Unraveling Autism
A brief overview of the symptoms, treatments, and research findings.
Autism, a brain disorder that affects 1 to 2 in 1,000 Americans,1 too often results in a lifetime of impaired thinking, feeling and social functioning—our most uniquely human attributes. Autism typically affects a person's ability to communicate, form relationships with others, and respond appropriately to the external world. The disorder becomes apparent in children generally by the age of 3.2
Some people with autism can function at a relatively high level, with speech and intelligence intact. Others have serious cognitive impairments and language delays, and some never speak. In addition, individuals with autism may seem closed off and shut down, or locked into repetitive behaviors and rigid patterns of thinking. An infant with autism may avoid eye contact, seem deaf, and abruptly stop developing language. The child may act as if unaware of the coming and going of others, or physically attack and injure others without provocation. Infants with autism often remain fixated on a single item or activity, rock or flap their hands, seem insensitive to burns and bruises, and may even mutilate themselves. Although autism is about 3 to 4 times more common in boys, girls with the disorder tend to have more severe symptoms and greater cognitive impairment.2
Individuals with autism often have symptoms of various co-occurring mental disorders, including ADHD, psychoses, depressive disorders, obsessive-compulsive disorder, and other anxiety disorders.3 About one-third of children and adolescents with autism develop seizures.
Research Findings and Directions
The National Institute of Mental Health—in collaboration with the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and other Communication Disorders—is searching for answers about the causes, diagnosis, prevention, and treatment of this devastating disorder. Research findings have made it possible to identify earlier those children who show signs of developing autism and thus to initiate early intervention, which can lead to improved cognitive and behavioral outcomes.4,5
Improved early diagnosis and differentiation of various forms of autism is a goal of brain imaging studies that are building a database on normal brain development in children. Scans of the normal structural and functional maturation of the brain will be compared with those from individuals with autism, speeding development of targeted treatments and evaluations of their effects. Yet even the most advanced scanners cannot substitute for post-mortem brain tissue. Brain banks are working with families to arrange for tissue donation following the deaths of individuals with autism.
While it is known that heredity plays a major role in complex disorders like autism, the identification of specific genes that confer vulnerability to such disorders has proven extremely difficult.6 Once autism-linked genes are identified, however, scientists will bring to bear sophisticated research tools to find out what activates them, what brain components they code for, and how they affect behavior. The prospect of acquiring such molecular knowledge holds great hope for the engineering of new therapies.
Evidence suggests that unaffected family members may share with their ill relatives genes that predispose for milder behavioral characteristics that are qualitatively similar to those of autism.7 For example, some relatives of people with autism may have mild social, language, or reading problems. Family members also may share telltale neurochemical signatures that may be implicated in the disorder.8 Researchers are studying such families to characterize these behavioral and biological traits, in hopes of tracing the variations in the genetic blueprint that contribute to autism.
Treatments
The behavioral and cognitive functioning of individuals with autism can improve with the help of psychosocial and pharmacological interventions.4 Among psychosocial treatments, intensive, sustained special education programs and behavior therapy early in life can increase the ability of children with autism to acquire language and the ability to learn.4,5 NIMH-funded research teams are evaluating the effectiveness of parent-training interventions that are tailored to the particular characteristics of the child and family.
In adults with autism, some studies have found beneficial effects of the antidepressant medications clomipramine and fluoxetine.9,10 There is also evidence that the antipsychotic medication haloperidol can be helpful; however, the risk of serious side effects is significant in children.11
The increasing use of psychotropic medications to treat autism in children has spotlighted an urgent need for more studies of such drugs in youths. A network of five NIMH-supported research centers that combine expertise in psychopharmacology and psychiatry are evaluating the atypical antipsychotic risperidone for reducing aggressive self-injurious behavior in children with autism. Other NIMH research is investigating valproate for diminishing this behavior in adolescents with autism. Studies are examining dose range and regimen of medications, and their mechanisms of action, safety, efficacy, and effects on cognition, behavior, and development.
For More Information
Please visit the following links for information about organizations that focus on child and adolescent mental health and autism.
