RESUMO
Abstract Introduction The mother and child attachment could have an important and long-lasting impact. An insecure attachment could lead to emotional development difficulties. It has been suggested that maternal care in infants is associated with personality. However, more studies in adults are needed. Objective To determine if attachment styles in subjects with affective or anxiety disorders are associated with the expression of personality traits, and if this effect can be modulated by the presence of the short allele of the 5-HTTLPR polymorphism. Method Our sample included 87 patients with mood or anxiety disorders. The NEO-PI-R questionnaire and the Adult Attachment questionnaire by Melero were used. Results Insecure attachment styles were associated with a higher expression of neuroticism, and a lower expression of extraversion, conscientiousness, and agreeableness, especially in individuals with the most insecure attachment. An interaction was identified between the attachment style and the 5-HTTLPR genotype on the expression of agreeableness. Higher neuroticism, and lower extraversion and conscientiousness tended to be present in carriers of the S allele. Discussion and conclusion There was a significant association between the attachment styles and the expression of neuroticism, extraversion, agreeableness, and conscientiousness-responsibility according to the Big Five Model. The short allele may be associated with the modulation of certain aspects of personality. Prevention strategies should be established to promote adequate attachments between infants and caregivers to avoid a possible risk factor for future maladaptive personality traits.
Resumen Introducción El apego entre la madre y el hijo puede tener un impacto importante. Un apego inseguro podría afectar el desarrollo emocional. Se ha sugerido que los cuidados de la madre en la infancia temprana se asocian a la personalidad. Sin embargo, se requieren más estudios en adultos. Objetivo Determinar si los estilos de apego en personas con trastornos del afecto o ansiedad se asocian a la expresión de rasgos de personalidad y si esta expresión es modulada por la presencia del alelo corto del polimorfismo 5-HTTLPR. Método Se incluyeron 87 pacientes. Se emplearon los cuestionarios NEO-PI-R y el de Apego en el Adulto de Melero. Resultados Los estilos de apego inseguro se asociaron con una expresión mayor de neuroticismo y menor de extroversión, conciencia y amabilidad, especialmente en los individuos con el estilo de apego más inseguro. Se identificó una interacción entre el estilo de apego y el genotipo del 5-HTTLPR en la expresión de amabilidad. En los portadores del alelo corto hubo una tendencia hacia mayores valores de neuroticismo y menores niveles de extroversión y conciencia. Discusión y conclusión Los estilos de apego se asocian con la expresión de neuroticismo, extroversión, amabilidad y conciencia/responsabilidad. El alelo corto del 5-HTTLPR podría asociarse con la modulación de algunos aspectos de la personalidad. Los resultados sugieren la importancia de promover un apego adecuado entre los niños y sus cuidadores primarios para evitar posibles riesgos que se asocien con rasgos desadaptativos de la personalidad.
RESUMO
Many precise aspects of the etiology and pathophysiology of mental disorders are still unknown. Susceptibility to these disorders depends in part on variability in the genome sequence among individuals. The genotype, a given environment, a specific epigenetic profile and stochastic factors affect the phenotype, which includes body structures, physiological processes, and behavior. Since the access to the Central Nervous System is generally difficult and in most cases there are still no biological tests that necessarily contribute to diagnosis, psychiatric phenotypes are usually limited to clinical symptoms and functioning. Therefore, researchers are currently seeking alternatives to facilitate the identification of genetic risk factors. One strategy is to identify measurable biological, cognitive, and behavioral markers, intermediate phenotypes, or endophenotypes, which in the best case may be simpler than general psychiatric diagnoses, ideally with a precise biological meaning and a more direct relationship with the action of specific genes. Endophenotypes have been very useful in other fields of medicine. Currently, there are several proposed criteria and specifications for endophenotypes. Examples of possible types of endophenotypes or biomarkers, as well as treatment response phenotypes in some psychiatric disorders will be discussed in this review.
Aún se desconocen diversos aspectos de la etiología y fisiopatología de los trastornos mentales. La susceptibilidad a éstos depende en parte de la variabilidad en la secuencia genómica en las personas. El genotipo, un ambiente dado, un perfil epigenético específico y factores estocásticos afectan el fenotipo, el cual incluye estructuras corporales, procesos fisiológicos y conducta. Los fenotipos psiquiátricos generalmente se limitan al funcionamiento y a los síntomas clínicos, debido a que el acceso al Sistema Nervioso Central es complicado y en la mayoría de los casos no hay pruebas biológicas que necesariamente contribuyan al diagnóstico. Por esta razón, en la actualidad se buscan alternativas para facilitar la identificación de factores de riesgo de tipo genético. La identificación de marcadores biológicos, cognitivos o conductuales medibles, fenotipos intermedios o endofenotipos podría ser una de estas nuevas opciones. Estos marcadores podrían ser más simples que el diagnóstico psiquiátrico general, y de manera ideal tendrían un significado biológico preciso y una acción más directa en los genes. El empleo de endofenotipos ha sido útil en otras ramas de la medicina. Hasta ahora se han propuesto diversos criterios y especificaciones para los endofenotipos. En esta revisión se describirán posibles tipos de endofenotipos o biomarcadores, así como fenotipos relacionados con la respuesta farmacológica en algunos trastornos psiquiátricos.
