Genetic Predisposition to Autism Spectrum Diseases - Essay Example

? Increased Genetic Risk for Autistic Spectrum Disorders 05-02-12 Increased Genetic Risk for Autistic Spectrum Disorders Introduction: Autism was indentified in 1943 and the disease was not classified in a distinct diagnostic category until the third edition of Diagnostic and Statistical Manual of Mental Disorders. (Akshoomoff 2005). In recent revision of DVM-IV, autism is placed under the category of Pervasive Developmental Disorder. Autistic Spectrum Disorders refers to both autism and Asperger’s disorder. The characteristic impairment in ASD occurs in three domains: social, behavioral and communication. With regard to behavioral presentation ASD is highly heterogeneous but in case of social development ASD exhibits a central characteristic which is manifested in several ways. Generally, individuals with ASD are unable to appropriately utilize nonverbal behaviors. Thus, during social interaction individuals are unable to utilize facial expressions and body language to communicate. Moreover, these individuals also fail to use interactive verbal and non verbal behaviors. (Abraham 2008). Individuals with ASD are unable to communicate appropriately in social interactions because of qualitative impairment. (Abraham 2008).Lack of social interaction is manifested in several ways including: lack of participation in activities, remaining alone and increased use solitary and disinterest in the activities of others. As compared to typically developing individuals, ASD individuals exhibit a failure to develop relationships. (Waltz 2002). Finally, the rules of social interaction and understanding of basic social knowledge is not appropriately developed in individuals with ASD. The deficit in communication further compounds the impairments in social interaction. Such individuals face both expressive and receptive difficulties. Use of underdeveloped grammar, pronoun reversals, and echolalic and preseverative speech, are some of the characteristics of communication deficit in ASDs. Furthermore, the use of expressive language is only limited to the communication of desires and wants. (Abraham 2008). Limitation language comprehension and literal interpretation of meaning are the two common characteristics of receptive language impairment. Individuals with ASD also have difficulty in understanding and interpreting figurative and inferential language. (Worth 2005). The characteristic behavioral excesses are manifested due to impairments in communications and social interactions. Stereotypic, repetitive and ritualistic behaviors are included in behavioral excesses. Furthermore, behavioral excesses also include over indulgence in limited activities and interests, and extreme intolerance towards environmental changes. Individuals with ASD also exhibit inflexible attention towards nonfunctional routines and exhibit certain characteristic behaviors such as pica, self injurious behaviors, tantrums and self stimulatory behaviors. (Abraham 2008). Mutation and Genetic Variation: Autism is a syndrome of separate, different diseases rather than just a single disease entity with a large spectrum.The determination of autistic chromosomal mutation is essential for the identification of molecular pathways responsible for the production of characteristic autistic phenotype. In accordance with a theory, excessive interruption of the molecular pathways governing social skills results in the production of characteristic phenotypes of autistic spectrum disorders. The interruptions mediate their effects by either slowing down the development of social skills or causing their complete shut down. The autistic chromosomal abnormalities are responsible for the degradation, disruption of neural connections, growth of brain tissue and dendritic morphology. Most autistic chromosomal abnormalities commonly consist of both allelic heterogeneity and non allelic heterogeneity. (Coleman et al 2012). Mutations in certain genes have been linked with an increased susceptibility of Autistic Spectrum Disorders. (Hollander et 2011). In accordance with a recent genetic research, it was revealed that approximately 75% of the ASD cases develop due to simple subtelomeric deletions. On the other hand, the rest of the cases are a result of more complex structural rearrangements including ring chromosome or such a translocation which is unbalanced. The critical 100 Kb region associated with phenotype comprises three genes: SHANK3, ACR, and Rabl2b. Each of which is responsible for characteristic phenotypes. Various researchers consider SHANK3 to be the critical gene in the development of phenotypic characteristics of ASD. SHANK3 belongs to the family of synaptic scaffolding proteins which are concentrated in the postsynaptic density. Due to the presence of multiple protein interaction domains, SHANK3 