Individuals Diagnosed with Binge-Eating Disorder Have DNA Hypomethylated Sites in Genes of the Metabolic System: A Pilot Study.

Binge-eating disorder, recently accepted as a diagnostic category, is differentiated from bulimia nervosa in that the former shows the presence of binge-eating episodes and the absence of compensatory behavior. Epigenetics is a conjunct of mechanisms (like DNA methylation) that regulate gene expression, which are dependent on environmental changes. Analysis of DNA methylation in eating disorders shows that it is reduced. The present study aimed to analyze the genome-wide DNA methylation differences between individuals diagnosed with BED and BN. A total of 46 individuals were analyzed using the Infinium Methylation EPIC array. We found 11 differentially methylated sites between BED- and BN-diagnosed individuals, with genome-wide significance. Most of the associations were found in genes related to metabolic processes (ST3GAL4, PRKAG2, and FRK), which are hypomethylated genes in BED. Cg04781532, located in the body of the PRKAG2 gene (protein kinase AMP-activated non-catalytic subunit gamma 2), was hypomethylated in individuals with BED. Agonists of PRKAG2, which is the subunit of AMPK (AMP-activated protein kinase), are proposed to treat obesity, BED, and BN. The present study contributes important insights into the effect that BED could have on PRKAG2 activation.

Los pacientes con delgadez constitucional presentan un fenotipo diferente al de los pacientes con trastornos de la alimentación / Patients with constitutional thinness have a different phenotype than patients with eating disorders

Los pacientes con delgadez constitucional suelen presentar un peso habitual reducido pero estacionario en el tiempo, con dificultad para aumentarlo incluso luego de someterse a dietas hipercalóricas. A diferencia de otras entidades, no se suelen encontrar trastornos de la alimentación, enfermedades sistémicas, desnutrición o sobre-ejercitación. Sin embargo, su presencia suele despertar preocupación y motivar la búsqueda de causas patológicas asociadas, tanto por parte delos pacientes como de los profesionales de la salud. Partiendo de la viñeta clínica de una paciente que presenta estas características, el autor realiza una búsqueda bibliográfica para intentar esclarecer cuán diferentes resultan los pacientes con delgadez constitucional de aquellos que presentan el principal diagnóstico diferencial a tener en cuenta, la anorexia nerviosa. (AU)

Patients with constitutional thinness tend to have a reduced but stationary habitual weight over time, with difficulty to increase it even after undergoing hypercaloric diets. Unlike other entities, eating disorders, systemic diseases, malnutrition or over-exercising are not usually found. However, its presence tends to arouse concern and motivates the search for associated pathological causes, both by patients and health professionals. Based on the clinical vignette of a patient who presents these characteristics, the author performs a literature search in order to clarify how different patients with constitutional thinness are from those who present the main differential diagnosis to consider:anorexia nervosa. (AU)

Sequence analysis of five exons of SLC6A4 gene in Mexican patients with anorexia nervosa and bulimia nervosa.

BACKGROUND: Accumulating evidence indicates that alterations in the serotonin system are related to changes in eating behavior. The serotonin transporter is encoded by the SLC6A4 gene and has been an interesting candidate for anorexia nervosa- restrictive type (AN-R) and bulimia nervosa (BN). Interestingly, functional variants have been identified in the coding region that could contribute to understand the role of this gene in eating disorders. The aim was to identify genetic variants in five exons of SLC6A4 gene using Sanger-sequencing in anorexia nervosa-restrictive and bulimia nervosa patients, and a control group. METHOD: The sample consisted of 86 patients and 50 control subjects. We obtained DNA samples from all subjects and performed Sanger-sequence analysis of the 1, 2, 3, 8 and 9 exons. The sequences were compared with the reference sequence of the SLC6A4 gene. RESULTS: The sequence analysis of the five exons of the gene identified several variants. In the AN-R, we observed two novel variants (g.130delA and c.1740G > A), three synonymous variants (rs57172732, rs55908624, rs74478645) and a missense variant (L90F) reporting a probably deleterious and damaging variant. In BN, we identified two novel variants (g.295C > G and c.1725G > A), and the non-synonymous (rs28914832/I425V), reported as benign. Interestingly, we observed the 425V variant in three patients in the BN, variant that previously was reported in patients with a spectrum obsessive-compulsive disorder. CONCLUSION: The results of our study suggest that variants of the SLC6A4 gene are related with a possible damaging or gain-of-function and may be involved in the susceptibility to AN-R and BN patients. However, the present findings should be considered as preliminary until replicated in large samples.