RESUMO
In recent years, consumption of alcoholic beverages has become a common practice among young adults attending higher education institutions in Mexico. Over the past two decades, prevalence of alcohol consumption in this population has doubled. In campuses located in Mexico City, 70-90% of undergraduate students have consumed alcoholic beverages during the past year and approximately 25% have engaged in binge drinking. Past year prevalence of Alcohol Dependence (AD) has been estimated in 4.6% and 18.4%. Higher education institutions around the world have implemented programs aimed at reducing students' drinking that have included educational interventions and/or psychosocial treatments delivered individually or in group format. In this regard, the available evidence suggests that programs that have included elements of the Motivational Enhancement Therapy (MET) or components of the Cognitive Behavioral Therapy (CBT) have shown the greatest efficacy in reducing drinking problems in this population. Despite this, there are no studies examining the efficacy of these interventions in Mexico's college student population. In the report presented here, we aim at examining the efficacy of Individual or Group MET and CBT in reducing drinking among undergraduate students diagnosed with AD. We hypothesized that in comparison to CBT, MET would show evidence of a greater reduction in alcohol consumption. To evaluate this hypothesis we examined the treatment effects on the number of consumed drinks, on the number of drinking days, and on the number of drinks per drinking day during the preceding 30 days. Methods We prospectively evaluated during an 8-week treatment phase and during a 12-month follow-up period, 158 undergraduate students who received a diagnosis of AD (ICD-10) at the students' Mental Health and Counseling Center of the National Autonomous University of Mexico (UNAM) in Mexico City. Instruments. In order to screen and to establish the diagnosis of AD we respectively used the Alcohol Use Disorders Identification Test (AUDIT) Mexican version and the Composite International Diagnostic Interview (CIDI). We also used The Alcohol Time line Followback (TLFB) method to retrospectively record the amount and frequency of alcohol consumption. Procedures. Students seeking services at the UNAM Mental Health and Counseling Center, and who had a diagnosis of AD, were invited to participate in the study. After informed consent was obtained, they were randomly assigned to one of four manualized treatment interventions: Individual or Group MET, or Individual or Group CBT. These were delivered in eight weekly sessions lasting one hour. The alcohol TLFB was administered at the beginning and at the end of the 8-week treatment phase, and subsequently monthly for the following 12 months. Statistical analysis. An analysis of variance (ANOVA) for repeated measures was used to examine the treatment effect on drinking during the treatment phase and separately during the 12-month follow-up period. A one-way ANOVA was used to examine differences between treatment groups at specific assessment points. Results Demographic characteristics. In the entire sample the majority of students were men (73.2%), while the mean age was 18.8 [± 2.9] years. There were no differences between intervention groups in their demographic characteristics. Baseline characteristics of alcohol consumption. In the entire sample and separately in each of the intervention groups there was a predominant pattern of weekly heavy drinking. There were no baseline differences between treatment groups in the monthly amount or frequency of drinking, or in the number of drinks consumed during drinking days (all comparisons P>0.50). The average number of Alcohol Dependence symptoms was 6.0 [± 2.6]. There were no differences among groups in the number of these symptoms (P=0.10). Patient Retention during the Treatment Phase and the Follow-up Period. At the end of the 8-week treatment phase, 92% of the students remained in treatment. During this phase, the Individual CBT group had the greatest number of dropouts with 18% of them leaving prematurely (Pearson X² = 15.7, df=3, P = 0.001). During the follow-up period, specifically at the 3, 6 and 12-month follow-up, the retention rates in the study were respectively 91%, 89% and 86%. There were no differences among groups in this variable at any of these follow up points. Alcohol consumption during the treatment phase. In the ANOVA for repeated measures we found that during the treatment phase there was a main effect of time over the three indicators of alcohol consumption (range of F: 7.59-11.81, df=1.142, range of P:0.001-0.007). This reflected the fact that at the end of the four interventions there was a reduction in the amount and frequency of monthly drinking and a reduction in the number of drinks during drinking days. There were no main effects of treatment (range of P:0.07- 0.56) or interactive time X treatment effects (range of P:0.55 to 0.79) on any of the drinking variables. However, at the level of a non-significant trend (F = 2.37, df=3.143, P = 0.07), there was a treatment effect reflecting that in