Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

Progressive cognitive impairment and familial spastic paraparesis due to PRESENILIN 1 mutation: anatomoclinical characterization.

INTRODUCTION: Autosomal dominant Alzheimer's disease (ADAD) due to presenilin 1 (PSEN1) mutation can induce atypical neurological symptoms such as movement disorders and epileptic seizures in the context of early-onset progressive cognitive impairment. METHODS: This study includes the anatomoclinical description of three patients of two generations of the same family with movement disorders and progressive cognitive impairment. All were evaluated by trained neurologists, underwent protocolized neuropsychological evaluation, and were assessed by structural (magnetic resonance) and functional (SPECT, PET-18FDG, or PET-18F-Florbetapir) brain imaging tests. A molecular genetic study was performed for all patients, and post-mortem confirmatory anatomopathological evaluation for one of them. RESULTS: The three female patients had an age of onset of symptoms of 38-51 years. All developed progressive multidomain cognitive impairment, paraparesis, and dysarthria, two with ophthalmoparesis and one with untriggered epileptic seizures since early stages. Bilateral cortical fronto-parietal atrophy and global cortical hypoperfusion or posterior bilateral hypometabolism were detected. PET-18F-Florbetapir, when performed, was positive for amyloid cortical deposit. The molecular genetic study confirmed the PSEN1 mutation c.869-2 A>G. Postmortem study of one of them confirmed Alzheimer's disease anatomopathological features with classic cotton wool plaques (CWP), including coexistence of amyloid angiopathy and Lewy body co-pathology. DISCUSSION: The phenotype of ADAD due to PSEN1 mutations is very heterogeneous between and across the same family. Family history assessment should include information not only about cognitive decline, but also about movement disorders and untriggered epileptic seizures. Further studies are needed to identify genetic or epigenetic factors that determine phenotypic diversity in this disease.

Tres victimarios y una víctima. Presentación de un caso / Three victimizers and a victim. Presentation of a case

El peritaje psiquiátrico es la actuación médico legal donde convergen la Psicología, la Psiquiatría, el Derecho y la Sociología; con cuyos conocimientos permite evitar que los resultados de la peritación sean pobres o contraproducentes, al intentar esclarecer a través de un conjunto de pruebas el estado mental de un sujeto determinado, al aportar elementos científicos concretos a la administración de justicia sobre fenómenos psíquicos, mediante la investigación de la personalidad de los mismos. En esta ocasión se presenta el caso de tres individuos masculinos, de 20, 21 y 22 años de edad, a quienes se les realizó un peritaje medicolegal tras haber cometido un delito de asesinato, constatándose en sus antecedentes que los tres procedían de familias disociales. Durante la peritación salieron a relucir características de la personalidad de los victimarios que los clasifican como portadores de personalidades patológicas de tipo disocial, lo cual justifica su actuación, resultando ser individuos con incapacidad de adoptar normas de convivencia adecuadas al medio sociocultural en el que se desarrollan, con escasos valores morales y éticos, relacionándose este resultado con sus antecedentes familiares.

The psychiatric expertize is the medico-legal performance where Psychology, Psychiatry, Law and Sociology meet. Their knowledge allows avoiding self-defeating and poor expertize results when intending to elucidate the mental status of certain individual through a group of evidences. It gives concrete scientific elements to law administration on psychic phenomena, studying the individual personality. This time we present the case of three male individuals, aged 20, 21 and 22 years who were medico-legally expertized after committing a murder, establishing that all of them came from dissocial families. During the expertizing came into sight characteristics of the victimizers' personalities classifying them as carriers of dissocial-kind pathologic personalities justifying their performance, and being individuals who are incapable of adopting life-together norms fitting the socio-cultural surroundings they live in, with scarce ethic and moral values. These results are related with their familiar antecedents.

Caracterización psicológica de los ancianos / Psychological characterization of elderly people

Se realizó una caracterización psicológica de un grupo de ancianos enfermos, se compararon sus diferentes padecimientos con sus edades y rasgos fundamentales, para demostrar que cuanto mayor salud mental tengan mayor será la duración de su vida y menores sus trastornos cognitivos. Se realizó un estudio prospectivo, observacional del universo de enfermos ingresados en nuestras salas y la muestra la constituyeron los ancianos. Se estudiaron las variables edad, sexo, hábitos y enfermedades existentes. Se realizó el Mini Mental Test de Folstein y la Escala Psicoafectiva del Centro Ibero-latinoamericano de la Tercera Edad (CITED), además de un examen físico completo. Se encontró que los ancianos se deprimen con gran frecuencia, lo que está en relación con su entorno familiar; que se enferman más con entidades orgánicas aquellos que tienen peor estado psicoafectivo y que todo esto contribuye al deterioro cognitivo de nuestros ancianos y por lo tanto afecta nuestras expectativas de longevidad feliz

Longevity is the aspiration of the developed world, but it should be achieve with a high quality of these patients’ life, in such a way that they may stay in the social environment around them, but without being a burden for society. Everybody must be prepared in all fields, since we should guarantee not only old people’s physical health, but also their mental health as well. There are several disorders in the cognitive and affective field which influence decisively on the preservation of elderly people’s useful life. A psychological characterization of a group of sick old people is carried out. Their different pathologies are compared to their ages and main features to show that the better mental health they have, the longer their life will be, and the lesser cognitive disorders they will have. An observational prospective study of patients taken from those admitted in our wards is carried out, and elderly people were taken as a sample. Age, sex, habits and illness are studied. Folstein mini- mental test and the Psycho-affective Test from the Iberian Latin American Center for Elderly People (CITED) were applied, together with a whole physical exam. It was found that old people are frequently depressed due to family environment; those who have worst psycho affective states get much more organic illness than the others. All this contributes to old people’s cognitive impairment, and therefore it affects our expectation of happy longevity