Impaired theory of mind in unaffected first-degree relatives of patients with anorexia nervosa.

OBJECTIVE: Previous studies have shown theory of mind (ToM) is affected in patients with anorexia nervosa (AN). There has also been growing interest in the study of endophenotypes in psychiatric disorders, since they allow better understanding of genetic mechanisms underlying different conditions, making them potential targets for future treatment. The goal of this study was to investigate whether ToM inefficiencies observed in patients with AN, are shared by unaffected first-degree relatives. METHOD: Performance on two ToM tasks (Reading the Mind in the Eyes and Faux Pas Test) were compared in 17 unaffected first-degree relatives of AN patients and in 17 healthy individuals matched for age and level of education. Depression, anxiety, obsessive compulsive, and eating disorder symptoms were also assessed and correlated with ToM and clinical/demographic variables. RESULTS: Significant differences between groups were observed in all ToM tasks, with relatives of AN patients showing poorer performance. ToM assessment did not correlate with any clinical or demographic variable. CONCLUSIONS: The preliminary results of this study suggest unaffected first-degree relatives of AN patients display similar patterns of difficulty in ToM as reported previously for AN patients, supporting the hypothesis that ToM inefficiencies are a familial trait in this condition.

A family-based association study of the HTR1B gene in eating disorders.

OBJECTIVE: To explore the association of three polymorphisms of the serotonin receptor 1Dß gene (HTR1B) in the etiology of eating disorders and their relationship with clinical characteristics. METHODS: We analyzed the G861C, A-161T, and A1180G polymorphisms of the HTR1B gene through a family-based association test (FBAT) in 245 nuclear families. The sample was stratified into anorexia nervosa (AN) spectrum and bulimia nervosa (BN) spectrum. In addition, we performed a quantitative FBAT analysis of anxiety severity, depression severity, and Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) in the AN and BN-spectrum groups. RESULTS: FBAT analysis of the A-161T polymorphism found preferential transmission of allele A-161 in the overall sample. This association was stronger when the sample was stratified by spectrums, showing transmission disequilibrium between the A-161 allele and BN spectrum (z = 2.871, p = 0.004). Quantitative trait analysis showed an association between severity of anxiety symptoms and the C861 allele in AN-spectrum participants (z = 2.871, p = 0.004). We found no associations on analysis of depression severity or preoccupation and ritual scores in AN or BN-spectrum participants. CONCLUSIONS: Our preliminary findings suggest a role of the HTR1B gene in susceptibility to development of BN subtypes. Furthermore, this gene might have an impact on the severity of anxiety in AN-spectrum patients.

A family-based association study of the HTR1B gene in eating disorders

Objective: To explore the association of three polymorphisms of the serotonin receptor 1Dβ gene (HTR1B) in the etiology of eating disorders and their relationship with clinical characteristics. Methods: We analyzed the G861C, A-161T, and A1180G polymorphisms of the HTR1B gene through a family-based association test (FBAT) in 245 nuclear families. The sample was stratified into anorexia nervosa (AN) spectrum and bulimia nervosa (BN) spectrum. In addition, we performed a quantitative FBAT analysis of anxiety severity, depression severity, and Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) in the AN and BN-spectrum groups. Results: FBAT analysis of the A-161T polymorphism found preferential transmission of allele A-161 in the overall sample. This association was stronger when the sample was stratified by spectrums, showing transmission disequilibrium between the A-161 allele and BN spectrum (z = 2.871, p = 0.004). Quantitative trait analysis showed an association between severity of anxiety symptoms and the C861 allele in AN-spectrum participants (z = 2.871, p = 0.004). We found no associations on analysis of depression severity or preoccupation and ritual scores in AN or BN-spectrum participants. Conclusions: Our preliminary findings suggest a role of the HTR1B gene in susceptibility to development of BN subtypes. Furthermore, this gene might have an impact on the severity of anxiety in AN-spectrum patients.