comparison to Individual CBT, there was a trend toward a greater reduction in the frequency of monthly drinking in Group MET (one-way ANOVA: F=2.60, df=3.146, P=0.05, Tukey HSD P=0.07). Alcohol consumption during the follow-up period. In the ANOVA for repeated measures, there was a main effect of time on the amount and frequency of monthly alcohol consumption (range of F: 8.54-9.53, df=3.393, P range: 0.001-0.004), reflecting that during this period there was a reduction in these two drinking variables in the entire sample. This effect was observed mainly during the first six months of follow-up. During the following six months, there was a gradual increase in the amount and frequency of drinking (range of F for the quadratic component of Time: 5.36-10.36, df=1.131, range of P: 0.02-0.002) that approached the levels seen at the end of treatment. There were no main effects of time on the number of drinks consumed during drinking days (P=0.27). There was a treatment X time interaction (F=2.65, df=3.131, P=0.05) on monthly frequency of drinking, indicating that, in comparison to Individual CBT, there was a greater reduction in this drinking variable in Group MET. This effect was specifically observed during the first three months of follow-up (one-way ANOVA: F=3.63, df=3.142, P=0.02, Tukey HSD P=0.007). Subsequently, there were no differences among the intervention groups in this variable for the remaining nine months of follow-up. Finally, there were no main effects attributable to treatment or interactive effects of time X treatment on the number of monthly drinks (P range: 0.49 to 0.65) or on the number of drinks consumed per drinking day (P range: 0.55 to 0.79). Discussion In this sample of alcohol dependent college students, we found that at the end of the 8-week treatment phase there was a comparable reduction in the amount and frequency of alcohol consumption and in the number of drinks consumed during drinking days across the four intervention groups. However, we observed that at the level of a non significant trend (P=0.07), Group MET appeared to be more effective than Individual CBT in reducing the frequency of alcohol drinking.
Introducción Se ha descrito que entre los estudiantes de educación superior de nuestro país la prevalencia del consumo de alcohol se ha duplicado durante las últimas dos décadas. Se han estimado prevalencias durante los últimos 12 meses del diagnóstico de Dependencia al Alcohol (DA) de 4.6%. Aunque se desconoce la magnitud de las consecuencias de estos problemas entre los estudiantes universitarios mexicanos, en Estados Unidos han sido identificados como un problema de salud pública mayor y como el principal problema de salud en las universidades. Para reducir estos problemas, se ha evidenciado que las intervenciones como la Terapia de Incremento de la Motivación (TM) o la Terapia Cognitivo Conductual (TCC) podrían ser igualmente efectivas a largo plazo. Se ha observado una ligera ventaja del formato individual sobre el grupal. Pero al analizar el costo-beneficio, el formato grupal suele ser el más utilizado en las universidades. A pesar de la importancia de los problemas por consumo de alcohol en las universidades y no obstante la efectividad demostrada de estas intervenciones, no hay, hasta lo que sabemos, investigaciones publicadas que comparen la eficacia de la TM y la TCC en el tratamiento de los universitarios con problemas por consumo de alcohol en México o en otros países de habla hispana. Objetivo Examinar los efectos de las intervenciones TM y TCC tanto en su modalidad individual como grupal, en el tratamiento de estudiantes universitarios con diagnóstico de dependencia al alcohol. Material y métodos Se evaluó prospectiva y comparativamente a 158 estudiantes universitarios con diagnóstico de Dependencia al Alcohol. Instrumentos: 1. Alcohol Use Disorders Identification Test (AUDIT); 2. Composite International Diagnostic Interview (CIDI); 3. Línea Base Retrospectiva (LIBARE); 4. Cuestionario de Datos Demográficos. Procedimientos. A los estudiantes con problemas con su manera de beber, se les aplicó el AUDIT; a los que tuvieran respuestas positivas para Dependencia al Alcohol, se les aplicó la sección de <
RESUMO
Alcohol dependence is a major global problem, associated with lower quality of physical and mental health, higher mortality and an enormous familial and social cost. Prevention strategies and treatment of this condition are therefore crucial. Success of psychosocial programs and pharmacological treatments has been frequently reported, but a better understanding of the etiology of this chronic disease is needed. For this purpose, the identification of associated factors in different populations is of great significance. It has been clearly demonstrated by twin and adoption studies and supported by animal models that both genetic and environmental components play a substancial role in alcohol dependence. Heritabil ity estimates range from 40 to 60%, depending on the specific analyzed sample. Several coexisting genetic variants in each affected individual, rather than a single gene transmitted in a Mendelian manner, may be the rule in alcohol