is well suited to its function in spine morphogenesis and synaptic plasticity. (Hollander et 2011). Over the years, numerous genetic studies have been conducted in order to determine the authenticity of genetic variation in SHANK3 leading to the development of ASD. The use of fluorescent in situ hybridization (FISH) analysis revealed that indeed SHANK3 alterations were responsible for the development for ASD. A study identified certain common traits in 400 ASD cases. All theses cases appeared to be the result of one de novo SHANK3 mutation, two 22q13 deletions and an additional deletion in a different cohort. Another subsequent study identified one de novo deletion and one missense change in a group of 427 cases of ASD. All these results point an indication that monogenic form of ASD having a frequency of 0.5% to 1% is a result of haploinsufficiency of SHANK3. Moreover, CNV in SHANK2 in ASDs has been recently identified by the Autistic Genome Project Consortium. Furthermore, point mutations in SHANK2 have also been identified in a parallel study. A frameshift mutation in NLGN4 and a C-T transition in NLGN3 that led to R451C change were identified following a screening of 150 cases for mutations in NLGN3 and NLGN4 located on the X chromosome. Another extensive study found that a mutation in NLGN4 is responsible for the insertion of a premature stop codon that leads to genetic variation. Al these studies reveal the tremendous importance of NLGN3 and NLGN4 genes in the development of ASD. A recent study established a link between variants of CNTNAP2 and increased risk of ASD in male dominant families. Some recent studies have also indicated an association between increased risk on ASDs and rare variants of CNTNAP2 and 1869 variant. (Hollander et 2011). Environmental Interactions: Some researchers claim that Autism is a cumulative result of premature environmental insult coupled with the interaction of genetic predisposition. A number of theories indicate a link between environmental factors and increased risk of autism. (Trottier et al 1999). In epidemiological studies, five environmental exposures have been found to have an association with autism and autism spectrum disorders. The five environmental exposures are valproic acid, thalidomide, misoprostol, rubella infection and the organophosphate insecticide cholpyrifos. The studies found that the exposure had occurred during the first trimester of pregnancy. Such studies have provided “proof of the concept” that ASDs can be resulted due to environmental exposures. (Hollander et 2011). Monogenic and Polygenic Inheritance in Humans: In monogenic disorders, the primary cause of the disease is a mutation in asingle gene or a pair of genes. Mendelian conditions are classified into three categories: autosomal dominant, autosomal recessive and X-Linked conditions. One the other hand, Multifactorial or Polygenic disorders are a cumulative result of multiple effects including either gene environment interactions or multiple genes. (Goldstein et al 2005). Autistic Spectrum Disorders fall into the categories of both monogenic and Multifactorial or polygenic inheritance i.e. the diseases are either a result of mutation in a single gene or mutation in multiple genes or multiple gene environment interactions. (Coleman et al 2012). Psychosociological Implications of being at risk: In most cases, Autistic spectrum disorder is a hereditary polygenetic disease and being at risk poses tremendous challenges not only for the individual but for their family members as well. Most individuals feel overawed and intimidated with their genetic counselors or health practitioners. (Boucher et al 2009). Intimidated and not being able to communicate with their medical professionals only increases the incidence of depression, anxiety and increased use of solitary. The problem further intensifies for parents when the individual at risk is their child. Due to the prevalent myths and societal stigmatization regarding autistic spectrum disorder the parents are thrown into a floundering sea of fear and isolation. Due to lack of information and intimidation with medical professionals, parents are unable to provide the required support and palliative care to their child at risk. Psychiatrist Elizabeth Kubler-Ross states that being at risk for adults is a different story and comprises of five stages: denial and isolation, anger, depression, bargaining and finally acceptance. The faster the acceptance stage is achieved the better it is not only for the individual but for their family members as well. In most cases, when an individual is informed about their risk of developing ACDs they respond by isolating themselves which later on leads to the death of the future they had envisioned for themselves. Apart from these issues, societal stigmatization and myths further intensifies the