This web page was produced as an assignment for an undergraduate course at Davidson College.
The Gene for Autism: could it be SLC25A12?
“Autism is one of the most heritable complex genetic disorders in psychiatry. Despite this high heritability, autism has a heterogeneous etiology, with multiple genes and chromosomal regions likely to be involved. Scientists are using both indirect and direct approaches to identify autism susceptibility genes. Indirect approaches include the characterization of less complex genetic disorders that share some of the symptoms of autism, including Rett syndrome or fragile X syndrome, in the hope that these analyses will provide clues to the more complex disorder of autism. Direct approaches include three overlapping methodologies to identify genes or regions of interest in autism: chromosomal methods, such as karyotyping and fluorescence in situ hybridization (FISH); linkage studies, such as genome screens in affected sibling pairs; and gene association studies, including candidate gene studies” (Veenstra-VanDerWeele, 2003).
Introduction and Purpose
"The primary role of the journalist is to translate science into non-scientific language," that can be consumed and understood by the general public; however, the popular press often fails to accurately convey the conclusions of scientific papers (Kua et al., 2004). Autism is quite complex and it is my desire to clarify some of the misconceptions concerning the origins of this disease and to encourage critical analysis of reports intended for the general public. With this web page, I hope to explore the discrepancies between findings of scientific investigators and news reported in popular press stories.
Image from ASA
Background Information: What is autism?
Before I begin to analyze relevant literature, I would like to provide a foundation for readers by describing the symptoms, manifestation, and treatment of autistic disorder. Autism is classified as a Pervasive Development Disorder by the American Psychiatric Association. Affected children exhibit communication difficulties, impaired social interaction, and abnormal imaginative play. These symptoms appear prior to the age of three and boys are four times more likely to be affected by autism than girls. Like most disorders, there is a broad range in the severity of presentation. Nearly 75% of children with autism also have some degree of mental retardation. Autism is the most highly genetic of all psychiatric disorders (WebMD, 2004).
Autism is the fastest growing developmental disability with an estimated prevalence of 1 case per 250 births; currently 1- 1.5 million Americans have autism and the annual cost is $90 billion (Autism Society of America, 2003).
To learn more about the details of autism spectrum disorders please access this informative booklet created by the NIMH.
What are the symptoms and specific diagnostic criteria for autism?
Diagnostic Criteria for 299.00 Autistic Disorder (DSM-IV-TR, 2000).
What are the current treatment options and therapies available for autistic patients?
Since autism is such a complex disorder, there is no easy cure for the associated symptoms. However, treatment often allows for more normal development and reduction of undesirable behaviors. A sincere effort to provide effective therapy must be made by parents and teachers. The unavoidable emotional drain of raising an autistic child can only be overcome with steadfast dedication, compassion, patience, and love. A special education program is designed and implemented to meet the specific needs of the child by encouraging social adjustment and speech development (DSM-IV-TR, 2000). Occasionally, dietary limitations to reduce food sensitivities may be helpful. Currently, there are no medications approved to treat autism although drugs intended for associated identifiable symptoms such as anxiety, seizures, hyperactivity, and self destructive behavior may be prescribed (NINDS, 2003).
What causes autism?
Autism is caused by both genetic and environmental factors. The biological basis for the disorder can be found in, "abnormalities in several regions of the brain, including the cerebellum, amygdala, hippocampus, septum, and mamillary bodies. Neurons in these regions appear smaller than normal and have stunted nerve fibers, which may interfere with nerve signaling" (NIMH, 2004). Researchers currently believe that autism is exceptionally complex and therefore a single 'gene for autism' does not exist. However, this may not be such a bad thing, one investigator explained, "although a disadvantage in studying a complex genetic disorder is the difficulty in identifying the variants, a potential advantage is that more options for intervention may be implicated by multiple genes, and these genes may be related to a developmental neurobiological system that is not yet fully understood" (Veenstra-VanDerWeele, 2003). In addition to the gene I am focusing on I want to provide basic information on other genes that potentially play a role in autism. Studies have shown that maternally inherited duplications of chromosome 15q11-13, account for up to 3% of autism cases. Associations have specifically been made with a polymorphism in the GABA type A receptor b3 subunit (Buxbaum, 2004).
The following figure illustrates the crucial connection of genes found on chromosome 2 with autism rates.
Figure 1 Chromosome 2 linkage map generated in ASPEX for autism sibling pairs analyzed by case type.
The black line represents all 153 sibling pairs.
The yellow line represents pairs in which both siblings met the following criteria: clinical diagnosis of autism; Autism Diagnostic Inventory (ADI) and Autism Diagnostic Observation Schedule (ADOS) criteria for autism; IQ > 35; and language delay (44 type I-type I pairs).
The blue line represents pairs in which one sibling met the above criteria and the other met at least the following criteria: clinical diagnosis of autism, Asperger’s syndrome, or pervasive developmental disorder (PDD); no more than 1 point below threshold in only one behavioral domain on the ADI; at least ADOS criteria for PDD; measurable IQ; language delay not necessary (81 type I-type II pairs).
The red line combines the two types of strict criteria pairs described above (125 strict criteria pairs).
Dark triangles represent markers typed in the original 86 sib pairs and pink triangles markers typed in all 153 sib pairs. MLS = multipoint maximum LOD score.