dependence. Similarly, many environmental factors can increase susceptibility, and because of their diversity, they do not have to be the same in every affected person. Environmental contribution may be linked to epigenetics, which refers to chemical processes that can modify gene activity without changing the sequence of DNA. In humans, the most stable epigenetic process is the union of a methyl group (one carbon atom surrounded by three hydrogen atoms) to cytosines in DNA. Other epigenetic mechanisms are modifications to nuclear proteins called histones, which alter the way DNA is packed. Moreover, non-protein coding RNAs such as microRNAs have been associated with the development of alcohol dependence. MicroRNAs could work as epigenetic intermediaries that allow ethanol to affect complex and divergent developmental mechanisms, which is added to the effect of DNA methylation, histone acetylation, and other epigenetic modifications. Most reasearch points to an association between alcohol dependence and genes related with alcohol metabolism, with neurotransmission of dopamine, GABA, serotonin, glutamate, endogenous opioids, and cannabinoids, signal transduction within the mesolimbic dopamine reward system, and stress response system, among others. During pregnancy, there are several non-genetic factors that may have an important impact on vulnerability to alcohol dependence. Given that the Central Nervous System is developing throughout the entire pregnancy and that alcohol consumed by the mother can reach the fetus through the placental barrier, the brain of a baby is always vulnerable to harm caused by alcohol exposure. Children born to alcoholic mothers may inherit genetic susceptibility variants but at the same time they may be exposed to early effects of ethanol. Heavy alcohol exposure during pregnancy has been associated with mental retardation, epilepsy, attention deficit/ hyperactivity disorder, learning disabilities, and later on with substance abuse, anxiety, personality, affective and psychotic disorders, as well as with engagement in antisocial behaviors and school or work problems. Furthermore, it has been shown that animals exposed to prenatal stress exhibit persisting modifications related to dopamine and glutamate transmission in limbic structures associated with dependence to alcohol and other substances. These alterations may later contribute to increase motivation to drink, to use large amounts of drugs of abuse or to relapse after periods of drug withdrawal. It was shown that after exposure to prenatal stress, male mice consumed more ethanol during alcohol reinforcement in adulthood. In addition, it has been well documented that affective disorders are associated with alcohol dependence. A recent meta-analysis including 54 studies that together involved more than 40749 individuals, confirmed that the 5-HTTLPR polymorphism at the promoter of the serotonin transporter gene moderates the association between stress and depression, where the short allele is related with an increased risk for depression under stress (p = 0.00002). A strong association was detected when the stressful factor was childhood maltreatment (p = 0.00007). Childhood maltreatment, including neglect as well as physical and sexual abuse, is associated with developmental difficulties, low social competence and self-esteem, and it is an important risk factor for binge drinking in adolescence and alcohol dependence in adulthood. Childhood maltreatment may interact with factors such as variants of the monoamine oxidase-A and catechol-o-methyltransferase gene. Adolescence is a critical period for initiation of alcohol intake, experimentation, and establishment of regular drinking patterns. Substance use at this age is considered a risk factor for the development of later alcohol and other drug-related problems, as well as for externalizing disorders such as antisocial personality disorder. Alcohol use initiation is affected by environmental factors such as ethanol availability, parental attitudes, and peer pressure. It has been reported that heavy drinking during adolescence can have a negative impact on brain development. Moreover, dopaminergic and GABAergic systems undergo important changes during adolescence, and they can be affected by alcohol intake. Dopamine is implicated in the rewarding effects of ethanol, and GABA in its sedating effects and development of tolerance. The way an adult copes with environmental challenges is notably influenced by early life experiences and by the familial environment he or she had as an infant, which affects neurodevelopmental behavior. While environmental factors tend to have a crucial role in drinking habits in adolescence, adultood may be characterized by a weaker effect of environment and a higher effect of genetic components. It is probable that a complex set of gene-environment interactions determine the risk to alcohol dependence. Environmental factors that may affect this vulnerability appear at different stages from pregnancy to adulthood. These interactions are mediated by DNA methylation, histone modifications, protein complexes and non-protein-coding RNAs such as microRNAs.
