Nueva mutación para xantomatosis cerebrotendinosa causa demencia familiar temprana en Colombia

Introduction: Cerebrotendinous xanthomatosis is an infrequent cause of dementia. It is an autosomal recessive disorder with clinical and molecular heterogeneity.Objective: To identify the presence of a possible mutation in a Colombian family with several affected siblings and clinical characteristics compatible with cerebrotendinous xanthomatosis associated to early dementia.Materials and methods: We studied a series of cases with longitudinal follow-up and genetic analysis.Results: These individuals had xanthomas, mental retardation, psychiatric disorders, behavioral changes, and multiple domains cognitive impairment with dysexecutive dominance that progressed to early dementia. CYP27A1 gene coding region sequencing revealed a novel mutation (c.1183_1184insT).Conclusion: The mutation found in this family is responsible for the described dementia features. Early identification of familial history with mental retardation, xanthomas and cognitive impairment might prevent the progression to this treatable type of dementia. Even though this mutation lies in the most frequently mutated codon of CYP27A1 gene, it has not been reported previously.Introducción. La xantomatosis cerebrotendinosa es una causa poco frecuente de demencia. Es un trastorno autosómico recesivo con heterogeneidad clínica y molecular.Objetivo. Identificar la presencia de una posible mutación en una familia colombiana con varios hermanos afectados y con características clínicas indicativas de xantomatosis cerebrotendinosa asociada a demencia precoz.Materiales y métodos. Se estudió una serie de casos, con seguimiento longitudinal y análisis genético.Resultados. Estos individuos tenían xantomas, retraso mental, trastornos psiquiátricos, cambios de comportamiento y alteraciones cognitivas de múltiples dominios con predominio de la disfunción ejecutiva, que progresaron a demencia temprana. Se identificó una nueva mutación (c.1183_1184insT) en el gen CYP27A1.Conclusión. La mutación encontrada en esta familia es responsable de la demencia descrita en los sujetos de estudio. La detección temprana de una historia familiar con retraso mental, xantomas y deterioro cognitivo, podría prevenir la progresión de este tipo de demencia tratable. A pesar de que esta mutación se encuentra en el codón más frecuentemente mutado del gen CYP27A1, no se había informado anteriormente

Surgical and rehabilitation treatment for patients with Muscular Dystrophies. Evidence-based recommendations for clinical practice guidelines in Colombia

ABSTRACT: Surgical and rehabilitation treatment for patients with Muscular Dystrophies. Evidence-based recommendations for clinical practice guidelines in Colombia Muscular dystrophies (MD) are genetic diseases that cause progressive weakness and degeneration of muscles. The Guide to clinical practice for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy developed recommendations for the comprehensive care of patients diagnosed with the most common MD. The Methodological guide for the development of clinical practice guidelines with economic assessment in the general social security system in health of Colombia was used, which mainly includes the use of the GRADE methodology. This article includes recommendations related to the surgical and rehabilitation treatment of people with MD. In general, we recommend spinal fixation surgery, elongation of the Achilles tendon, scapular fixation and tendon elongation; also the use of positive pressure devices, respiratory therapy, exercises of submaximal strengthening and aerobics, avoid prolonged immobility, use of knee ankle foot orthotic, manual and motorized wheel chairs, previously examining the feasibility of prescribing them and the patient, psychological intervention, family therapy and the use of functional scales. Spinal orthoses, high resistance exercises and leisure and recreational therapies are not recommended.RESUMEN: Las distrofias musculares (DM) son enfermedades genéticas que causan debilidad y degeneración progresiva del músculo. La Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular desarrolló recomendaciones para la atención integral de pacientes con las DM más comunes. Se utilizó la Guía metodológica para la elaboración de guías de práctica clínica con evaluación económica en el sistema general de seguridad social en salud colombiano, que incluye principalmente el uso de la metodología GRADE. El siguiente artículo recoge las recomendaciones relacionadas con el tratamiento quirúrgico y de rehabilitación de las personas con DM. Se recomiendan, en general, la cirugía de fijación espinal, de alargamiento del tendón de Aquiles, de fijación escapular y de alargamiento tendinoso; los dispositivos de presión positiva, la terapia respiratoria, los ejercicios de fortalecimiento submáximos y aeróbicos, evitar la inmovilidad prolongada, el uso de órtesis rodilla tobillo pie, las sillas de ruedas manual y motorizadas, examinando previamente la factibilidad de la prescripción y al paciente, la intervención psicológica, la terapia familiar y el uso de escalas funcionales. No se recomiendan las órtesis espinales, los ejercicios de alta resistencia y las terapias lúdicas y recreativas

