Rattling Autism's Lock
on the Brain
words by Eve Jacobs / photograph by John Emerson
Members of UMDNJ's Oxidative Stress Translational Research Group (left to right): Bernd Spur, PhD, assistant professor, UMDNJ-School of Osteopathic Medicine (SOM); Sherie Novotny, MD, associate professor, UMDNJ-Robert Wood Johnson Medical School (RWJMS); T. Peter Stein, PhD, professor, SOM; Xue Ming, MD, associate professor, UMDNJ-New Jersey Medical School; Steve Buyske, PhD, associate research professor, Rutgers University; Edward Scot Stenroos, laboratory manager, neurogenetics laboratory, RWJMS neurology; Martha Mulvey, nurse practitioner, UMDNJ-Newark; George Lambert, MD, associate professor, RWJMS. Not pictured: William Johnson, MD, professor, RWJMS
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oving quickly is a crucial factor when a child is diagnosed with autism. Perceived until recently as a gargantuan and immovable lock on the brain, this diagnosis now raises a slew of questions, possibilities and windows for change — and maybe even prevention — that can’t be ignored. With no cure on the horizon, a new approach — not unlike the drug “cocktails” used to keep HIV/AIDS patients alive and ticking for decades — relies on combining many different therapies, including some that are very new, and is bringing additional hope for a better life to those with autism.
Tackling the Medical Issues, One by One
ertainly a major aspect of this sea change in outlook is the recognition that many children with autism have specific medical issues that seriously impact their everyday lives and abilities. While no one yet fully comprehends why these medical problems are so prevalent, oftentimes they are treatable, and when treatment is successful, can make a world of difference.
Xue Ming, MD, an associate professor of neurosciences and pediatrics, conducts research in autism and provides hands-on care for more than 600 children with this diagnosis at The Autism Center of NJ at UMDNJ-New Jersey Medical School in Newark. In her practice, she sees many children suffering from sleep problems, as well as gastrointestinal reflux, bloating, and intolerance to various foods. Autonomic dysfunction — a disorder producing increased blood pressure and heart rate, among other symptoms — is another concern and psychological issues such as anxiety, depression and rage attacks are not uncommon in these children.
“Many of these symptoms are interconnected. Aggressive behavior and lack of sleep, for instance, are often related,” Ming comments. She enrolled 32 children with autism in a sleep study — quite a challenge since spending two nights in a sleep lab is clearly not a possibility for many of them. “Some couldn’t tolerate it,” she says, so the actual number who completed the study turned out to be 23. A sleep technician and a parent were present at all times. What she confirmed was an increased rate of parasomnias (14 out of 23 with autism were affected, compared with 1 out of 23 in the healthy group), with such symptoms as night terrors, confusion on waking and bed-wetting. “We also found an increase in apnea and abnormalities in sleep structure,” she explains. “In many of these kids, the sleep disorders are exacerbated by medications.”
Sleep structure refers to the pattern of sleep stages — measured in a sleep laboratory by examining the results of such tests as the EEG, EOG and EMG — in relation to total sleep time. Transitions between sleep stages and disruptions of sleep are also noted.
Ming says sleep problems, which become family problems since parents and siblings are frequently wakened several times each night, are often treatable. Large tonsils, for instance, were the culprits in several cases of apnea, and “Tonsils are easily removed,” she says. Even when interventions don’t work, the majority of these children will eventually outgrow the sleep problems, states the physician.
Oftentimes, sleep is disrupted by gastrointestinal disorders, a very common complaint of children with autism. Constipation, diarrhea, bloating, general discomfort and pain will often make a child restless, and break up sleep, but “Dietary manipulation works,” says Ming.
High on the list of culprits for many children with autism are casein and gluten, which show up in numerous foods. Gluten is a protein found in all wheat products, as well as rye, barley, and, sometimes, oats, and is also used as an additive for flavoring, stabilizing and thickening foods. Casein is a protein found in milk. Elimination of all foods containing both proteins often improves the gastrointestinal symptoms, allowing the child — and family — uninterrupted nights and better days, says the specialist, who encourages the parents and child to follow the diet. Many gluten-free products are now generally available in markets, and even casein-free cheeses are on the shelves, she says. There are also medications that may work when the diet is not effective.