[The amygdala and its relation to autism, behavioural disorders and other neurodevelopmental disorders]. / La amígdala y su relación con el autismo, los trastornos conductuales y otros trastornos del neurodesarrollo.

The amygdala is related with the recognition of the emotional meaning of stimuli, long-term memory, the orientation of social stimuli and the perception of gaze orientation. It plays a fundamental role in the recognition of faces, especially those expressing fear, and makes it possible to comprehend different emotional states, which will facilitate an appropriate social cognition. Dysfunctions of the amygdala have been associated to a number of different neurodevelopmental disorders as well as neurocognitive and behavioural disorders in specific neurogenetic entities. A number of studies focused on the amygdalic complex have allowed researchers to understand many pathophysiological aspects and to formulate new hypotheses regarding their origins. Given that the disorders or conditions in which the role of the amygdala has been evoked are becoming increasingly more extensive, this article refers the reader to those that have aroused the most interest in recent years. Thus, they can be divided into two groups: developmental and behavioural disorders (autism, anxiety disorders, bipolar disorder, alexithymia and anorexia nervosa) and specific neurogenetic entities (fragile X, Rett, Prader-Willi and Williams syndromes), in which structural or dysfunctional alterations have been observed that may be related with their neurocognitive and behavioural symptoms. It is important to remember that the amygdala is a highly connected structure that forms truly functional networks and has been associated to different disorders with varied explanations and includes several different pathophysiological phenomena. Its role must not, therefore, be simplified in a reductionistic manner, but also placed upon a hierarchy of dysfunctions in other areas that interact with it.

TITLE: La amigdala y su relacion con el autismo, los trastornos conductuales y otros trastornos del neurodesarrollo.La amigdala esta relacionada con el reconocimiento del significado afectivo del estimulo, la memoria a largo plazo, la orientacion del estimulo social y la percepcion de orientacion de la mirada. Desempeña un papel fundamental en el reconocimiento de caras, en especial la de temor, y permite la comprension de diversos estados emocionales, los cuales facilitaran una adecuada cognicion social. Disfunciones de la amigdala se han relacionado con diversos trastornos del neurodesarrollo y con alteraciones neurocognitivas y conductuales en entidades neurogeneticas especificas. Multiples estudios focalizados en el complejo amigdalino han permitido comprender muchos aspectos fisiopatologicos y formular nuevas hipotesis en relacion con su genesis. Dado que los trastornos o entidades en que se ha evocado el papel de la amigdala son cada vez mas extensos, este articulo remite a aquellos que han despertado mayor interes en los ultimos años, dividiendolos en dos grupos: trastornos del desarrollo y conductuales (autismo, trastornos de ansiedad, trastorno bipolar, alexitimia y anorexia nerviosa), y entidades neurogeneticas especificas (sindromes del cromosoma X fragil, Rett, Prader-Willi y Williams), en las cuales se han comprobado alteraciones estructurales o disfunciones que pueden relacionarse con la sintomatologia neurocognitiva y conductual de estas. Es importante recordar que la amigdala es una estructura altamente conectada que conforma verdaderas redes funcionales, se ha asociado a diversos trastornos cuya explicacion es variada e incluye diversos fenomenos fisiopatologicos, por lo que no debe simplificarse de una forma reduccionista su papel, sino tambien jerarquizar disfunciones de otras areas que interactuan con ella.

