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Research Notes: AutismMol Psychiatry. 2007 Sep 25. Evidence both from animal and human studies suggests that common polymorphisms in the oxytocin receptor (OXTR) gene are likely candidates to confer risk for autism spectrum disorders (ASD). In lower mammals, oxytocin is important in a wide range of social behaviors, and recent human studies have shown that administration of oxytocin modulates behavior in both clinical and non-clinical groups. Additionally, two linkage studies and two recent association investigations also underscore a possible role for the OXTR gene in predisposing to ASD. We undertook a comprehensive study of all 18 tagged SNPs across the entire OXTR gene region identified using HapMap data and the Haploview algorithm. Altogether 152 subjects diagnosed with ASDs (that is, DSM IV autistic disorder or pervasive developmental disorder-NOS) from 133 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED set of programs. Significant association with single SNPs and haplotypes (global P-values <0.05, following permutation test adjustment) were observed with ASD. Association was also observed with IQ and the Vineland Adaptive Behavior Scales (VABS). In particular, a five-locus haplotype block (rs237897-rs13316193-rs237889-rs2254298-rs2268494) was significantly associated with ASD (nominal global P=0.000019; adjusted global P=0.009) and a single haplotype (carried by 7% of the population) within that block showed highly significant association (P=0.00005). This is the third association study, in a third ethnic group, showing that SNPs and haplotypes in the OXTR gene confer risk for ASD. The current investigation also shows association with IQ and total VABS scores (as well as the communication, daily living skills and socialization subdomains), suggesting that this gene shapes both cognition and daily living skills that may cross diagnostic boundaries. Eur Child Adolesc Psychiatry. 2007 Sep 14. Despite longstanding clinical experience of unusual feeding difficulties in children with autism, there is no published literature describing their association with early onset FTT. This paper examines literature that may link feeding problems and abnormal growth with developmental and psychiatric conditions and describes seven cases of children with autism, who showed growth failure caused by severe feeding problems starting in the first year of life. Inadequacies in existing classifications systems are highlighted. The presence of severe or atypical feeding problems and FTT in infancy should alert professionals to possible underlying ASD. The aetiology of feeding disorders in autism appears to involve an unusually complex interactional model with biological vulnerabilities due to dysfunction in sensory, cognitive and emotional response interacting with dysfunctional attachment and learnt behaviours to produce a severe and intractable problem. Effective treatment therefore requires a novel multifaceted approach that can address each of these areas. Eur Child Adolesc Psychiatry. 2007 Sep 14. Autism is a hereditary, pervasive neurodevelopmental disorder that starts early in life. The main characteristics of the autism are impairment in social interactions, difficulties in adapting to novel environmental situations and improper reaction to stress. Since the Hypothalamic-Pituitary-Adrenocortical (HPA) axis plays a key role in the response to stress and because the previous research found abnormalities in HPA system, we conducted a study to test several elements of the HPA axis. Because autism is a heritable disorder, autistic subjects were studied as well as their parents. Cortisol circadian rhythm, cortisol daily secretion and its suppression response to dexamethason had been measured from saliva or urine samples of the autistic children and their parents. Cortisol secretion response after ACTH stimulation was done with the autistic children only. The cortisol elevation after ACTH stimulation among the autistic individuals was slower (P = 0.017) than in healthy controls. No differences were found in salivary cortisol circadian rhythm or suppression response, as well as in cortisol daily excretion. These data indicate that, compared to healthy subjects, autistic individuals have fine differences in cortisol response to ACTH stimulation or possibly to other types of stress. J Neurol Sci. 2007 Jul 23. The incidence and prevalence of autism have increased during the past two decades. Despite comprehensive genetic studies the cause of autism remains unknown. This review emphasizes the potential importance of environmental factors in its causation. Alterations of cortical neuronal migration and cerebellar Purkinje cells have been observed in autism. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8-12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus-pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. The current surge of autism could be related to transient maternal hypothyroxinemia resulting from dietary and/or environmental exposure to antithyroid agents. Additional multidisciplinary epidemiological studies will be required to confirm this environmental hypothesis of autism. Clin Endocrinol (Oxf). 2007 Jun 4. Objective. Children with autism are known to have larger head circumferences; whether they are above average in height and weight is less clear. Moreover, little is known about growth-related hormone levels in children with autism. We investigated whether children with autism were taller and heavier, and whether they had higher levels of growth-related hormones than control children did. Design. A case-control study design was employed. Patients. Boys with autism spectrum disorder (ASD) or autism (n = 71) and age-matched control boys (n = 59) were evaluated at Cincinnati Children's Hospital. Measurements. Height, weight and head circumference were measured. Blood samples were assayed for IGF-1 and 2, IGFBP-3, growth hormone binding protein (GHBP) and for dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS). Results. Subjects with autism/ASD had significantly (P = 0.03) greater head circumferences (mean z-score 1.24, SD 1.35) than controls (mean z-score 0.78, SD 0.93). Subjects with autism also had significantly (P = 0.01) greater weights (mean z-score 0.91, SD 1.13) than controls (mean z-score 0.41, SD 1.11). Height did not differ significantly between groups (P = 0.65); subjects with autism/ASD had significantly (P = 0.003) higher body mass indices (BMI) (mean z-score 0.85, SD 1.19) than controls (mean z-score 0.24, SD 1.17). Levels of IGF-1, IGF-2, IGFBP-3 and GHBP in the group with autism/ASD were all significantly higher (all P </= 0.0001) than in controls. Conclusions. Children with autism/ASD had significantly higher levels of many growth-related hormones: IGF-1, IGF-2, IGFBP-3 and GHBP. These findings could help explain the significantly larger head circumferences and higher weights and BMIs seen in these subjects. Future studies should examine the potential role of growth-related hormones in the pathophysiology of autism. J Neurovirol. 2007 Jun. The role that virus infections play in autism is not known. Others have reported that antibodies against measles virus are higher in the sera/plasma of children with autism versus controls. The authors investigated antibody titers to measles, mumps, and rubella viruses and diphtheria toxoid in children with autism, both classic onset (33) and regressive onset (26) forms, controls (25, healthy age- and gender-matched) and individuals with Tourette's syndrome (24) via enzyme-linked immunosorbent assays. No significant differences in antibody titers to measles, mumps, and rubella viruses and diphtheria toxoid were found among the four groups. Additionally, there were no significant differences between the four groups for total immunoglobulin (Ig)G or IgM. Interestingly, the authors did find a significant number (15/59) of autism subjects (classic and regressive onset combined) who had a very low or no antibody titer against rubella virus, compared to a combine control/Tourette's group (2/49). Brain Res. 2007 May 21. Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 age-matched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD. J Toxicol Environ Health A. 2007 May 15. Impairments in social relatedness and communication, repetitive behaviors, and stereotypic abnormal movement patterns characterize autism spectrum disorders (ASDs). It is clear that while genetic factors are important to the pathogenesis of ASDs, mercury exposure can induce immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with ASDs. The Institutional Review Board of the Institute for Chronic Illnesses (Office for Human Research Protections, U.S. Department of Health and Human Services, IRB number IRB00005375) approved the present study. A case series of nine patients who presented to the Genetic Centers of America for a genetic/developmental evaluation are discussed. Eight of nine patients (one patient was found to have an ASD due to Rett's syndrome) (a) had regressive ASDs; (b) had elevated levels of androgens; (c) excreted significant amounts of mercury post chelation challenge; (d) had biochemical evidence of decreased function in their glutathione pathways; (e) had no known significant mercury exposure except from Thimerosal-containing vaccines/Rho(D)-immune globulin preparations; and (f) had alternate causes for their regressive ASDs ruled out. There was a significant dose-response relationship between the severity of the regressive ASDs observed and the total mercury dose children received from Thimerosal-containing vaccines/Rho (D)-immune globulin preparations. Based upon differential diagnoses, 8 of 9 patients examined were exposed to significant mercury from Thimerosal-containing biologic/vaccine preparations during their fetal/infant developmental periods, and subsequently, between 12 and 24 mo of age, these previously normally developing children suffered mercury toxic encephalopathies that manifested with clinical symptoms consistent with regressive ASDs. Evidence for mercury intoxication should be considered in the differential diagnosis as contributing to some regressive ASDs. Brain Dev. 2007 Apr 27. Autism spectrum disorders (ASD) are manifest as impairments in social interaction, language and speech development, and the appearance of repetitive behaviors with restricted interests. Motor impairments in individuals with ASD have been categorized as "associated symptoms". The objective of this study was to describe the prevalence of motor deficits in ASD. Specifically, using retrospective clinical record review, we report the prevalence of hypotonia, motor apraxia, reduced ankle mobility, history of gross motor delay, and toe-walking, as well as the improvement of these symptoms with age, in a cohort of 154 children with ASD. The possible association of motor deficits with epilepsy or developmental regression was also assessed. To address whether the motor deficits in children with ASD were properly identified and treated, we evaluated whether the children with the motor deficits were more likely to receive physical and/or occupational therapies as compared to the children with ASD who did not show motor deficits. Hypotonia was the most common motor symptom in our ASD cohort (51%) and this appeared to improve over time, as suggested by the significant reduction in prevalence in older children (p=0.002). Likewise, motor apraxia (34%) showed a tendency to be more prevalent among younger children as compared with older children (p=0.06). Historical intermittent toe-walking was found in 19% of children while reduced ankle mobility was a rare occurrence. Gross motor delay was reported in 9% of children, all of whom gained motor independence by the time of examination. Except for gross motor delay, ASD children with fine motor deficits were not more likely to receive interventional services, as compared with ASD children without the motor deficits. The results suggest that fine motor control and programming deficits are common co-occurrence of children with ASD in this cohort. The reduced prevalence of these motor deficits in older children suggests improvement over time, whether through natural progression, results of interventional therapy, or the combination of the two. However, ASD children with the motor deficits were not more likely to receive service than those without the motor deficits. (04/25/2007 - Los Angeles Time) PCBs cause autism-like condition in newborn rats Traces of a chemical banned 30 years ago cause brain abnormalities in newborn lab animals that are similar to defects in children with autism, according to a new study by University of California scientists. Many scientists say that an array of chemicals in the environment are scrambling brain development and could play a role in children's learning disorders. The new study adds to the evidence by showing that PCBs, polychlorinated biphenyls, disrupt the auditory cortex, a part of the brain that is impaired in autistic children. In the research at UC San Francisco, rats exposed to low levels of PCBs in the womb and during nursing had disorganized, malfunctioning auditory centers. The auditory cortex controls the brain's processing of sounds, which is essential for language development. "This is a red flag," said neuroscientist Michael M. Merzenich of UCSF's W.M. Keck Foundation Center for Integrative Neuroscience, the study's senior author. "The impact of this class of chemicals must be studied in human populations, and fast." The new research shows brain development is skewed when animals are exposed to amounts of PCBs in the same range as some highly exposed people. It will be published in this week's online Proceedings of the National Academy of Sciences. "This study indicates that there are chemicals out there, this being just one example, that could profoundly affect development," said Tal Kenet, who led the research team in Merzenich's lab while a postdoctoral fellow there. He is now a faculty member at Harvard Medical School. Last year, two internationally known environmental scientists reported in a medical journal that industrial chemicals may be causing a "silent pandemic" of learning disorders. Dr. Philippe Grandjean of Harvard School of Public Health and Dr. Philip J. Landrigan of Mount Sinai School of Medicine identified 202 chemicals — including PCBs and mercury — that could be contributing to autism, attention deficit disorders and other neurological disorders, and they urged more human studies. PCBs were one of the world's most widely used chemicals, their use peaking in the 1970s, mostly as insulating fluids in large electrical equipment. Although banned in the United States in 1977, they are still among the most pervasive contaminants on the planet, and exposure is difficult to avoid because they have spread globally and built up in food chains. Concentrations are highest in people who frequently eat fish from waters contaminated by industrial discharge, including the Hudson River, the Great Lakes and San Francisco Bay. Many scientists say there is substantial human evidence that PCBs are among five industrial chemicals that harm children's brains. Researchers in the 1990s reported that children in the Great Lakes region exposed to high levels of PCBs during their mothers' pregnancy had impaired cognitive development that led to reduced motor skills and short-term memory. In the new study, "we linked PCBs to an area of the brain that impacts one aspect of autism, language delays or language loss," said co-author Isaac N. Pessah, an autism researcher at the UC Davis M.I.N.D. Institute and director of the university's Center for Children's Environmental Health and Disease Prevention. "We don't see any reason why the PCBs in human tissues wouldn't be causing this mis-wiring of the auditory cortex too. Not necessarily in every child. We suggest that because of the mechanism involved, there may be populations of kids with predisposition to sensitivity," he said. The scientists compared the auditory cortex and nerve signals of unexposed rat pups to pups exposed to one type of PCB during gestation and nursing. One of the most profound disruptions from the PCBs involved abnormalities in signals sent by the brain to inhibit or trigger reactions to sounds. The brain also had diminished capacity to learn and change how it responds to sounds. Scientists believe that autistic children have such signaling imbalances. They respond differently to sound and other sensations, and their communication and language skills are impaired. "The animals could hear, but their brain's representations of what they heard was grossly disturbed," Merzenich said. Kenet urged human studies to see if babies breast fed by highly exposed mothers experience similar effects, particularly those with a family history of developmental disorders. They are unsure if damage to the rats occurred prenatally or during nursing. Researchers generally have found that benefits of breastfeeding outweigh risks. The Centers for Disease Control and Prevention reported in February that one in every 150 8-year-old children in 14 states had autism or related syndromes. Brain Cogn. 2007 Apr 21. Imitation ability has consistently been shown to be impaired in individuals with autism. A dysfunctional execution/observation matching system has been proposed to account for this impairment. The EEG mu rhythm is believed to reflect an underlying execution/observation matching system. This study investigated evidence of differential mu rhythm attenuation during the observation, execution, and