviar los datos obtenidos a una frecuencia establecida. La idea es que el ser humano no explore zonas peligrosas y buscar la forma de crear un sistema que permita eliminar ese riesgo, por otro lado, buscar la facilidad de uso de elementos ya disponibles en el mercado