problems and forces the individuals and their families to adopt isolation. (Sicile et al 2004). Ethical and Public Health Considerations in Genetic Screening: The development of each new genetic risk screening test raises new issues regarding its safety, ethical and social policies and financial implications. Self determination, self governance or self rule is known as Autonomy. Moreover, autonomy also refers to the right of the individuals to decide whether they wish to be screened for being at risk of ASDs or to avoid being informed about the results of genetic testing, in case, they wish to undergo the process of genetic screening. The respect for autonomy in the United States of America is quite important, however, certain cases indicate that it is not absolute. The absoluteness of autonomy is one of the major ethical implications of genetic screening for determining the risk of autistic spectrum disorders. In accordance with the central importance of autonomy in the United Stats of America, it is the right of every individual undergoing genetic screening to be informed about the facts of genetic testing such as the nature of their condition and prognosis, potential risks and benefits of the proposed treatment and alternatives to the proposed intervention. However, most individuals have complained regarding provision of inadequate facts prior to getting screened while others have complained that their health practitioners failed to inform them about the availability of genetic tests for polygenetic disorders. (Andrews et al 1994). Due to the development of various types of genetic screening tests numerous concerns have surfaced relating to confidentiality, privacy and equity. Moreover, financial implications further elevate the concern of the public regarding the benefits of genetic screening tests. Genetic screening is expensive which only serves to heighten public concern. (Andrews et al 1994). Role of Genetic Counseling in Health Care: Gathering accurate, detailed and relevant information is essential for genetic counseling. The family history is gathered in an effort to get an accurate compilation of information regarding the individual’s family members. (Uhlmann et al 2005). The process of informing and advising an individual at risk of having a genetic disorder is known as genetic counseling. The process is undertaken by a genetic counselor which provides information regarding genetic contributions of ASDs, physiological and familial ramifications of being at risk. (Bartels et al 2011). Individuals who are at risk of developing autistic spectrum disorders are guided regarding the consequences and nature of the disease. Genetic counseling also involves explaining the individuals regarding their probability of development and transmission of ASDs. It also involves the explanation regarding management and issues of family planning. The process of genetic counseling primarily involves the interpretation of family history and medical histories. The interpretation of family history is essential for the analysis of chances of occurrence or reoccurrence of autistic spectrum disorders. Once the interpretation of family history has been completed, the next step in genetic counseling is to educate the individual at risk about different aspects of inheritance and other related issues such as periodic testing and disease management strategies. Genetic counselors provide detailed information to individuals and their families about informed choices and strategies to be utilized to ease adaption to being at risk of developing polygenetic disease. On the other hand, genetic counseling not only helps the counselor to become an advocate of the individuals but also involves the provision of supportive care to their families. (Gardner et al 1989). References: Coleman, M., Gillberg, C., & Gillberg, C. (2012). The autisms. New York: Oxford University Press. Hollander, E., Kolevzon, A., & Coyle, J. T. (2011). Textbook of autism spectrum disorders. Washington, DC: American Psychiatric Pub. Trottier, G., Srivastava, L., & Walker, C. D. (January 01, 1999). 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Uhlmann, W. R., Schuette, J. L., Yashar, B. M., & Baker, D. L. (2009). A guide to genetic counseling. Oxford: Wiley-Blackwell. Gardner, R. J. M., & Sutherland, G. R. (1989). Chromosome abnormalities and genetic counseling. New York: Oxford University Press. Sicile-Kira, C. (2004). Autism spectrum disorders: The complete guide to understanding autism, Asperger's syndrome, pervasive developmental disorder, and other ASDs. New York: Berkeley Pub. Group. Bartels, D. M., LeRoy, B., & Caplan, A. L. (2011). Genetic counseling: Ethical challenges and consequences. New Brunswick: Transaction Publishers. Boucher, J. (2009). The autistic spectrum: Characteristics, causes, and practical issues. Los Angeles: SAGE. Read More