imitation of movements and examined its relation to behaviorally assessed imitation abilities. Fourteen high-functioning adults with autism spectrum disorder (ASD) and 15 IQ- and age-matched typical adults participated. On the behavioral imitation task, adults with ASD demonstrated significantly poorer performance compared to typical adults in all domains of imitation ability. On the EEG task, both groups demonstrated significant attenuation of the mu rhythm when executing an action. However, when observing movement, the individuals with ASD showed significantly reduced attenuation of the mu wave. Behaviorally assessed imitation skills were correlated with degree of mu wave attenuation during observation of movement. These findings suggest that there is execution/observation matching system dysfunction in individuals with autism and that this matching system is related to degree of impairment in imitation abilities. Arch Pediatr Adolesc Med. 2007 Apr. OBJECTIVE: To assess the sensitivity and specificity of decreased response to name at age 12 months as a screen for autism spectrum disorders (ASD) and other developmental delays. DESIGN: Prospective, longitudinal design studying infants at risk for ASD. SETTING: Research laboratory at university medical center. PARTICIPANTS: Infants at risk for autism (55 six-month-olds, 101 twelve-month-olds) and a control group at no known risk (43 six-month-olds, 46 twelve-month-olds). To date, 46 at-risk infants and 25 control infants have been followed up to 24 months. Intervention Experimental task eliciting response-to-name behavior. MAIN OUTCOME MEASURES: Autism Diagnostic Observation Schedule, Mullen Scales of Early Learning. RESULTS: At age 6 months, there was a nonsignificant trend for control infants to require a fewer number of calls to respond to name than infants at risk for autism. At age 12 months, 100% of infants in the control group "passed," responding on the first or second name call, while 86% in the at-risk group did. Three fourths of children who failed the task were identified with developmental problems at age 24 months. Specificity of failing to respond to name was 0.89 for ASD and 0.94 for any developmental delay. Sensitivity was 0.50 for ASD and 0.39 for any developmental delay. CONCLUSIONS: Failure to respond to name by age 12 months is highly suggestive of developmental abnormality but does not identify all children at risk for developmental problems. Lack of responding to name is not universal among infants later diagnosed with ASD and/or other developmental delays. Poor response to name may be a trait of the broader autism phenotype in infancy. (03/22/2007) Discover: Autism: It's Not Just in the Head. "There were days I considered shutting the garage door and letting the car run until I was dead," says Colorado mom Erin Griffin, of the time nine years ago when she learned that both her boys - not just her firstborn - suffered from autism. Brendan, her angular, dark-haired older child, was diagnosed in 1996 at age 4. Kyle, her round-faced, hazel-eyed younger son, was diagnosed in 1998 at age 2˝. But Kyle and Brendan's story does not have a tragic ending. After interventions that included occupational and speech therapy, as well as dietary change and nutritional supplements, both boys improved significantly. Their tale of slow, steady recovery reflects the changing landscape of autism today. The condition, traditionally seen as genetic and originating in the brain, is starting to be viewed in a broader and very different light, as a possible immune and neuroinflammatory disorder. As a result, autism is beginning to look like a condition that can, in some and perhaps many cases, be successfully treated. That is astonishing news about a disorder that usually makes headlines because it seems to be growing rapidly more widespread. In the United States, the diagnosis of autism spectrum disorders has increased about tenfold over the past two decades, and a 2003 report by the Centers for Disease Control suggests that as many as one in every 166 children is now on the autism spectrum, while another one in six suffers from a neurodevelopmental delay. This explosion of cases has raised countless questions: Is the increase real, is it the result of increased awareness and expanding diagnostic categories, is it due to environmental changes, or all of the above? There may be no single answer. But the public concern about autism has caught the ear of federal lawmakers. The Combating Autism Act, approved last December, authorized nearly $1 billion over the next four years for autism-related research and intervention. Meanwhile, on the sidelines of that confusing discussion, a disparate group - immunologists, naturopaths, neuroscientists, and toxicologists - is turning up clues that are yielding novel strategies to help autistic patients. New studies are examining contributing factors ranging from vaccine reactions to atypical growth in the placenta, abnormal tissue in the gut, inflamed tissue in the brain, food allergies, and disturbed brain wave synchrony. Some clinicians are using genetic test results to recommend unconventional nutritional therapies, and others employ drugs to fight viruses and quell inflammation. Above all, there is a new emphasis on the interaction between vulnerable genes and environmental triggers, along with a growing sense that low-dose, multiple toxic and infectious exposures may be a major contributing factor to autism and its related disorders. A vivid analogy is that genes load the gun, but environment pulls the trigger. "Like cancer, autism is a very complex disease," says Craig Newschaffer, chairman of Epidemiology and Biostatistics at the Drexel University School of Public Health, "and it's exciting to start asking questions about the interaction between genes and environment. There's really a very rich array of potential exposure variables." In one way, the field seems like a free-for-all, staggeringly disordered because it is littered with so many possibilities. But one can distill a few revolutionary insights. First, autism may not be rigidly determined but instead may be related to common gene variants, called polymorphisms, that may be derailed by environmental triggers. Second, affected genes may disturb fundamental pathways in the body and lead to chronic inflammation across the brain, immune system, and digestive system. Third, inflammation is treatable. "In spite of so many years of assumptions that a brain disorder like this is not treatable, we're helping kids get better. So it can't just be genetic, prenatal, hardwired, and hopeless," says Harvard pediatric neurologist Martha Herbert, author of a 14,000-word paper in the journal Clinical Neuropsychiatry that reconceptualizes the universe of autism, pulling the brain down from its privileged perch as an organ isolated from the rest of the body. Herbert is well suited to this task, a synthetic thinker who wrote her dissertation on the developmental psychologist Jean Piaget and who then went to medical school late, in her early thirties. "I no longer see autism as a disorder of the brain but as a disorder that affects the brain," Herbert says. "It also affects the immune system and the gut. One very striking piece of evidence many of us have noticed is that when autistic children go in for certain diagnostic tests and are told not to eat or drink anything ahead of time, parents often report their child's symptoms improve - until they start eating again after the procedure. If symptoms can improve in such a short time frame simply by avoiding exposure to foods, then we're looking at some kind of chemically driven 'software' - perhaps immune system signals - that can change fast. This means that at least some of autism probably comes from a kind of metabolic encephalopathy - a systemwide process that affects the brain, just like cirrhosis of the liver affects the brain." In 1943 Johns Hopkins University psychiatrist Leo Kanner first described autism as a now-famous collection of symptoms: poor social engagement, limited verbal and nonverbal communication, and repetitive behaviors. Back then, autism was considered rare; Kanner first reported on just 11 patients, and Johns Hopkins still has records of about 150 patients he examined in total. Even within this small group of patients, other, less visible symptoms were evident. In his 1943 paper, "Autistic Disturbances of Affective Contact," Kanner noted immune and digestive problems but did not include them in the diagnosis. One reads with a shiver sentences lifted out of various case histories: "large and ragged tonsils . . . she was tube-fed five times daily . . . he vomited all food from birth through the third month . . . he suffered from repeated colds and otitis media. . . ." Herbert believes that the clues linking the obvious