La dependencia al alcohol es un problema mundial grave, que se asocia con mucho sufrimiento, problemas de salud mental y física, una elevada tasa de mortalidad y un costo social y familiar muy alto. Es por esto que las estrategias de prevención y el tratamiento de la enfermedad resultan cruciales. Se ha reportado que programas psicosociales y tratamientos farmacológicos son hasta cierto punto exitosos actualmente. Sin embargo, se requiere conocer más profundamente la etiología de la enfermedad. Por esta razón, es muy importante identificar los factores que se asocien con el incremento a la susceptibilidad en distintas poblaciones. Se ha demostrado claramente a través de estudios en gemelos y de adopción, así como por investigaciones en animales, que tanto factores genéticos como ambientales son relevantes en la dependencia al alcohol. Se ha estimado que la heredabilidad de esta enfermedad se encuentra entre 40 y 60%, dependiendo de la muestra estudiada, lo cual indica que el ambiente y la genética tienen un peso similar en la susceptibilidad. Muchas variantes genéticas que aumentan la susceptibilidad, en lugar de una sola, podrían coexistir en las personas más vulnerables a la dependencia. De manera similar, muchos factores ambientales parecen estar relacionados, los cuales, debido a su diversidad, intensidad y etapas de la vida en la que se presentan, no son exactamente iguales en diferentes personas con dependencia al etanol. La contribución ambiental podría relacionarse con cambios en la expresión de genes, lo cual involucra a la epigenética. Ésta se encarga del estudio de los procesos químicos, afectados por el ambiente, que pueden modificar la actividad de los genes sin cambiar la secuencia del ADN. En humanos, el proceso epigenético más estable es la unión de un grupo metilo (un átomo de carbón unido a tres átomos de hidrógeno) a las citosinas en el ADN. Otros mecanismos epigenéticos son modificaciones a proteínas nucleares llamadas histonas, proceso que modifica la manera en que se encuentra empaquetado el ADN. Por otra parte, ARNs que no codifican para proteína, como los microARNs, se han asociado al desarrollo de la dependencia al alcohol. Ciertos microARNs podrían funcionar como intermediarios epigenéticos, lo cual propiciaría que el etanol afectara procesos complejos y divergentes del neurodesarrollo, sumándose al efecto de la mutilación en el ADN y de la acetilación de histonas, entre otros procesos epigenéticos. La mayoría de las investigaciones señalan que los genes importantes en la vulnerabilidad a la dependencia al alcohol incluyen algunos que codifican para proteínas del metabolismo del alcohol; de neurotransmisión de dopamina, GABA, serotonina, glutamato, opiodes endógenos y canabinoides; de transducción de señal en el sistema de recompensa mosolímbico; y de respuesta al estrés, entre otros. Durante el embarazo, diversos factores no genéticos tienen un impacto importante en la vulnerabilidad a la dependencia al alcohol. Por ejemplo, debido a que el Sistema Nervioso se desarrolla a lo largo de toda la gestación y que el alcohol consumido por la madre puede llegar al feto a través de la barrera placentaria, el cerebro de un feto siempre es vulnerable al daño provocado por la exposición al etanol. Se ha demostrado que los hijos de mujeres alcohólicas no sólo pueden heredar variantes genéticas de riesgo sino que también pueden estar expuestos tempranamente a los efectos del alcohol consumido por sus madres. El consumo excesivo en el embarazo se ha asociado con retraso mental, epilepsia, déficit de atención/ hiperactividad, problemas de aprendizaje, y más adelante con abuso de sutancias, ansiedad y trastornos afectivos, de personalidad y psicóticos, así como con conductas antisociales y problemas en la escuela o el trabajo. Además, se ha demostrado que animales expuestos a estrés prenatal mostraban modificaciones persistentes relacionadas con la transmisión dopaminérgica y GABAérgica en estructuras límbicas que se relacionan con dependencia al alcohol y a otras drogas. Más adelante, estas alteraciones podrían contribuir a la motivación para beber, a utilizar mayores cantidades de alcohol u otras susancias de abuso o a la recaída después de periodos de abstinencia. Se encontró que ratones macho expuestos a estrés prenatal consumían más alcohol en la edad adulta. La depresión y el estrés se han asociado fuertemente con la dependencia al alcohol. Con un metaanálisis reciente en el que se incluyeron datos de 54 estudios en los que en conjunto se habían reclutado 40 749 personas, se confirmó que el polimorfismo 5-HTTLPR del promotor del gen que codifica para el transportador de serotonina modera la asociación entre el estrés y la depresión y el alelo corto (<
RESUMO