Image and caption are reprinted in Veenstra-VanDerWeele, 2003. Original figure adapted with permission from International Molecular Genetic Study of Autism Consortium (IMGSAC) (2001), A genome wide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 69:570–581 (published by The University of Chicago Press). r 2001 by The American Society of Human Genetics.
American Journal of Psychiatry Article
This investigation "mapped a susceptibility locus for autism to chromosome region 2q24-q33" To do this investigators compared genes of autistic patients with nonautistic subjects to examine genetic variants in exons and flanking sequences within candidate genes. They discovered two single nucleotide polymorphisms (SNPs) within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). Next, investigators typed the two SNPs in SLC25A12 for 411 autistic families and preformed linkage association tests and comprehensive statistical analysis. The SNPs are rs2056202 and rs2292813.
Figure 2. Ideogram of SLR25A12 gene locus (in red) at 2q24-q33. NCBI.
Figure 3. Genomic Organization of the Autism Susceptibility Locus in Chromosome Region 2q24-q33 (For the organization of positional candidate genes, arrows indicate orientation of transcription. Variants within the SLC25A12 gene identified in the study are indicated, with the two SNPs, rs2056202 (I3-21A/G) and rs2292813 (I16+70A/G), underlined. (Figure and caption courtesy of Buxbaum et al., 2004)
I examined two popular press stories released shortly after this scientific article appeared in the American Journal of Psychiatry. The first, written by the Associated Press and printed in USA Today was terse and extremely vague but respectable for not sensationalizing the findings of the study. This report cited Buxbaum stating, "The new work provides strong evidence that the gene influences susceptibility to autism, but more studies will be needed to confirm the link"(AP, 2004). Only a trivial amount of information about experimental methods, previous studies, and the strength of data was provided; also, the name of the new autism associated gene(SLC25A12) is not mentioned in this story making it difficult for readers to conduct follow up research. Although the information reported was accurate, the article failed to provide the context necessary to fit information into the bigger picture, a flaw Rodgers believes is quite common in popular press articles (Kau, 2004).
In contrast to the article found in USA Today, the BBC News Report successfully describes the significance of the genetic linkage found by Buxbaum's team. The article begins by disclosing the basic function of SLC25A12 and then provides general information about autism. Proper emphasis is placed on investigators' desire to understand the genetic components of autism by stating, "Autism affects about one in every 1,000 people... Studies suggest parents with one child with autism are 100 times more likely to have another child with the condition compared with other families." The article continues with an appropriate description of the methods employed by researchers and genetic mechanisms as well as the conclusions and implications of the study. Another strength comes with the multiple quotations of Baxbaum; this excerpt serves as a particularly effective take home message, "Having one of these variants appears to approximately double an individuals risk for the disorder, but it is an accumulation of genetic factors that cause the disease. Our current challenge is to identify more of these genes." This article is well written because it refuses to sacrifice contextual information as scientific jargon is eloquently explained in a manner that can be easily understood by the general public.
Links and References
Autism Research Institute
CBS News: Examining Autism
CDC Autism Information Center
Center for the Study of Autism
Exploring Autism: A look at the genetics of autism
Gene Card for SLR25A12
National Alliance for Autism Research
Associated Press. 2004 April 1. Scientists identify gene that might raise autism risk. USA Today. <http://www.usatoday.com/news/health/2004-04-01-autism-genetics_x.htm>. Accessed 6 September 2004.
Autism Society of America. 2003 February. Autism Facts. <http://www.autism-society.org/site/PageServer?pagename=Autism_Facts>. Accessed 2004 September 10.
Buxbaum, J. D., Ramoz, N., Reichert, J. G., Smith, C. J., Silverman, J. M., Bespalova, I. N. and Davis, K.L. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry. 2004 Apr;161(4):662-9.
BBC News. 31 March 2004 Gene 'increases risk of autism'. BBC News. <http://news.bbc.co.uk/1/hi/health/3585315.stm>. Accessed 4 September 2004.
The Cleveland Clinic Department of Psychiatry and Psychology and edited by Charlotte E. Grayson. May 2004. Your Guide to Mental Illnesses in Children: Autism. WebMD. <http://my.webmd.com/content/article/60/67141.htm>.Accessed 2004 September 2.
Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC, American Psychiatric Association, 2000.
The National Institute of Neurological Disorders and Stroke. 2004 July 1. NINDS Autism Information Page. National Institutes of Health. <http://www.ninds.nih.gov/health_and_medical/disorders/autismshortdoc.htm/>. Accessed 2004 September 4.
Strock, Margaret. 2004 April 9. Autism Spectrum Disorders (Pervasive Developmental Disorders). National Institute of Mental Health Publication No. NIH-04-5511. <http://www.nimh.nih.gov/publicat/autism.cfm>. Accessed 2004 September 2.
Veenstra-VanDerWeele, J. and Cook, E. Jr. (2003) Genetics of Childhood Disorders: XLVI Autism, Part 5: Genetics of Autism. Journal of the American Academy of Child and Adolescent Psychiatry. 42:1, 116-118. Available at < http://info.med.yale.edu/chldstdy/plomdevelop/genetics/03jangen.htm>
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