behavioral symptoms to more basic, but less obvious, biological dysfunction were missed early on. "What I believe is happening is that genes and environment interact, either in a fetus or young child, changing cellular function all over the body, which then affects tissue and metabolism in many vulnerable organs. And it's the interaction of this collection of troubles that leads to altered sensory processing and impaired coordination in the brain. A brain with these kinds of problems produces the abnormal behaviors that we call autism." Herbert's full-body perspective helps make sense of the confusion surrounding the diagnosis of autism and helps justify the increasingly common use of the plural "autisms" to describe the wide variations in this disorder. As Newschaffer points out, "Children with Asperger's syndrome certainly share a lot of the behaviors of those with more severe autism. But is it the same disease, and is it caused by the same thing? A number of significant features of autism are not part of the diagnostic schema right now, but eventually, those features may end up distinguishing one causal pathway from another. How is a child sleeping? Does he or she have gastrointestinal symptoms? By looking at those things we may see risk-factor associations pop out that we've never seen before." Herbert likens autism to a hologram: "Everything that fascinates me is in it. It's got epidemiology, toxicology, philosophy of science, biochemistry, genetics, systems theory, the collapse of the medical system, and the failure of managed care. Each child that walks through my door is a challenge to everything I ever knew, and each child forces me to think outside the box and between categories." Each child's path to autism may be distinct, she says, but they may share common inflammatory abnormalities. She has shown through morphometric brain imaging that white matter - which carries impulses between neurons - is larger in children with autism. "It was the most absolutely outstanding piece of information in all the brain data I looked at," Herbert recalls of the years 2001 and 2002, when she was analyzing this brain imaging data. "People were saying, don't look at the white matter, look at the cerebral cortex, but I knew we had an important finding." Could white matter become chronically inflamed? It may well be, according to new research from Carlos Pardo, a neurologist at Johns Hopkins. In a 2005 study in the Annals of Neurology, he found inflammation in immune-responsive brain cells of autistic patients. "Patients with autism report lots of immunological problems. We looked for the fingerprints of those problems in the brain," says Pardo. "We had brain tissue from autistic individuals as young as 5 and as old as 45 and we found neuroglial inflammation in all of them. Neuroglia are a group of brain cells that are important in the brain's immune response. This inflammatory reaction appears to happen both early and late in the course of the disorder. If it happens early, it could dramatically influence brain development. We're very excited about this research because one potential treatment approach, then, is to downregulate the brain's immune response." To study that approach, Pardo is collaborating on a pilot study funded by the NIH to test minocycline, an anti-inflammatory antibiotic drug, on autistic children. "Minocycline is a very selective downregulator of microglial inflammation," he says. "Neurologists already use it in multiple sclerosis and Parkinson's." "What we've got here is a far more comprehensive set of characteristics for autism," says Herbert, "one that can include behavior, cognition, sensorimotor, gut, immune, brain, and endocrine abnormalities. These are ongoing problems, and they're not confined just to the brain. I can't think of it as a coincidence anymore that so many autistic kids have a history of food and airborne allergies, or 20 or 30 ear infections, or eczema, or chronic diarrhea." All this marks a Copernican-scale shift in our approach to the disorder. I myself was irresistibly drawn to the subject when viewing an online video of a heavily affected 11-year-old who, after a series of chelation treatments to remove mercury, announced to his mother, "Mom, I'm back from the living dead." The statement was heartbreaking in its simple eloquence. Mercury chelation, in this particular child's case, was a near panacea. Lisa Beck, of Oviedo, Florida, tells a similar story. Her son Joshua was diagnosed with autism in 2004 at about age 2. After 18 intensive months of treatment that involved chelation - a treatment that draws heavy metals out of the body - and dietary changes, among other therapies, Josh appears neurotypical. "We took him to Dr. Leslie Gavin, a specialist at Nemours Children's Clinic, who administers the ADOS test, a diagnostic test to see where on the spectrum a child falls," she says. "After the two-hour evaluation, Gavin said he did not meet the criteria for autism. In her words, he was 'responsive, curious, and active, able to engage in the test without a problem, able to express himself clearly.'?" But, fascinating anecdotes aside, does hard evidence exist of specific vulnerability genes or how they might impair the immune system, brain, and gut - and most important, do we have any rational, reliable approaches to help repair the damage? The answer is a provisional yes. "We're beginning to understand that genetics is really about vulnerability," says neuroscientist Pat Levitt, director of the Vanderbilt Kennedy Center for Research on Human Development. Levitt and his colleagues recently discovered that a common variant of a gene called MET doubles the risk of autism. The finding was widely regarded as a breakthrough because MET modulates the nervous system, gut, and immune system - just the kind of finding that matches up with the emerging new view of autism. "Everyone was focusing on genes expressed in the brain," says Levitt, "but this gene is important for repair of the intestine and immune function. And that's really intriguing because a subset of autistic children have digestive and immune problems." Equally interesting is that the gene variant occurs in 47 percent of the population - in other words, it is just one contributing factor, and it probably works in concert with other vulnerability genes. And finally, in a twist that intrigues other researchers, the activity of the gene is affected by what is known as oxidative stress - the kind of damage one sees with excessive exposure to toxins. "As we identify other vulnerability genes like this," says Levitt, who hopes to engineer a mouse model of this gene variant for study, "we may be able to develop effective interventions for children." In other provocative research, Jill James, director of the Autism Metabolic Genomics Laboratory at the Arkansas Children's Hospital Research Institute (and professor of pediatrics at the University of Arkansas for Medical Sciences) has found that many children with autism do not make as much of a compound called glutathione as neurotypical children do. Glutathione is the cell's most abundant antioxidant, and it is crucial for removing toxins. If cells lack sufficient antioxidants, they experience oxidative stress, which is often found with chronic inflammation. In her most recent study, published in the American Journal of Medical Genetics in 2006, James found that common gene variants that support the glutathione pathway may be associated with autism risk. Intriguingly, this pathway is linked metabolically to the methylation pathway. Methylation is a fundamental biochemical process that helps regulate which genes are expressed; abnormal methylation can cause disease. Because the pathway provides the precursors to glutathione, impairments in methylation can also lead to oxidative stress. "It's very provocative," James says. "It suggests that some autistic behaviors are a neurologic manifestation of a genetically based systemic, metabolic derangement." Some of the abnormalities James saw in this study have already been associated with gastrointestinal and immunologic dysfunction. The good news is that oxidative stress in some autistic children may be treatable with targeted nutritional intervention. James and her colleagues have tracked eight autistic children who were taking supplements of key nutrients in the methylation pathway - folinic acid, trimethylglycine, and methyl-B12 - and found a significant increase in important markers of methylation and glutathione synthesis. The next step is to see if the symptoms improve as well. James and her colleagues just received a $2.4 million grant from the NIH, part of which will be devoted to sorting out the relationship between metabolism, genes, and behavior. "What would be incredible is if we could correlate individual differences in behavior with specific abnormal metabolites," James says. They will then look at children between 18 to 24 months old, which is usually before autism is diagnosed. That could help identify the causes of the disease, as well as permit earlier intervention. "We also plan to look at mitochondrial dysfunction," she says. "Since mitochondria are the energy powerhouses of the cell, they're also the place where the most free radicals (which play a role in oxidative stress) are produced. If the electron transport chain in the mitochondria is faulty and you're not efficiently making ATP, you'll produce more free radicals and deplete your glutathione. If this hypothesis turns out to be correct, we can give nutrients like coenzyme Q10, magnesium, and acetyl-L-carnitine to help stabilize the mitochondria. Now, this is just a hypothesis, but that's the risk you take with science. You make your best guess and you carry out your study and you see." "It's interesting to see metabolic abnormalities addressed this way," says Isaac Pessah, chairman of Molecular Biosciences and director of the Center for Children's Environmental Health and Disease Prevention at the University of California at Davis. "I think glutathione balance in the kids is potentially very important in terms of toxic environmental exposures." There is a growing sense, Pessah adds, that our heavily industrialized, chemical-soaked environment - and the way it acts on vulnerable genes in some individuals - may be a major culprit. In December 2006, Harvard researchers boldly announced in The Lancet that industrial chemicals may be impairing the brain development of children around the entire world. And at a November 2006 conference at the University of California at Davis's M.I.N.D. Institute, Pessah gathered experts to discuss the clinical implications of environmental toxicology in autism. Says Herbert, "We discussed the enormous number of chemicals in our environment and how little we know about chronic, low-dose, multiple exposures and their effect on diseases like autism. Maybe the many autism cases we are now seeing are a new illness of the current generation." Several large-scale, federally funded epidemiological studies are under way to pinpoint possible environmental triggers, as well as early biomarkers of autism. "We have to build a large enough study to be able to look at both genes and environment together," says Newschaffer, who is a principal investigator on a study by the Centers for Disease Control that will look at 2,700 children over the next five years. In another ambitious study, called the Autism Birth Cohort, Columbia University and the Norwegian Institute of Public Health will follow 100,000 pregnant women for 72 months, studying their health and genetics and testing everything from blood to urine samples. The hope is to discover environmental factors that contribute to autism risk, from diet or infection to toxins like heavy metals, pesticides, and the countless synthetic molecules in products today. Other large NIH- and EPA-funded studies are teasing out immune abnormalities that may contribute to autism. In research on more than 700 families with an autistic as well as a neurotypical child, Pessah and his colleagues have found in the autistic child a significant reduction in immunoglobulins and an abnormal profile of cytokines, which are critical to immune response. "The immune system is involved in important aspects of neurodevelopment," says Pessah. "We've found the presence of immune antibodies that we think may influence brain proteins. In the next five years, as the study continues, we hope to reach about 1,600 families total. We need that many to get real statistical power. We hope to find out what type of skewed immune response the typical autistic child has and to isolate toxic exposures, such as proximity to highways or toxic waste dumps." Herbert argues that "we can address the disturbed pathways now, before the gene hunters have definitive information. Genes, after all, don't specify behaviors. They make regulatory factors that interact in highly complex ways. And as far as the impact of chemicals on neurodevelopment, only about 20 to 30 of the 85,000 chemicals made have been studied. We can, at the very least, try to modulate autism by treating the tissue inflammation." In other words, treat now, before the gavel of science strikes a final judgment, which might be decades away. That's what Erin and her husband, Michael, did for Brendan and Kyle: They blended mainstream treatments like speech and occupational therapy with the best biomedical approaches available. "I was told to take my boys home and love them," recalls Erin. "The neurologist said don't waste your time on alternative treatments, nothing about them is proven. My boys could have ended up institutionalized, or my husband and I would have had to take care of them their whole adult lives. When your child gets a diagnosis of autism, you lose the child you were dreaming about, the one who will go to college, get married, become a parent. That just wasn't an option." The boys first saw an alternative Colorado practitioner who had been trained by a group called Defeat Autism Now! (DAN!). DAN! was cofounded in 1995 by the psychologist Bernard Rimland, whose own son was autistic. DAN! treatments focus on intestinal issues, detoxification, nutrition, and neuroinflammation. Recommendations include dietary restriction, usually eliminating gluten (present in wheat and other grains) and dairy. "For weeks after Kyle stopped drinking milk, he had welts all over his body," Erin recalls, "as if he were going through a detoxification reaction. At the same time, he had his first formed, regular bowel movements. His sleep improved." Other DAN!-recommended treatments include detoxification to remove heavy metals and other suspected pollutants, nutritional supplementation, and sometimes off-label use of anti-inflammatories, antivirals, and allergy medications. These so-called biomedical treatments range from relatively inexpensive dietary changes costing a few hundred dollars a month to doses of antifungal drugs that can cost several hundreds of dollars. Many DAN! supplements play critical roles in the pathways studied by scientists like Jill James. DAN! practitioners are, of course, leaping into the deep end of the pool before science has truly proved these treatments effective, but there are many anecdotal cases of improvement. Not surprisingly, there has been criticism of the biomedical approach, especially when doctors promise too much or parents hope too desperately for recovery. As James notes, one mother killed herself after seeking every possible treatment for her autistic daughter to no avail, causing a furor among parents with autistic children. Some children just do not get better, no matter what the intervention. Elizabeth Mumper is CEO of a group called Advocates for Children and former director of pediatric education at the Lynchburg Family Practice Program affiliated with the University of Virginia. Of the 2,000 children in her practice, about 400 have autism spectrum disorders. She describes one boy whom "I have not helped despite my best efforts. He is 17 and still nonverbal and has horrible, erosive esophagitis in spite of the fact that he works very closely with a gastroenterologist. He has to sleep standing up and leaning over his dresser because of the pain, and he has very idiosyncratic reactions to medications. And even though he is nonverbal, he can type anything to me. He's alpha-smart. The horror is that he's trapped in a body that doesn't work." "I hate the term 'full recovery,'?" James adds, "because of this false hope. Some children do lose the diagnosis, but that's rare. I don't think that should be out there as a goal. We need to accept [the kids] and love them for who they are - because they are lovable. They're quirky." Erin's boys benefited from their DAN! doctor, she says, but it was in 2003, when she switched to a highly unconventional molecular biologist and naturopath based in Maine, Amy Yasko, that she began to see more striking changes. Yasko blends the new findings on methylation with a scientist's background in the finer steps of fundamental detoxification pathways in the body. However, she largely favors herbs, dietary change, and nutritional supplements over prescription medications. She monitors biomarkers of detoxification in the urine as often as every week or two and tweaks supplements accordingly. Her program is intensive and steeped in molecular biology; her twice-yearly conferences are extremely dense, scientific, and intended to help parents become at least semiproficient in the biology and chemistry themselves. It is a far cry from the old doctor-patient model - Yasko works primarily on the Internet now, with phone consultations, to