Computational classifiers for predicting the short-term course of Multiple sclerosis

The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS). METHODS: We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center. RESULTS: We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later. CONCLUSIONS: The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability

Progressive external ophthalmoplegia (PEO) due to a mutation in the C10orf2 (PEO1) gene mimicking a myasthenic crisis

We described a case of a patient with autosomal dominant progressive external ophthalmoplegia (PEO) who presented with the acute onset dysphagia, quadriparesis, ptosis and respiratory insufficiency following a cardiac procedure and mimicking a myasthenic crisis. A pathogenic mutation in the C10orf2 (PEO1) gene was confirmed. The unusual presentation of our patient contributes to expand the clinical phenotype of PEO1 mutations and reinforces the need to consider mitochondrial myopathy as differential diagnosis of myasthenia gravis even in the case of acute onset symptoms.Fil: Gonzalez Moron, Dolores. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bueri, José. Hospital Universitario Austral. Departamento de Neurología; ArgentinaFil: Kauffman, Marcelo Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentin

Transcriptionally Less Active Prodynorphin Promoter Alleles are Associated with Temporal Lobe Epilepsy: A Case-Control Study and Meta-Analysis

We performed an association study in a population of patients with Mesial Temporal Lobe Epilepsy (TLE) with Hippocampal Sclerosis (MTEHS) together with a systematic revision of the literature to investigate the role of transcriptionally less active polymorphic alleles of Prodynorphin (PDYN) gene in this pathology. We included 102 patients with a diagnosis of MTEHS and 86 healthy controls. The positive antecedent of family history for epileptic events defined a TLE subgroup with familial predisposition for epileptic disorders. The PDYN promoter polymorphism was genotyped by means of a PCR assay. For meta-analysis, we identified case-control association studies between TLE and PDYN by searching PUBMED. The pooled OR was estimated using a fixed effects model under dominant and co-dominant heredity models. No differences in genotypic and allelic frequencies were found between cases and controls (p = 0.61) in our population, neither in the whole cohort nor in the analysis limited to TLE with familial predisposition (p = 0.71). The Meta-Analysis included 591 TLE patients and 1117 healthy controls. We found an association between L allele (p = 0.003; OR = 1.40; IC 95 = 1.12–1.74) and a modestly higher risk to develop TLE in the group of patients with familial predisposition. Therefore, functional allelic variants in the PDYN promoter might modify the risk to develop TLE in subjects with familial predisposition

Personalized genomic neurology: Future is now

Introducción y objetivos: Las nuevas técnicas de secuenciación genómica masiva han revolucionado el diagnóstico de las enfermedades neurológicas. Nuestro objetivo general es ilustrar, mediante la presentación de 3 casos clínicos, el abordaje diagnóstico de la patología neurológica desde la genómica. Para ello nos proponemos: explorar herramientas bioinformáticas de anotación e interpretación funcional de variantes, describir un algoritmo de análisis para los datos obtenidos del exoma y con estos resultados correlacionar en nuestros pacientes fenotipo-genotipo-vía funcional. Material y métodos: Fueron incluidos 3 pacientes que concurrieron a la consulta con síntomas neurológicos crónicos y progresivos. Secuenciamos el exoma en los 3. Mediante el uso de herramientas bioinformáticas, utilizando un algoritmo de selección, se filtraron las variantes por frecuencia poblacional, patogenicidad y modelo de herencia. Se estableció la correlación funcional con el fenotipo en cada caso y finalmente se validaron las variantes candidatas por Sanger en los afectados y se buscó su segregación en familiares. Resultados: Se elaboraron algoritmos de aproximación diagnóstica genómica para cada caso. En el caso 1 se llegó al diagnóstico de leucodistrofia asociada a POLR3A con las siguientes mutaciones c.G3781A:p.E1261K y c.G3014A:p.R1005H. En el caso 2 el diagnóstico probable fue de retraso mental sindromático secundario a la mutación p.Arg198* en homocigosis para GRIK2. Y, finalmente, en el caso 3 la causa de paraparesia espástica hereditaria fue el haplotipo patogénico en heterocigosis compuesta c.6763insA y c.6726A>T, p.Gln2242His en SPG11. Conclusiones: La aproximación diagnóstica genómica en conjunto con una completa evaluación clínica resulta útil para el abordaje de la patología neurológica, permitiendo una correlación fenotipo genotipo y vía funcional afectada, arribando a un diagnóstico molecular sólido.Introduction and objectives: The new techniques of mass genome sequencing have revolutionized the diagnosis of neurological diseases. Our overall objective is to illustrate the genomic diagnostic approach of neurological pathology by presenting three cases. To do this we will: explore bioinformatic annotation tools and functional interpretation of variants, describe an algorithm for exome data analysis and to correlate these results with our phenotype-genotype -functional pathway. Material and methods: We included 3 patients who attended the talks with chronic and progressive neurological symptoms. We sequenced the exome in all three. We performed the analysis through annotation and functional bioinformatic tools Results: Algorithms genomic diagnostic approach were developed for each case. In case 1 the diagnosis was reached Leukodystrophy associated with the following mutations POLR3A c.G3781A: p.E1261K and c.G3014A: p.R1005H. In case 2 the diagnosis was probable syndromic mental retardation secondary to homozygous mutation p.Arg198* for GRIK2. And finally in case 3 the cause of hereditary spastic paraparesis was compound heterozygous pathogenic haplotype c.6763insA and c.6726A > T, p.Gln2242His in SPG11. Conclusions: The genomic diagnostic approach along with a complete clinical evaluation is useful for addressing neurological pathology allowing genotype and phenotype correlation with functional pathways arriving to a solid molecular diagnosis.Fil: Córdoba, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Gonzalez Moron, Dolores. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez Quiroga, Sergio Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Kauffman, Marcelo Andres. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentin

Expanding the spectrum of Grik2 mutations: intellectual disability, behavioural disorder, epilepsy and dystonia

Fil: Córdoba, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Rodríguez Quiroga, Sergio Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Gonzalez Moron, Dolores. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Medina, Nancy. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Kauffman, Marcelo Andres. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Timely diagnosis of Wilson's disease using whole exome sequencing

Wilson's disease (WD) is a rare inborn error of copper metabolism caused by mutations in ATP7B gene. Although there is no genetic heterogeneity in WD etiology, the widespread clinical presentation of WD makes its diagnosis not always straightforward, particularly when atypical symptoms are present and a number of differential diagnoses must be considered.Fil: Rodríguez Quiroga, Sergio Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Rosales, Julieta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Arakaki, Tomoko. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Córdoba, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Gonzalez Moron, Dolores. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Medina, Nancy. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Garreto, Nélida S.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Kauffman, Marcelo Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentin

Computational classifiers for predicting the short-term course of Multiple sclerosis

Abstract Background The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS). Methods We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center. Results We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later. Conclusions The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.</p

Vaccine effcicacy against malaria by the combination of porcine parvovirus-like particles and vaccinia virus vectors expressing CS of plasmodium

With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8+ T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8+ T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malariaThis work was supported by SAF-2008-02036 and the Marcelino Botín Foundation (to Dr. Esteban) La Caixa Foundation International PhD Program Fellowship (to Dr. Vijayan)Peer reviewe