Genetics in eating disorders: extending the boundaries of research / Genética em transtornos alimentares: ampliando os horizontes de pesquisa

OBJECTIVE: To review the recent literature relevant to genetic research in eating disorders and to discuss unique issues which are crucial for the development of a genetic research project in eating disorders in Brazil. METHOD: A computer literature review was conducted in the Medline database between 1984 and may 2005 with the search terms "eating disorders", "anorexia nervosa", "bulimia nervosa", "binge eating disorder", "family", "twin" and "molecular genetic" studies. RESULTS: Current research findings suggest a substantial influence of genetic factors on the liability to anorexia nervosa and bulimia nervosa. Genetic research with admixed populations should take into consideration sample size, density of genotyping and population stratification. Through admixture mapping it is possible to study the genetic structure of admixed human populations to localize genes that underlie ethnic variation in diseases or traits of interest. CONCLUSIONS: The development of a major collaborative genetics initiative of eating disorders in Brazil and South America would represent a realistic possibility of studying the genetics of eating disorders in the context of inter ethnic groups, and also integrate a new perspective on the biological etiology of eating disorders.

OBJETIVO: Revisar a literatura atual concernente à pesquisa genética em transtornos do comportamento alimentar e discutir questões relevantes ao desenvolvimento de um projeto de pesquisa genética nessa área no Brasil. MÉTODO: A revisão realizada utilizou a base de dados Medline, no período de 1984 a maio de 2005, com os seguintes termos de busca: "anorexia nervosa", "bulimia nervosa", "eating disorders", "binge eating disorder", "family studies", "twin studies", "molecular genetics studies". RESULTADOS: Os dados atuais apontam para uma contribuição relevante dos fatores genéticos na suscetibilidade à anorexia e à bulimia nervosa. A pesquisa genética com populações miscigenadas deve levar em consideração o tamanho da amostra, a densidade de genotipagem e a estratificação populacional. Através de "admixture mapping" é possível estimar a estrutura genética destas populações e localizar genes relacionados à variação étnica de doenças ou traços de interesse. CONCLUSÕES: O desenvolvimento de uma grande iniciativa de colaboração em genética de transtornos alimentares no Brasil e na América Latina viabilizará estudar os fatores genéticos em transtornos do comportamento alimentar no contexto de grupos inter-étnicos, e integrar uma nova perspectiva biológica à etiologia destes distúrbios.

[Genetics in eating disorders: extending the boundaries of research]. / Genética em transtornos alimentares: ampliando os horizontes de pesquisa.

OBJECTIVE: To review the recent literature relevant to genetic research in eating disorders and to discuss unique issues which are crucial for the development of a genetic research project in eating disorders in Brazil. METHOD: A computer literature review was conducted in the Medline database between 1984 and may 2005 with the search terms "eating disorders", "anorexia nervosa", "bulimia nervosa", "binge eating disorder", "family", "twin" and "molecular genetic" studies. RESULTS: Current research findings suggest a substantial influence of genetic factors on the liability to anorexia nervosa and bulimia nervosa. Genetic research with admixed populations should take into consideration sample size, density of genotyping and population stratification. Through admixture mapping it is possible to study the genetic structure of admixed human populations to localize genes that underlie ethnic variation in diseases or traits of interest. CONCLUSIONS: The development of a major collaborative genetics initiative of eating disorders in Brazil and South America would represent a realistic possibility of studying the genetics of eating disorders in the context of inter ethnic groups, and also integrate a new perspective on the biological etiology of eating disorders.

Anorexia nervosa: III. aspectos epidemiológicos, genéticos e sócio-culturais / Anorexia nervosa: III. epidemiological, genetic and socio-cultural aspects

Faz-se um levantamento de dados epidemiológicoss, genéticos e sócio-culturais referentes à anorexia nervosa. Pretende-se avaliar a participaçäo de tais fatores na gênese e no desenvolvimento da condiçäo. Conclui-se que os fatores sócio-culturais participam do aumento da incidência observado, mas que a contribuiçäo näo pode ser tida como causa. Por outro lado, os dados epidemiológicos e os estudosde gêmeos näo estäo aprimorados o suficiente para permitir a diferenciaçäo entre as influências genotípicas e as fenotípicas