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Guía de práctica clínica para la prevención, diagnóstico, tratamiento y rehabilitación de la falla cardiaca en población mayor de 18 años, clasificación B, C y D

La falla cardíaca es un síndrome clínico caracterizado por síntomas y signos típicos de insuficiencia cardíaca, adicional a la evidencia objetiva de una anomalía estructural o funcional del corazón. Guía completa 2016. Guía No. 53Población mayor de 18 añosN/

Analysis of family stigma and socioeconomic factors impact among caregivers of patients with early- and late-onset Alzheimer's disease and frontotemporal dementia.

To the best of our knowledge, there are no research studies about socioeconomic factors, family stigma, and their psychological impact on early-onset dementia caregivers. We assessed the impact of family stigma and socioeconomic factors on psychological outcomes, quality of life (QoL), and caregiver burden among 150 caregivers of patients with early-onset Alzheimer's disease due to E280A mutation in presenilin 1 (EOAD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease (LOAD). Caregivers of patients with EOAD presented a higher frequency of socioeconomic risk factors. Caregivers of FTD presented higher levels of family stigma and a higher prevalence of negative outcomes. We found family stigma to be a more suitable predictor of all outcomes. After adjusting for the type of dementia, dementia stage and behavioral changes, and caregiver age and education, family stigma was the most important factor associated with a higher risk of caregiver burden and a reduction in QoL in terms of energy fatigue and emotional wellbeing among early-onset dementia caregivers

¿cuándo inicia la enfermedad de alzheimer? kaplan-meier versus turnbull: una aplicación a datos con censura arbitraria

La mayoría de los análisis de supervivencia se basan en tiempos de falla exactos y observaciones censuradas a la derecha, utilizándose métodos ampliamente difundidos como el método de Kaplan-Meier (KM). Para estimar la edad de inicio de la Enfermedad de Alzheimer (EA) familiar cuando las censuras son arbitrarias (censura a derecha, a izquierda o en intervalo), ¿cuál es el cambio en los resultados clínicos, si se utiliza el método de KM mediante imputación comparado con el método de Turnbull sugerido para este tipo de datos? El método de Turnbull se comparó con el método de KM mediante un estudio de simulación y una aplicación con datos reales. Se realizó KM con imputación a través del punto medio del intervalo (PM) y en el extremo derecho (ED). Se analizaron diferentes tamaños de muestra y diferentes tiempos entre visitas. En todos los escenarios de simulación, las funciones que fueron estimadas, usando imputación de datos, difieren significativamente de la verdadera función de supervivencia S(t). La edad de inicio de la EA determinada a través de un método de imputación tiene implicaciones clínicas relevantes que afectarían la toma de decisiones a la hora de iniciar una terapia preventiva. El método de Turnbull presenta un menor sesgo cuando se necesita realizar un análisis de supervivencia con censuras arbitrarias.Most of the survival analysis are based on exact failure times and right censored observations, using methods widely known as the Kaplan-Meier (KM). To estimate the onset age of familial Alzheimer’s Disease (AD) when the censor times are arbitrary (right, left or interval censor), what is the change in clinical outcomes, using the KM method with data imputation compared with procedure proposed by Turnbull for this kind of data? Turnbull’s method was compared with KM method in a simulation study and an application with real data. KM method was based on data imputation through the midpoint of the interval (MP) and the right side of the interval (RS), considering several sample sizes and different times between visits. In all simulation scenarios estimated functions using data imputation differ significantly from the actual simulated survival function S(t). The estimated onset age of AD through data imputation methods has relevant clinical implications that would affect decision-making in initiating preventive therapy. Turnbull’s method has fewer bias when was compared with KM with imputation to perform a survival analysis with arbitrary censure data

Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease.

Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer's Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P < .001). On the awareness index, a decrease with age (mean [SE] estimate, -0.04 [0.02] discrepant-points per years; t = -2.2; P = .03) in the noncarriers and in the variant carriers (mean [SE] estimate, -0.21 [0.04] discrepant-points per years; t = -5.1; P < .001) was observed. In this cohort study, increased participant complaints were observed in both groups, suggesting that increased awareness of memory function was common and nonspecific to AD in this cohort. In variant carriers, awareness of memory function decreased in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset, providing support for the usefulness of awareness of memory decline

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimers disease.

Autosomal dominant Alzheimers disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease

Abstract Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors