Autism

DeLong presents a new hypothesis that about two-thirds of children with the most common form of infantile autism actually have a treatable, genetically linked, early-onset form of severe depression. The argument is based on recent genetic analyses, behavioral studies and brain chemistry and imaging analyses on autistic children by researchers at Duke and several other institutions. The research was funded by the Charles and Sara Goldberg Charitable Trust and the Duke Children's Telethon. "Several lines of evidence are now coming together to form a cohesive picture of the biological basis of a disease that has long baffled the medical community," said DeLong. "Genetic and brain imaging studies, as well as a re-examination of the classical symptoms of autism, all point to the conclusion that many autistic children have an inherited disease that we know how to treat." Children with autism appear to be prisoners of their own minds because they are unable to learn the language or social skills necessary to get along in the world. Autism is actually a spectrum of disorders with similar symptoms, said DeLong. Children who develop autism, usually in the second year of life, lose the ability to interact with people or their environment and don't speak or use language, even though many have normal intelligence. While some autism is caused by diseases or injury to certain areas of the developing brain, most cases of autism have no known cause, and of these so-called idiopathic cases, DeLong asserts that 70 percent now appear to be an inherited form of an affective disorder, such as manic depression or obsessive-compulsive disorder. "Many years ago I noticed that if you look carefully at the symptoms of autism, they look very much like those of depression and manic depression," said DeLong. "These children show none of the cheerfulness or spontaneity of normal children. And they often have extreme moods swings, tantrums and excessive fearfulness." DeLong has identified several lines of evidence that together show a distinct subgroup of autistic children who have a genetic disease that can be treated with anti-depressive medications. When researchers examine the brains of children with idiopathic autism, they find very low levels of the neurotransmitter serotonin on the left side of the brain in the area responsible for language. Serotonin is also important in influencing mood and is low in people with clinical depression. "In the developing brains of children, serotonin not only acts as a transmitter of information, but it is also an agent of development that influences growth in the brain," said DeLong.
"When serotonin levels in the left hemisphere of the brain don't reach a critical level in early childhood, one might expect to see the symptoms we see in autism: blunting of the child's cognitive, social and emotional development." Studies of people in which the connection between the left and right hemispheres of the brain are split surgically to relieve symptoms of epilepsy, so-called "split brain" experiments, show the left hemisphere is responsible for language and reasoning skills, while the right hemisphere is responsible for visual-spatial skills, musical ability and some types of rote memorization. Serotonin levels in the right hemisphere of most idiopathic autistic children are normal and their visual and spatial skills are also normal. In fact, some autistic savants show a type of overcompensation on the right side of the brain that gives them extraordinary abilities in math computation, music or artistic skills.
When the researchers studied older children and adolescents diagnosed with manic depression, they found these children also have greater visual-spatial abilities and lower language skills, although the differences were not as great as in autistic children. All these lines of evidence led DeLong to try treating autistic children with Prozac and other specific serotonin re-uptake inhibitors (SSRIs). These medications, well known for treating depression, work by making more serotonin available to the brain. In a study reported in the October 1998 issue of the Journal of Developmental Medicine and Child Neurology, DeLong and his colleagues showed that when 37 autistic children ages three to seven were treated with Prozac (fluoxetine) for up to three years, 22 responded well to the medication, regaining language abilities, becoming more sociable and losing obsessive compulsions such as fixating on a single object for hours on end. Of those children who responded to the medication, all had a family history of a major depressive disease, such as bipolar disorder.
"It is tempting to say that autism and manic depression are caused by a defect in the same gene," said DeLong, "and genetic evidence is beginning to point in that direction." Recent studies by DeLong and his colleagues at Duke point to a gene somewhere on chromosome 15 as a potential autism gene. And now several studies by investigators at other institutions studying manic depression have narrowed down their search to the same general area on chromosome 15 as well. "While we can't yet definitively say that the genes are one and the same, the evidence is tantalizing, and we expect to have answers in the near future," said DeLong.
Such genetic studies offer hope of an earlier diagnosis, said DeLong, and the development of more specific medications to increase the availability of serotonin in the developing brains of autistic children offers the hope of even more effective treatment for the disease. "Instead of seeing autism as a disease we can't do anything about, we now see it as treatable, rather than hopeless," said DeLong. "My hope is that these new lines of research will lead to earlier identification and earlier intervention to make autism a highly treatable disease."
(March 23,1999 issue of the Journal Neurology)