The sequence of the human genome integrates the keystone of our life. Part of it is transcribed to RNA, which in turn provides the information required by our cells to produce proteins. Discoveries in the genetics field have been essential to medicine and have been used to develop strategies to modify, prevent and propose new therapeutic approaches for human diseases. In the 19th Century, Gregor Johann Mendel developed a theoretical model which was able to predict in an accurate way hereditary mechanisms; indeed, his laws still explain the basis of human inheritance. Almost ninety years later, James Watson and Francis Crick announced their double-helix model of the DNA molecule. Then, positional cloning and the polymerase chain reaction (PCR) were introduced; more recently, almost 99% of the sequence of our genome was made public. The current period of time is known as the post-genomic era, due to the fact that researchers are not only obtaining the complete sequences of thousands of genomes, but are also searching for clues that may help understand the mechanisms that affect gene activation and deactivation, in which epigenetic factors are also involved. In medical domains, twins constitute a suitable group to study inherited disorders. Dizygotic or fraternal twins are produced by different egg and sperm cells, and even when these two fertilization events occur simultaneously, dizygotic twins share approximately the same percentage of genetic material than any pair of siblings, that is, around 50%. Some authors have suggested that the tendency for spontaneous dizygotic twinning could be attributed to a double ovulation which is genetically determined in an autosomal dominant manner. Monozygotic, as opposed to dizygotic twins, are produced by a single zygote whose cells are dissociated and originate two independent organisms; approximately a third of monozygotic twins are separated before the 5th day after fertilization, and the rest between the 5th and the 15th day. Most monozygotic twins are very similar; nevertheless, some few exceptions prove that in fact they actually do not have to be identical. Relatives of a person with a mental disorder tend to share traits associated with this disease, especially if the patient and the relative are monozygotic twins. However, important differences may be detected even between each pair of identical twins. Parameters such as concordance and heritability have shown that a monozygotic twin can develop an inherited disorder while his or her co-twin will always be disease-free. In addition to differences in susceptibility to inherited diseases, this kind of twins can display dissimilarities in somatic cell mutations (more overtly noticeable when ageing), their set of antibodies and T cell receptors, their number of mitochondrial DNA molecules, and chromosome X inactivation patterns in women, all of which are the main subject of many ongoing studies. A recent report shows that from 160 monozygotic twin pairs who were 3 to 74 years old, epigenetic patterns were identical early in life, but differences were more obvious at older ages, especially if twins were raised apart or if they had different medical history. Medical conditions, but also environmental factors such as pregnancy tobacco exposure, physical activity, and diet could contribute to differences in epigenetic patterns. It has been shown that epigenetic modifications (or epi-mutations) are more frequent than the ones that modify DNA sequence, so they are part of the fundamental causes of biological diversity, and they show how environment can modulate gene expression and contribute to our phenotype. Even when twin studies are sometimes considered purely genetic, they also give information about the influence of environmental factors. However, it is important to consider with caution the results from this type of studies. Heritability estimates are not unchangeable facts. They depend on the sample being analyzed, the genes involved in the specific sample, the characteristics of the environmental factors which members of this group were exposed to, and the precise moment the study was done. Epigenetics refers to changes that do not alter the DNA sequence but affect gene function due to chemical modifications which mainly occur in DNA cytosines and in chromatin-related histones. Epigenetic processes are covalent modifications which include the addition of functional groups (methyl, acetyl, phosphate, etc.) or proteins (ubiquitin, SUMO, etc.) to the DNA molecule or to associated proteins. These modifications contribute to the activation or inhibition of transcription, which leads to changes in messenger ARN expression that can ultimately influence the onset of disease. Pseudogenes are still being excluded while new genes are being confirmed in our genome sequence, but the current estimates indicate that each one of our nucleated cells contains almost 22000 genes (excluding mitochondrial DNA) which encode for polypeptides and more than 4,000 whose final product is RNA. Gene expression is partially controlled by DNA coiling around globular proteins called histones, which constitute a structure known as chromatin, a DNA-protein complex that represents the packaging of 3.25 billion base pairs of our genetic information. Physical and chemical chromatin modifications can also affect gene expression by changing DNA-protein interactions; in general terms, genes are inhibited when chromatin is packed and they are active when it is free. These dynamic states are controlled by epigenetic reversible modifications on DNA methylation or by changes in histones. It has been shown that subtle epigenetic differences between any two human beings are associated with dissimilar final chromatin remodeling, as well as expression/repression of genes.