References
1 Bryson SE, Smith IM. Epidemiology of autism: prevalence, associated characteristics, and service delivery. Mental Retardation and Developmental Disabilities Research Reviews, 1998; 4: 97-103.
2 Fombonne E. Epidemiology of autism and related conditions. In: Volkmar FR, ed. Autism and Pervasive Development Disorders. Cambridge, England: Cambridge University Press, 1998; 32-63.
3 Volkmar F, Cook EH Jr, Pomeroy J, et al. Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. American Academy of Child and Adolescent Psychiatry Working Group on Quality Issues. Journal of the American Academy of Child and Adolescent Psychiatry, 1999; 38(12 Suppl): 32S-54S.
4 Bristol MM, Cohen DJ, Costello EJ, et al. State of the science in autism: report to the National Institutes Health. Journal of Autism and Developmental Disorders, 1996; 26(2): 121-54.
5 McEachin JJ, Smith T, Lovaas OI. Long-term outcome for children with autism who received early intensive behavioral treatment. American Journal of Mental Retardation, 1993; 97(4): 359-72; discussion 373-91.
6 NIMH Genetics Workgroup. Genetics and mental disorders. NIH Publication No. 98-4268. Rockville, MD: National Institute of Mental Health, 1998.
7 Piven J, Palmer P, Jacobi D, et al. Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. American Journal of Psychiatry, 1997; 154(2): 185-90.
8 Cook EH. Autism: review of neurochemical investigation. Synapse, 1990; 6(3): 292-308.
9 McDougle CJ, Naylor ST, Cohen DJ, et al. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Archives of General Psychiatry, 1996; 53(11): 1001-8.
10 Gordon CT, State RC, Nelson JE, et al. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Archives of General Psychiatry, 1993; 50(6): 441-7.
11 Campbell M, Armenteros JL, Malone RP, et al. Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study. Journal of the American Academy of Child and Adolescent Psychiatry, 1997; 36(6): 835-43.
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NIH Publication No. 01-4590
Gene Linked to Autism in Families with More Than One Affected Child
A version of a gene has been linked to autism in families that have more than one child with the disorder. Inheriting two copies of this version more than doubled a child's risk of developing an autism spectrum disorder, scientists supported by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH) National Institute on Child Health and Human Development (NICHD) have discovered. In a large sample totaling 1,231 cases, they traced the connection to a tiny variation in the part of the gene that turns it on and off. People with autism spectrum disorders were more likely than others to have inherited this version, which cuts gene expression by half, likely impairing development of parts of the brain implicated in the disorder, report Drs. Daniel Campbell, Pat Levitt, Vanderbilt Kennedy Center at Vanderbilt University, and colleagues, online during the week of the October 16, 2006 in the Proceedings of the National Academy of Sciences.
"This common gene variant likely predisposes for autism in combination with other genes and environmental factors," said Levitt. "It exerts the strongest effect detected thus far among autism candidate genes."
Autism is one of the most heritable mental disorders. If one identical twin has it, so will the other in nearly 9 out of 10 cases. If one sibling has the disorder, the other siblings run a 35-fold greater-than-normal risk of having it. Still, scientists have so far had only mixed success in identifying the genes involved.
While most previous studies had focused on genes expressed in the brain, Levitt's team saw a clue in the fact that some people with autism also have gastrointestinal, immunological or neurological symptoms in addition to behavioral impairments. They focused on a gene that affects such peripheral functions as well as the development of the cortex and cerebellum, brain areas disturbed in autism. Moreover, it is located in a suspect area of chromosome 7 that has been previously linked to autism spectrum disorders.
This MET receptor tyrosine kinase gene codes for a protein that relays signals that turn on a cell's internal machinery and is known to play a key role in both normal and abnormal development, such as cancer metastases (hence its name). Levitt's group and others had earlier found that impairing the receptor's signaling interferes with neuron migration and disrupts neuronal growth in the cortex and similarly shrinks the cerebellum — abnormalities also seen in autism.
To explore this possible connection, the researchers looked for associations between the brain disorder and nine markers in the MET gene, sites where letters in the genetic code vary among individuals. They tested two samples: the first, 204 families, including 26 with more than one child with autism spectrum disorders, the second, 539 families, including 452 with such multiple affected children.
One marker, the C version, emerged as over-transmitted at "highly significant" levels in people with autism spectrum disorders in both samples. Moreover, this association held only for families with more than one affected child and was strongest in a sub-sample of those with more narrowly-defined autism. The C version was significantly less prevalent in a group of 189 unrelated controls than in the individuals with autism or their parents.
In cell culture tests, the researchers determined that the C version is weak at making the MET receptor protein, resulting in a two-fold reduction in gene expression compared to the other common G version of the gene, with presumably adverse consequences on brain development. Inheriting two copies of the C version boosted risk for autism spectrum disorders 2.26-fold, while inheriting one copy of C and one of G increased risk 1.54-fold.
"Since autism likely involves complex interactions between many different genes and other factors, common genetic predisposing factors are likely more influential in families with multiple affected members," explained Levitt. "Some cases in families with only one affected member more likely stem from rarer genetic glitches or other sporatic events. Hence, finding the link with the MET gene variant only in the former 'multiplex' families strengthens its candidacy."
The researchers propose that in some individuals with autism spectrum disorders who also develop digestive and immune system or non-specific neurological problems, the MET gene variant might play a role in impairing both brain and peripheral organ development.
"We know that autism is the most heritable of neuropsychiatric disorders, but, thus far, we have not identified genes that consistently are associated with this developmental brain disease," said NIMH Director Thomas Insel, M.D. "This new finding is an important clue, which if replicated in an independent sample, will take us closer to understanding the genetic basis of autism."
Also participating in the study were: Daniel Campbell, James Sutcliffe, Philip Ebert, Vanderbilt University; Roberto Militerni, Carmela Bravaccio, University of Naples (Italy); Simona Trillo, Associazione Anni Verdi; Maurizio Elia, Oasi Maria SS; Cindy Schneider, Center for Autism Research and Education; Raun Melmed, Southwest Autism Research and Resource Center; Roberto Sacco, Antonio Persico, University Campus Bio-Medico and Fondazione Santa Lucia.
The research was also supported by The Autism Genetic Resource Exchange (AGRE), Cure Autism Now, the Marino Autism Research Institute, Telethon-Italy, National Alliance for Autism Research, Foundation Jerome Lejeune, and NARSAD.
The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website.
The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Web site at http://www.nichd.nih.gov/ .
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Science Update
July 26, 2006
Males with Autism Have Fewer Cells in Brain’s Emotional Memory Hub
Males with autism have fewer cells in a part of the brain that has a key role in emotion and memory, according to NIMH-funded researchers at the University of California, Davis. This study provides the first scientific evidence that it is the number of cells in the area of the brain called the amygdala that is affected by the disorder and not the density of cells or volume of tissue. Research results were published in the July 19 issue of the Journal of Neuroscience.
David Amaral, Ph.D., and Cynthia Mills Schumann of the U.C. Davis Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute used modern techniques to study the three-dimensional structure of brain areas known to show differences in autism. Comparing the postmortem brain tissue of nine males who had autism to 10 males who did not, the researchers counted and measured representative samples of cells in the amygdala. Based on their current findings, the researchers aim to determine why there are fewer cells and whether other brain areas are similarly affected in autism.
Autism is a developmental disorder that causes severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others. The disorder develops in childhood and generally is diagnosed by age three. Autism is about four times more common in boys than girls.1 Girls with the disorder, however, tend to have more severe symptoms and greater cognitive impairment.1,2
Schumann CM, Amaral DG. Stereological Analysis of Amygdala Neuron Number in Autism. Journal of Neuroscience. 19 Jul 2006; 26(29): 7674-7679.
1. Fombonne E. Epidemiology of autism and related conditions. In: Volkmar FR, ed. Autism and pervasive developmental disorders. Cambridge, England: Cambridge University Press, 1998; 32-63.
2. Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of Autism in a US Metropolitan Area. The Journal of the American Medical Association. 2003 Jan 1;289(1):49-55.