Autonomic dysfunction, which Ming has diagnosed in many of her patients, can also create sleep disturbances for the child with autism, she explains. The autonomic nervous system — divided into the sympathetic nervous system, the parasympathetic nervous system and the enteric nervous system — regulates unconscious body functions, which include heart rate, blood pressure and temperature, as well as gastrointestinal secretions and metabolic and endocrine responses to stress. “One sign of autonomic dysfunction is larger pupils — when compared to those of healthy children or siblings — which you see in many children with autism,” she explains. “The pupil takes longer to constrict in reaction to light.”
Normal sleep requires a balance between the sympathetic system (which revs-up the body) and parasympathetic system (which calms it down). “Kids with autism can’t settle down to sleep,” she says, because the two systems are not in balance.
“Rage attacks are also related to autonomic dysfunction,” she continues. “You need the parasympathetic system to control rage. In many cases, very caring parents are suddenly attacked, seemingly out of nowhere.” These instantaneous rages are associated with a parasympathetic system that is not functioning as it should. Ming has published data concerning 45 children in her practice with this impairment.
Autonomic nervous system problems are also treatable, she explains, by dampening down the sympathetic, and enhancing the parasympathetic, systems. Clonidine, a blood pressure medicine that has also been used for aggressive behavior in ADHD, seems to work well, although this has not yet been proven in clinical trials. It acts on the sympathetic nervous system and works best when administered by patch in a sustained-release form. “Unfortunately, most of these kids are irritated by the patch and peel it off,” she says. A clonidine sustained release pill is under development.
“Autism is not a single disease and we are yet to find the pathogenesis that explains the diverse clinical presentations of the disorder,” Ming says. “We know these children have larger brains and there is more white matter, but we don’t really understand what that means. We’ll put this puzzle together eventually.”
But in the meantime, there’s a lot that can be done for the child with autism. “We are trying to deal with each symptom, eliminating or improving as many as we can; and remarkably, some children in my practice have lost their ‘label’ of autism when the medical treatments take effect,” she says.
The Little Molecule that Could – One Giant Step for Autism?
Inflammation — a result of oxidative stress — is credited with an enormous amount of misery in our bodies, and when it’s in high gear is a devil-of-an-enemy to get under control. It has been linked to the joint destruction of arthritis, the arterial constriction of heart attack, the breathless suffocation of asthma, the chronic digestive symptoms of inflammatory bowel disease, and the slow drainage of memory called Alzheimer’s. None of that is headline-worthy.
What is still news — but already has solid footing in the research world in large part due to the work of Ming and other UMDNJ autism researchers — is the contention that oxidative stress leading to chronic inflammation may be causing havoc in the brains of children with autism. And the beauty behind that ugly vision is that a potent remedy to counteract this destructive process may not be far away.
In short, oxygen radicals are formed as a byproduct of normal metabolism; and a healthy body is capable of coping with them. These unstable molecules are highly destructive when they are produced in higher numbers than the body can deal with. The theory — based on a fair amount of research — is that autistic children may be doing battle with the challenge of out-of-control oxidative stress due to an impaired antioxidant defense system. A build-up of free oxygen radicals — producing what is called oxidative stress — sets cellular actions and reactions in motion that can impair the cells’ ability to function normally, potentially causing tissue inflammation, premature cell aging and autoimmunity. Oxidative stress seems to strike neurons more quickly and dramatically than other cells, mucking up their communication systems; and infants are likely candidates because their detoxification systems are not fully up and running yet.
Two other factors add fuel to the fire. One is the fact that modern life places a heavy antioxidant burden on a baby’s system with such well-known toxins as phthalates, a family of compounds used to make plastics soft and flexible, as well as lead, mercury, and other heavy metals in high concentrations in our environment. The other is that genes come into play, determining how quickly and effectively the body can react to oxidative stress by producing antioxidants. Glutathione — one of the body’s chief antioxidant/detox molecules, which is relevant for detoxification of metals — has been shown to be reduced in quantity in those with autism. It has also been determined that when there are variations in certain glutathione-related genes, the capacity of the body to counteract oxidative stress may be impaired.