La secuencia de ADN genómico que caracteriza a nuestra especie constituye la piedra fundamental de la vida humana; parte de ella se refleja en la secuencia del ARN y a través de éste se dicta la información necesaria para que nuestras células produzcan proteínas. La genética contribuye de manera importante a los avances en el campo médico. Los descubrimientos genéticos han permitido desarrollar estrategias para modificar, prevenir y proponer nuevas terapias para diversas enfermedades. En el siglo XIX, Gregor Johann Mendel desarrolló un modelo teórico capaz de predecir la naturaleza y propiedades de los mecanismos de la herencia, que sigue siendo indispensable para explicar la base de la herencia humana. Otro suceso determinante en la historia de la Medicina se dio a conocer casi nueve décadas después cuando James Watson y Francis Crick describieron su modelo estructural para el ADN. Posteriormente se introdujeron la clonación posicional y la reacción en cadena de la polimerasa; más recientemente se publicó cerca del 99% de la secuencia del genoma humano. El período actual se conoce como la era post-genómica, ya que además de descifrar genomas completos, los investigadores pretenden, entre otras cosas, esclarecer los mecanismos que influyen en la activación e inactivación de los genes, lo cual en parte involucra un nivel epigenético. En las ciencias médicas los gemelos constituyen un grupo idóneo para abordar el estudio de las enfermedades hereditarias. En este tipo de padecimientos suelen observarse similitudes entre parientes, en especial si se trata de gemelos monocigóticos. Sin embargo, aun en este tipo de hermanos se detectan diferencias importantes. Parámetros como los grados de concordancia y porcentajes de heredabilidad han puesto de manifiesto que un gemelo monocigótico puede presentar trastornos hereditarios que su co-gemelo nunca tendrá. La epigenética es el estudio de los cambios en la función de los genes que no afectan la secuencia del ADN, por modificaciones que tienen lugar principalmente en las citosinas de éste y en las histonas de la cromatina. Se ha determinado que las modificaciones epigenéticas son mucho más frecuentes que aquellas que modifican la secuencia del ADN, por lo que constituyen uno de los fundamentos de la diversidad biológica, muestran la manera en que el ambiente puede modular la expresión genética y contribuyen así a nuestro fenotipo. Esta revisión reúne datos sobre la posible relevancia de la epigenética en el estudio de los trastornos mentales y como posible explicación parcial de las diferencias observadas entre gemelos <
RESUMO
Tourette syndrome (TS) was named after Georges Albert Edouard Brutus Gilles de la Tourette, who made its first formal description at the end of the 19th century. Nevertheless, some evidence indicates the disorder may have been recognised at least two thousand years ago. Tic like behaviours were recorded by Aretaeus of Cappadocia and several centuries later by Sprenger and Kraemer, followed by other descriptions. The English writer Samuel Johnson, author of the first English Language Dictionary, showed repetitive body twitches, facial grimaces, barks and grunts, among other tics. He was observed in situations such as going in or out at a door using a certain number of steps, from a certain point, which indicated he had also obsessive-compulsive behaviour. There was some evidence of features of TS as well as co-morbid conditions such as hyperactivity, obsessive-compulsive behaviour or rage attacks in other famous artists and world leaders. Some authors have even proposed that the creative, determined, competitive, and persistent nature of certain people may be related to the presence of TS. Clinicians have observed that some patients are particularly sensitive to the feelings and experiences of others, and more prone to outside stimuli. In this way, empathy could be a common quality in these patients. In 1825, Jean Marc Gaspard Itard made the first known medical description of TS based on two cases, one of which was later followed by Jean-Martin Charcot. In 1885 Gilles de la Tourette put together information from previous fragmented reports and wrote a complete and formal description, thus establishing a novel clinical entity. Behavioural abnormalities such as obsessions, compulsions, inattentiveness and hyperactivity, commonly observed in TS patients, were considered mental tics at the time. Current diagnostic criteria are very similar to Gilles de la Tourette's description. TS is characterized by the presence of multiple motor and one or more vocal tics. In this disorder, tics are not caused by the direct physiologic effects of a substance or a general medical condition. Tic symptomatology is persistent for over a year, and in this period, tics are not absent for more than three consecutive months. There is no exact consensus between the DSM-IV and the Tourette Syndrome Classification Study Group of whether the age of onset should be prior to 18 or 21 years of age, how cases of onset after 21 years should be diagnosed, and if marked distress or significant impairment caused by tics is necessary to define the condition as definite TS. However, the text revision of the DSM-IV (TR) no longer specifies that TS symptoms have to cause distress or impair the functioning of the patients. With respect to the age of onset, the ICD-10 Classification of Mental and Behavioural Disorders describes the onset almost always in childhood or adolescence, and in this way it would no longer exclude cases with later onset. Numerous studies confirmed in the 20th century that genetics plays an important role in the etiology of TS. Family studies proved that the disease runs in families. First-degree relatives of TS patients are indeed in greater risk for TS than the general population. Twin and adoption studies demonstrated that genes have an important role in the etiology of TS, and as much as 90% of the vulnerability to this syndrome could be affected by genes. In addition, environmental, epigenetic and even stochastic factors may affect the susceptibility to TS. At the molecular level, linkage in families and association in unrelated TS subjects have been the main methods used to search for vulnerability genes. Sequencing of almost the entire human genome made it possible to assess the gene expression of thousands of genes on a single chip; recent studies reported a preliminary specific profile in the blood of TS patients. If confirmed, this finding could be useful in the identification of genetic factors related with TS. Given the multi-factorial nature of TS, a thorough clinical description in large samples should be considered; besides association, linkage and sequencing studies, possible gene-gene and gene-environment interactions would also need to be analysed, as well as epigenetic factors, and gene expression patterns.
El síndrome de Gilles de la Tourette (SGT) se nombró asi en honor de Georges Albert Edouard Brutus Gilles de la Tourette, alumno de Charcot, quien realizó la primera descripción formal de esta entidad clínica a finales del siglo XIX. Sin embargo, hay evidencias que indican que probablemente el trastorno se había identificado de alguna manera desde hace por lo menos dos mil años. Areteo de Capadocia registró conductas similares a los tics, también descritas por Sprenger y Kraemer en el siglo XV y más adelante por otros. El escritor inglés Samuel Johnson, autor del primer Diccionario de la Lengua Inglesa, mostraba contorsiones en todo el cuerpo, muecas, ladridos y gruñidos, entre otros tics. Se le observaba entrando o saliendo por una puerta con un número determinado de pasos a partir de un punto dado, lo cual indica que también presentaba conducta obsesivo- compulsiva. Además, otros artistas y líderes mundiales han presentado características del SGT y de padecimientos comórbidos como el trastorno por déficit de atención e hiperactividad, el trastorno obsesivo-compulsivo o ataques de ira. Un grupo de autores ha llegado a considerar que la naturaleza creativa, determinada, competitiva y persistente en ciertas personas podría relacionarse con el SGT. Algunos especialistas del área médica han observado que ciertos pacientes con SGT son particularmente sensibles a los sentimientos y experiencias de otras personas y más propensos a los estímulos externos. Por lo tanto, la empatía podría ser una cualidad común en estos pacientes. En 1825, Jean Marc Gaspard Itard realizó la primera descripción médica conocida del SGT, basándose en dos casos, uno de los cuales fue estudiado más adelante por Charcot. En 1885, Gilles de la Tourette reunió fragmentos de información de reportes previos y redactó una descripción formal y completa del trastorno, con lo que estableció una nueva entidad clínica. Las anormalidades del tipo de obsesiones, compulsiones, inatención e hiperactividad se consideraban tics mentales en esa época. Los criterios diagnósticos actuales del SGT son muy similares a los publicados por Gilles de la Tourette. El SGT se caracteriza sobre todo por la presencia de dos o más tics motores y uno o más tics fónicos. En este trastorno, los tics no son causados por el efecto fisiológico directo de una droga o por una affeción médica general. La sintomatología de los tics persiste por más de un año y en este periodo los tics no se ausentan por más de tres meses consecutivos. No hay un consenso preciso entre el DSM-IV y el Grupo de Estudio de la Clasificación del Síndrome de Gilles de la Tourette en relación con la edad de inicio: si debe ser antes de los 18 o los 21 años, cómo deben considerarse casos de inicio posterior a los 21 años y si para definir un caso definitivo de SGT se requiere que la persona presente malestar o incapacidad importante a causa de los tics. Sin embargo, en el texto revisado del DSM-IV (TR) ya no se especifica que los síntomas del SGT deban causar necesariamente malestar o incapacidad en el funcionamiento diario de los pacientes. En cuanto a la edad de inicio, si la Clasificación de los Trastornos Mentales y de la Conducta (CIE-10) describe que la edad de inicio casi siempre es en la niñez o adolescencia, de esta manera ya no excluye la posibilidad de edades de inicio más avanzadas. Gracias a diversos estudios, durante el siglo XX se pudo confirmar que la genética es decisiva en la etiología del SGT. Por medio de estudios en familias se confirmó que el trastorno se concentra particularmente en ciertas familias. Los parientes en primer grado de un paciente con SGT se encuentran en mayor riesgo de presentar el trastorno que la población en general. Estudios realizados en pares de gemelos y personas adoptadas confirmaron que los genes tienen un peso importante en el aumento de la susceptibilidad al SGT. Se ha estimado que hasta 90% de la vulnerabilidad al trastorno podría estar afectada por los genes. Aunados a estos factores hereditarios que dependen directamente de la secuencia del ADN de nuestras células nucleadas, se encuentran otros factores que afectan en cierto grado la susceptibilidad al SGT, como los de tipo ambiental, epigenético o aleatorio. A nivel molecular, los principales diseños para el estudio del SGT y la búsqueda de genes de susceptibilidad han sido el enlace genético (linkage) en familias y los estudios de asociación en pacientes no emparentados. La secuenciación de prácticamente todo el genoma humano ha permitido, entre otras cosas, identificar la expresión de miles de genes en un solo chip. De acuerdo con estudios preliminares recientes, podría haber un patrón específico de expresión en sangre de pacientes con SGT. Si esto se llegara a confirmar, los hallazgos podrían emplearse para facilitar la identificación de factores genéticos de riesgo para el SGT. Tomando en cuenta la naturaleza multifactorial del SGT, se requiere además de estudios de enlace genético, asociación y secuenciación, análisis sobre interacciones de tipo gen-gen y gen-ambiente, así como la identificación de factores epigenéticos y de niveles de expresión genética en el SGT.