A group of UMDNJ scientists — whose expertise covers biochemistry, neurogenetics, pediatric toxicology, pharmacology, pediatric neurology, nutrition, synthetic chemistry and hands-on autism care — has been steadily making progress in this area for several years. They meet every Thursday afternoon to pool their collective knowledge and push their work in developing an autism therapy, or therapies, to the next step. The team members believe they’re on to a treatment that could make autism manageable in the same way as diabetes — by providing the body with what it is not able to produce enough of. Certain fatty acids — that counteract the production of excessive free oxygen radicals and may be in low supply in those with autism — are the key here. The premise is simple, but brilliant.
Ming, a participant in the group, and T. Peter Stein, PhD, a professor in the Department of Surgery at UMDNJ-School of Osteopathic Medicine (SOM) in Stratford, and also a member, found that children with autism secrete significantly more isoprostane, a biomarker of oxidative stress, in their urine than other children. “There was an average four-fold increase in urinary isoprostane levels in 33 children with autism as compared with 29 age-matched healthy control children,” explains Ming. The researchers are currently conducting a test to see if low doses (200 milligrams, once a day) of Docosahexaenoic acid (more commonly known as DHA), a well-recognized lipid antioxidant, will counteract oxidative stress in children diagnosed with autism. This brand of DHA omega-3 is derived from an all-natural, vegetarian source, which does not have the ocean-borne pollutants and toxins found in certain fish. Ming is recruiting patients for the clinical trial from the autism center at NJMS and from her own practice, and providing before and after urine samples to Stein, who does blind testing of the samples, looking for changes in biomarkers (biochemical substances that can be measured). Forty children, ages 3 to 19, are currently enrolled in the 12-week trial; their goal is 60 participants, which the team hopes to achieve within the next few months.
“This is a pilot study to look at laboratory outcomes,” explains Ming. Although the data is not yet available, she says that parents of children in the study (who are not blinded) have been calling to discuss their observations. Five parents have reported definite positive changes in their autistic children, says the physician; and some are not sure. “One parent from overseas has been particularly happy,” she continues. Ming explains that if the researchers see biochemical changes in those taking DHA, then the trial will be expanded to include more children and the dosage of DHA may be altered , which may provide better results for some.
Martha Mulvey, a nurse practitioner in the neurology service at UMDNJ in Newark, assists Ming in identifying potential subjects, obtaining informed consent, and carrying out the methodology of the study. She says that many parents of autistic children are well informed about the current research endeavors in autism and are excited about having their children participate in clinical studies. She reports that early positive outcomes in several children include clearer pronunciation of words, increased attention, achieving toilet training, and improved interaction with others. Mulvey also provides education to parents about the study procedures and the possible side effects of DHA, and monitors the process with continuous communication before, during and after collection of data.
“Other researchers have published results of similar studies —using fish oil—that have looked for improved behavior in children with autism,” Ming says. One such NIH-funded study is currently being conducted at UMDNJ-Robert Wood Johnson Medical School (RWJMS) by child psychiatrist Sherie Novotny, MD, who is also a member of the group. “We are doing the complementary studies using fish oil — looking for biochemical changes,” she says. “By examining the data from both studies, including their different dosing regimens, we will learn more than from either study alone.”
Photograph: Veer
DHA may, or may not, be an effective antioxidant for children with autism. That remains to be seen. However, the human body — when it is functioning normally — produces an adequate amount of its own “good fatty acids” from DHA and other omega-3s. If, in fact, runaway oxidative stress is a major component of autism, then an effective antidote to this chronic inflammation may be providing one (or more) of these endogenous good fatty acids to children whose bodies do not produce enough. That is the premise that the UMDNJ research team is working with, and they feel certain that they are tantalizingly near to being able to provide such a molecule, or combination of molecules, in pill form. The group’s work is being supported by patent protection from the UMDNJ Office of Patents & Licensing and funding from the National Institutes of Health, the U.S Environmental Protection Agency, and NJ state and private agencies.
“The human body tries to shut down prolonged inflammation, but may get overwhelmed when it can’t generate a sufficient amount of the molecules needed to counteract oxidative stress,” explains Bernd Spur, PhD, assistant professor of cell biology at SOM, who has studied the chemistry of fats and lipids for 30 years and has had a longtime interest in inflammation.
“Normally, the body is equipped to control inflammation, but sometimes it can’t, probably because the proteins that are coded for by these genes, which take these compounds and detoxify them, have altered function,” explains George Lambert, MD, the group’s leader and the director of the EPA-funded Center for Childhood Neurotoxicology and Exposure Assessment from which this new group was formed. Lambert is an associate professor of pediatrics at RWJMS, whose specialization in pediatric toxicology and pharmacology made him a natural to lead the National Institutes of Health and Environmental Protection Agency/US EPA supported research into potential environmental causes of autism.
“We didn’t find a cause in the environment,” he says. “But the group’s recent research has clearly shown that oxidative stress metabolites are markedly increased in the urine of children with autism and there appears to be increased genetic susceptibility to oxidative stress, including oxidative stress from exposure to environmental chemicals. So that’s what we’re working on now.”
When the body gets injured, it uses certain endogenous “helpful molecules” to turn off the inflammation at the right time, explains Spur. For instance, if you get a cut on your finger, the cut will close, and then begin itching. The itching indicates the body is undergoing a process that produces healing, he says. But if the body’s balance is thrown off, its reaction to an injury could go on and on, and the reaction itself becomes injurious.
The researchers say that the bodies of children with autism may be unable to turn off the inflammatory process because they cannot metabolize key fatty acids that serve as antioxidants; and that this chronic inflammation damages the brain, as well as other organs and systems.
What they are focusing on is the chemical synthesis of a “healing molecule” that is efficient and cheap to produce. Because it’s a “natural” product, it should speed through the process required for FDA approval. Of course, “We must first show no harm,” states Lambert.
He explains that many chronic diseases of mankind are illnesses of chronic runaway oxidative stress and inflammation. When the researchers move into the testing phase of their anti-oxidative stress molecules, they can assess their effect on one of the inflammatory diseases using standard and new biomarkers of stress, making it possible for them to observe a quick response, and allowing for a shorter trial, faster answers and a more cost effective process.
One of the biggest challenges ahead, according to Lambert, is trying to understand why some people respond to such treatment and others don’t. “It’s in the genes,” says William Johnson, MD, professor of neurology, a neurogenetics researcher at RWJMS and a member of the team who identified two Parkinson’s genes, one of them the first Parkinson’s disease gene ever to be discovered.
“Our group has identified three antioxidant polymorphic genetic variants associated with autism — two of them have been published,” Johnson says. The altered genes may be less able to combat oxidative stress.
The team has pinpointed one gene called GSTM1, which is missing in a higher number of autism cases than controls and may be integral to the process of shutting off runaway inflammation. A variant of another gene, GSTP1, appears to act in mothers during pregnancy to contribute to autism in their offspring.
“There appears to be a gene/environmental interaction going on, and there are multiple genes involved,” Johnson explains. “The metabolism of these molecules and the control of the pathways are very complex. In addition, this pathway interacts with other pathways that are specific for the autism phenotype. There are many genetic risk factors for autism and different combinations of these variations in related pathways will be found in different patients. In each patient, the specific genes that interfere with a specific pathway can be different.
“What this means in simpler terms is that when the pathways are disturbed, the developing brain can become more sensitive to everyday components of our surroundings,” he states. “Whether or not a specific individual responds to a particular therapy may depend upon which genetic variant or variants the individual possesses. Testing for these gene variants could help select patients for treatment with a specific therapy.”
Lambert explains that when the molecules that Spur is synthesizing are approved for use, patients could conceivably check their urine for biomarkers of oxidative stress in the morning with a dipstick, and take one, or a combination, of the lipid molecules on an as-needed basis. “If someone’s oxidative stress level is high on Monday morning,” Lambert says, “he could take a pill tailored to his particular needs. If it’s low the next day, he would not need to take the pill.”
The group has submitted an application for testing to the NIH through their “Rapid Assessment of Innovative Drugs” program, which may mean a turn-around time of three to four months for an OK to start testing it, rather than the usual year or more. In one year, Lambert hopes the first of the molecules synthesized by Spur will be approved for one or two types of diseases.
“The first trial should show short term improvement for patients,” Lambert says. The therapy can then be made available.
“In this case, the toxicity will be close to zero. Mother Nature knows all about this,” he continues. It’s actually a nutraceutical — an alternative therapy. The beauty of this medicine is that, in the future, people can take it themselves and they can monitor themselves.
“Clearly, the research into autism is not only opening windows into autism, but also into many other disease states related to inflammation.”