interpret test results. She decided to do this when her waiting list for individuals stretched to five years, and, she says, she felt she was not helping enough children. Erin e-mailed me about 40 charts of metal "dumps" for both of her boys - urinalyses Yasko had ordered and charted on a graph to show the excretion of everything from arsenic to aluminum, mercury, and lead over time. "All these little things started clicking after we started with her," says Erin. "I call this approach biomolecular nutrigenomics, after Bruce Ames, a professor of biochemistry and molecular biology at the University of California at Berkeley," says Yasko. "He said that someday it would become routine to screen individuals for polymorphisms and that nutritional interventions to improve health were likely be a major benefit of the genomics area." Yasko tests for common polymorphisms in the methylation pathway, even though these findings are still preliminary. This has made her controversial among her peers. Yet several doctors and scientists with autistic children admitted privately to using Yasko's services while being unwilling to go on the record to support her. Yasko, who says she moved her husband and three daughters from Connecticut to a rural area of Maine to "hear the snowflakes fall on the snow and get to that quiet place inside where I can think," seems immune to the controversy. "I was in a research environment for a long time, where you had to publish. Then I was in biotech for a long time, where you had to keep everything quiet. When I began to focus on autistic children, I made a decision that instead of publishing in peer review journals, I was going to go directly to the moms and help them. I knew in making that decision I was going to get flak. That's OK. It was like I was on those cliffs you see in the movies, and you're going to jump. You don't know if there's water below, or enough momentum to get to the other side, but you just jump." Today Erin's boys participate in individualized programs at school and are being monitored in two national studies of families with more than one autistic child - one at the Duke Center for Human Genetics, another at the University of Washington. Kyle has, in addition, been tested three times at the University of Colorado Health Sciences Center's toddler development program. Both are still on the autism spectrum - but the incessant tantrums, digestive problems, and infections have vanished. Brendan no longer chews on his shirt, flaps his arms, and grinds his teeth. In fact, he made honor roll in his classes last year. Kelly Swift, the boys' schoolteacher since the autumn of 1996, describes them as "sociable and on the whole very happy, with a great sense of humor. Kyle is probably the most changed of any autistic child I've ever worked with." Kyle, who stopped speaking entirely at age 2, is now a font of creative language. I know this because Erin and the boys spent a weekend at my house. At lunch, Kyle poured a Vesuvius of ketchup onto his plate and began transforming his french fries into boats that sailed across the ketchup before they were disposed of in his mouth; he then began to entertain us by pretending he was an announcer at a regatta, where he, of course, was winning the race. What had once been autism had erupted into a geyser of quirky creativity. The boys' blossoming, according to their mom, is one not easily measured on tests. "It's the length of their sentences, their empathy and sense of humor. Last night we went by a house that was all lit up for the holidays and Kyle joked, 'Does that guy want to be seen from space?' When we used to take Kyle to the dentist, he would scream bloody murder and we'd try to papoose him - put him on a board and wrap him in sheets, but even that didn't work, so they put him to sleep just to clean his teeth. Last year we went to the dentist, and he heard a little boy crying, walked over to him, rubbed his back, told him it wouldn't hurt, and not to worry. My heart was melting." Can we cajole a mysteriously shuttered brain and body back toward normal? And if so, will autism give us new insight into other disorders? Martha Herbert thinks so: "A lot of these metabolic pathways are pretty fundamental to life. If we can crack the puzzle of autism and be clear about how we did it, that may have huge implications for other chronic environmentally triggered systemic illnesses. Autism could be a much-needed wake-up call to us all. Curr Pharm Des. 2007. Vasoactive intestinal peptide (VIP) mediates important events during the development of the nervous system. VIP can stimulate neuronogenesis as well as differentiation and neurite outgrowth; it can promote the survival of neurons and assist in neuronal repair; it is also anti-inflammatory and can modulate immune responses. In addition, VIP is necessary for the normal growth and development of the early postimplantation mouse embryo during the period when the major embryonic events are neural tube formation, neuronogenesis and expansion of the vascular system. Receptors for VIP appear during early postimplantation embryogenesis in the rodent and exhibit changing localization patterns throughout the development of the brain. During embryogenesis, unregulated VIP may have major and permanent consequences on the formation of the brain and may be a participating factor in disorders of neurodevelopment. VIP has been linked to autism, Down syndrome and fetal alcohol syndrome. This paper will review the role of VIP in neurodevelopment, its known involvement in neurodevelopmental disorders and propose ways in which VIP might be of therapeutic value. Epigenetics. 2006 Oct. Mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2), cause most cases of Rett syndrome (RTT), an X-linked neurodevelopmental disorder. Both RTT and autism are "pervasive developmental disorders" and share a loss of social, cognitive and language skills and a gain in repetitive stereotyped behavior, following apparently normal perinatal development. Although MECP2 coding mutations are a rare cause of autism, MeCP2 expression defects were previously found in autism brain. To further study the role of MeCP2 in autism spectrum disorders (ASDs), we determined the frequency of MeCP2 expression defects in brain samples from autism and other ASDs. We also tested the hypotheses that MECP2 promoter mutations or aberrant promoter methylation correlate with reduced expression in cases of idiopathic autism. MeCP2 immunofluorescence in autism and other neurodevelopmental disorders was quantified by laser scanning cytometry and compared with control postmortem cerebral cortex samples on a large tissue microarray. A significant reduction in MeCP2 expression compared to age-matched controls was found in 11/14 autism (79%), 9/9 RTT (100%), 4/4 Angelman syndrome (100%), 3/4 Prader-Willi syndrome (75%), 3/5 Down syndrome (60%), and 2/2 attention deficit hyperactivity disorder (100%) frontal cortex samples. One autism female was heterozygous for a rare MECP2 promoter variant that correlated with reduced MeCP2 expression. A more frequent occurrence was significantly increased MECP2 promoter methylation in autism male frontal cortex compared to controls. Furthermore, percent promoter methylation of MECP2 significantly correlated with reduced MeCP2 protein expression. These results suggest that both genetic and epigenetic defects lead to reduced MeCP2 expression and may be important in the complex etiology of autism. J Autism Dev Disord. 2006 Sep 28. Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome (PWS/AS) critical region have been described in individuals with autism. Maternal duplications and linkage disequilibrium in families with autism suggest the existence of a susceptibility locus at 15q11-q13. Here, we describe a 6-year-old girl diagnosed with autism, developmental delay, and delayed expressive and receptive language. The karyotype was designated de novo 47, XX, idic(15)(q13). Fluorescence in situ hybridization (FISH) and molecular analysis with 15q11-q13 markers revealed an additional copy of the region being of maternal origin. Duplication of the 15q11-q13 segment represents the most consistent known chromosomal abnormality reported in association with autism. This present case report reinforces the hypothesis that additional copies of this chromosome segment are causally related to autism. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5. Although Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis, is associated with autism [Tierney et al., 2001; Am J Med Genet 98:191-200.], the incidence of SLOS and other sterol disorders among individuals with autism spectrum disorders (ASD) is unknown. This study investigated (1) the incidence of biochemically diagnosed SLOS in blood samples from a cohort of subjects with ASD from families in which more than one individual had ASD and (2) the type and incidence of other sterol disorders in the same group. Using gas chromatography/mass spectrometry, cholesterol, and its precursor sterols were quantified in 100 samples from subjects with ASD obtained from the Autism Genetic Resource Exchange (AGRE) specimen repository. Although no sample had sterol levels consistent with SLOS, 19 samples had total cholesterol levels lower than 100 mg/dl, which is below the 5th centile for children over age 2 years. These findings suggest that, in addition to SLOS, there may be other disorders of sterol metabolism or homeostasis associated with ASD. Child Care Health Dev. 2006 Sep. Background: Melatonin is often used for autistic children with sleep disorders, despite a lack of published evidence in this population. Methods: A randomized, placebo-controlled double-blind crossover trial of melatonin was undertaken in 11 children with autistic spectrum disorder (ASD). Results: Seven children completed the trial. Sleep latency was 2.6 h [95% confidence intervals (CI) 2.28-2.93] baseline, 1.91 h (95% CI 1.78-2.03) with placebo and 1.06 h (95% CI 0.98-1.13) with melatonin. Wakings per night were 0.35 (95% CI 0.18-0.53) baseline, 0.26 (95% CI 0.20-0.34) with placebo and 0.08 (95% CI 0.04-0.12) with melatonin. Total sleep duration was 8.05 h (95% CI 7.65-8.44) baseline, 8.75 h (95% CI 8.56-8.98) with placebo and 9.84 h (95% CI 9.68-9.99) with melatonin. Conclusions: Although the study was small owing to recruitment difficulties, it still provides evidence of effectiveness of melatonin in children with sleep difficulties and ASD, which we predict a larger study would confirm. Am J Med Genet A. 2006 Jul 15. Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive condition caused by a defect in cholesterol synthesis. Affected children often have malformations and mental retardation. Autistic behaviors also are evident. The purpose of the present study was to determine the prevalence of autism spectrum disorders (ASDs) in children with SLOS. Fourteen children, 3-16 years old, were evaluated using three different methods to document autistic symptoms: (a) parent interview, (b) direct observation, and (c) a behavior checklist. Blood sterols were also measured at regular intervals. Each subject was determined to have Autistic Disorder, Pervasive Developmental Disorder, not otherwise specified (PDD NOS), or no diagnosis on the autism spectrum, based on DSM-IV criteria. Correlations among variables were calculated, and blood sterol levels were compared between diagnostic groups. Approximately three-fourths of the children with SLOS (71-86% depending on the evaluation method) had an ASD, about 50% diagnosed with Autistic Disorder and the rest with PDD NOS. The children's baseline cholesterol, 7-dehydrocholesterol (7-DHC), and 8-dehydrocholesterol (8-DHC) levels, and cholesterol levels following supplementation did not correlate with the presence or severity of autistic symptoms. These results suggest that most children with SLOS have some variant of autism. SLOS appears to have the most consistent relationship with autism of any single gene disorder. Therefore, a link between cholesterol metabolism and autism is suggested. With further study, these findings, together with knowledge of the genetic and biochemical defects in SLOS, will likely provide valuable insights into the causes of autism in general. J Altern Complement Med. 2006 Jan-Feb. Background: There have been many studies of the effect of high-dose supplementation of vitamin B6 on children and adults with autism, with all but one reporting benefits. Objective: The aim of this study was to investigate the biochemical basis for vitamin B6 therapy by measuring the level of total vitamin B6 in the plasma of unsupplemented children with autism spectrum disorder compared to unsupplemented control subjects. Participants: Children with autism spectrum disorders (n = 35, age 3-9 years) and unrelated typical children (n = 11, age 6-9 years), all from Arizona, were studied. (This includes the data from 24 children with autism from our previous study.) Methodology: A microbiologic assay was used to measure the level of total vitamin B6 (including phosphorylated and unphosphorylated forms), in a blinded fashion. Results: Children with autism had a 75% higher level of total vitamin B6 than the controls (medians of 56 versus 32 ng/mL, respectively, p = 0.00002). Most of the autistic children (77%) had levels that were more than 2 standard deviations above the median value of the controls. The autistic girls (n = 5) also had elevated levels (mean of 54.6 ng/mL, median of 60 ng/mL). Discussion: These results are consistent with previous studies that found that: (1) pyridoxal kinase had a very low activity in children with autism and (2) pyridoxal 5 phosphate (PLP) levels are unusually low in children with autism. Thus, it appears that the low conversion of pyridoxal and pyridoxine to PLP results in low levels of PLP, which is the active cofactor for 113 known enzymatic reactions, including the formation of many key neurotransmitters. Conclusions: Total vitamin B6 is abnormally high in autism, consistent with previous reports of an impaired pyridoxal kinase for the conversion of pyridoxine and pyridoxal to PLP. This may explain the many published studies of benefits of high-dose vitamin B6 supplementation in some children and adults with autism. J Pediatr. 2005 Dec. Objectives: To determine the prevalence and type of sleep-disordered breathing among patients with Prader-Willi syndrome (PWS) and its relationship to such neurobehavioral abnormalities as mental retardation, obsessive-compulsive behavior, and conduct disorders. Study design: Polysomnography (PSG) studies were conducted in 13 unselected subjects with PWS (age 1.5 to 28 years). PSG results were compared with tests of behavior and cognition (Development Behavior Checklist [DBC], Auditory Continuous Performance Test [ACPT], and Wechsler Intelligence Scale appropriate for age). Results: Nine of 13 (69%) subjects had > 10 apneas and hypopneas per hour of sleep. Apart from a 2-year-old subject with normal body weight who demonstrated severe central hypopnea in rapid eye movement sleep, the sleep-breathing disturbance was due to upper airway obstruction. Age-adjusted body mass index was associated with more severe hypoxemia during sleep (min SaO2, r = -.87, P < .005) and more sleep disruption (arousals/hour of sleep, r = .62, P < .05; sleep efficiency, r = -.66, P < .05). Increasing severity of obstructive sleep apnea (OSA) or sleep disturbance was associated with daytime inactivity/sleepiness and autistic-relating behavior (DBC) and with impulsiveness (ACPT). Unexpectedly, sleep hypoxemia appeared to be predictive of increased performance IQ. Conclusions: OSA is prevalent among subjects with PWS and is associated with increased body mass, daytime inactivity/ sleepiness, and some behavioral disturbances. Hum Mol Genet. 2004 Mar 15. Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Although MECP2 is ubiquitously transcribed, MeCP2 expression is developmentally regulated and heterogeneous in neuronal subpopulations, defined as MeCP2(lo) and MeCP2(hi). To test the hypothesis that pathways affecting MeCP2 expression changes may be defective in RTT, autism and other neurodevelopmental disorders without MECP2 mutations, a high-throughput quantitation of MeCP2 expression was performed on a tissue microarray containing frontal cortex samples from 28 different patients with neurodevelopmental disorders and age-matched controls. Combined quantitative analyses of MeCP2 protein and alternatively polyadenylated transcript levels were performed by laser scanning cytometry and tested for significant differences from age-matched controls. Normal cerebral samples showed an increase in total MeCP2 expression and the percentage of MeCP2(hi) cells with age that could be explained by increased MECP2 transcription within the MeCP2(hi) population. A significant decrease in the relative usage of the long transcript in the MeCP2(lo) population was observed in postnatal compared to fetal brain, but alternate polyadenylation did not correlate with MeCP2 expression changes at the single cell level. Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT. My abstract: Rett syndrome is a neurodevelopmental disorder that presents with cognitive impairment and autistic behavior and is caused by mutations in the MECP2 gene (on chromosome X) which carries the instructions for making methyl-CpG-binding protein 2 (MeCP2). The MeCP2 protein, which is found throughout both fetal and adult brains, has two different forms - a short form which contains a 1.9 kb transcript from the MECP2 grene and a long form which contains a 10 kb-long transcript that includes the 1.9 kb coding region of MECP2 as well as an exceptionally long untranslated region. Too make things more complicated, some brain neurons have relatively high levels of the MeCP2 protein and are called MeCP2(hi) neurons, while other neurons have relatively low levels of MeCP2 and are called MeCP2(lo) neurons. MeCP2 expression is developmentally regulated, that is, there are changes in the total amount of MeCP2 protein in the brain according to age, as well as changes in the amounts of short and long transcript forms of MeCP2 and changes in the number of MeCP2(lo) and MeCP2(hi) neurons. During normal brain development, the total amount of MeCP2 increases and there is a progressive increase in the number of MeCP2(hi) neurons from infancy to adulthood. At the same time, the amount of long-transcript MeCP2 falls relative to the amount of short-transcript MeCP2, even though juvenile and adult MeCP2(hi) neurons have more long-transcript MeCP2 than juvenile and adult MeCP2(lo) neurons. In PWS, there are significantly higher MeCP2 levels in the MeCP2(hi) neurons compared to control subjects, even though total MECP2 levels are significantly lower. In addition, there are higher levels of both short and long-transcript MECP2 proteins in PWS. In other words, PWS brains do not shift to more MeCP2(hi) neurons during growth, nor does the normal fall in the amount of long-transcript MeCP2 occur. That means that the loss of expression of the genetic information on the paternal chromosome 15 gene that occurs in PWS somehow affects the expression of the MECP2 gene on chromosome X. J Pediatr. 2004 Jan. OBJECTIVES: To further characterize mtDNA defects associated with autistic features, especially the A3243G mtDNA mutation and mtDNA depletion. Study design. Five patients with autistic spectrum disorders and family histories of mitochondrial DNA diseases were studied. We performed mtDNA analysis in all patients and magnetic resonance spectroscopy in three. RESULTS: Three patients manifested isolated autistic spectrum features and two had additional neurologic symptoms. Two patients harbored the A3243G mutation. In two others, the A3243G mutation was not found in accessible tissues but was present in tissues from their mothers. The fifth patient had 72% mtDNA depletion in skeletal muscle. CONCLUSIONS: Autistic spectrum disorders with or without additional neurologic features can be early presentations of the A3243G mtDNA mutation and can be a prominent clinical manifestation of mtDNA depletion. Mitochondrial dysfunction should be considered in patients who have autistic features and associated neurologic findings or who have evidence of maternal inheritance. Med Hypotheses. 2004. Long chain acyl-CoA dehydrogenase (LCAD) has recently been shown to be the mitochondrial enzyme responsible for the beta-oxidation of branched chain and unsaturated fatty acids [Biochim. Biophys. Acta 1393 (1998) 35; Biochim. Biophys. Acta 1485 (2000) 121]. Whilst disorders of short, medium and very long chain acyl dehydrogenases are known, there is no known disorder of LCAD deficiency in humans. Experimental LCAD deficiency in mice shows an acyl-carnitine profile with prominent elevations of unsaturated fatty acid metabolites C14:1 and C14:2 [Hum. Mol. Genet. 10 (2001) 2069]. A child with autism whose acyl-carnitine profile also shows these abnormalities is presented, and it is hypothesized that the child may have LCAD deficiency. Additional metabolic abnormalities seen in this patient include alterations of TCA energy production, ammonia detoxification, reduced synthesis of omega-3 DHA, and abnormal cholesterol metabolism. These metabolic changes are also seen as secondary abnormalities in dysfunction of fatty acid beta-oxidation, and have also been reported in autism. It is hypothesized that LCAD deficiency may be a cause of autism. Similarities between metabolic disturbances in autism, and those of disorders of fatty acid beta-oxidation are discussed. JAMA. 2003 Jul 16. CONTEXT: Autism most commonly appears by 2 to 3 years of life, at which time the brain is already abnormally large. This raises the possibility that brain overgrowth begins much earlier, perhaps before the first clinically noticeable behavioral symptoms. OBJECTIVES: To determine whether pathological brain overgrowth precedes the first clinical signs of autism spectrum disorder (ASD) and whether the rate of overgrowth during the first year is related to neuroanatomical and clinical outcome in early childhood. DESIGN, SETTING, AND PARTICIPANTS: Head circumference (HC), body length, and body weight measurements during the first year were obtained from the medical records of 48 children with ASD aged 2 to 5 years who had participated in magnetic resonance imaging studies. Of these children, 15 (longitudinal group) had measurements at 4 periods during infancy: birth, 1 to 2 months, 3 to 5 months, and 6 to 14 months; and 33 (partial HC data group) had measurements at birth and 6 to 14 months (n = 7), and at birth only (n = 28). MAIN OUTCOME MEASURES: Age-related changes in infants with ASD who had multiple-age measurements, and the relationship of these changes to brain anatomy and clinical and diagnostic outcome at 2 to 5 years were evaluated by using 2 nationally recognized normative databases: cross-sectional normative data from a national survey and longitudinal data of individual growth. RESULTS: Compared with normative data of healthy infants, birth HC in infants with ASD was significantly smaller (z = -0.66, P<.001); after birth, HC increased 1.67 SDs and mean HC was at the 84th percentile by 6 to 14 months. Birth HC was related to cerebellar gray matter volume at 2 to 5 years, although the excessive increase in HC between birth and 6 to 14 months was related to greater cerebral cortex volume at 2 to 5 years. Within the ASD group, every child with autistic disorder had a greater increase in HC between birth and 6 to 14 months (mean [SD], 2.19 [0.98]) than infants with pervasive developmental disorder-not otherwise specified (0.58 [0.35]). Only 6% of the individual healthy infants in the longitudinal data showed accelerated HC growth trajectories (>2.0 SDs) from birth to 6 to 14 months; 59% of infants with autistic disorder showed these accelerated growth trajectories. CONCLUSIONS: The clinical onset of autism appears to be preceded by 2 phases of brain growth abnormality: a reduced head size at birth and a sudden and excessive increase in head size between 1 to 2 months and 6 to 14 months. Abnormally accelerated rate of growth may serve as an early warning signal of risk for autism. J Neuroimmunol. 2001 Nov 1. We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production. Am J Med Genet. 2001 Jan 15. The behavior phenotype of Smith-Lemli-Opitz syndrome (SLOS) was studied by assessing behavior, social, and communication abilities, sensory hyperreactivity, and the deficits associated with autistic disorder. Fifty-six SLOS subjects, age 0.3 to 32.3 years, were evaluated by multiple age-dependent questionnaires and telephone interviews. Of the 56 subjects, 50 (89%) had a history of repeated self-injury: 30 (54%) bit themselves; 27 (48%) head-banged; and 30 (54%) threw themselves backward in a highly characteristic upper body movement ("opisthokinesis"). Forty-seven of these subjects were also evaluated by direct observation and by direct interview of the parent or caregiver. Of 11 subjects 10 years or older, three (27%) had a stereotypic stretching motion of the upper body accompanied by hand flicking. Additional measures showed sensory hyperreactivity, temperament dysregulation, sleep disturbance, and social and communication deficits. Nine of 17 subjects (53%) met the diagnostic criteria for autistic disorder by the Autism Diagnostic Interview-Revised (ADI-R) algorithm questions [Lord et al., 1993, 1994]. Thus, SLOS is a metabolic disorder that can be associated with autism and other behavioral characteristics that define a distinctive and diagnostically important behavioral disorder. Ment Retard Dev Disabil Res Rev. 2000. Smith-Lemli-Opitz syndrome (SLOS, RSH/SLO syndrome, MIM 270400) is an autosomal recessive multiple malformation/mental retardation syndrome initially described by Smith et al. [1964] that is due to a defect in cholesterol biosynthesis. The behavioral phenotype of Smith-Lemli-Opitz syndrome demonstrates cognitive abilities from borderline intellectual functioning to profound mental retardation, sensory hyperreactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In a recent study of 28 subjects, 14 subjects (50%) with SLOS also exhibited the behavior of throwing themselves backward in a characteristic upper body movement ("opisthokinesis") and 2 adolescents had a stretching motion of the upper body accompanied by hand flicking [Tierney et al., 1999]. In that same study, 6 of 13 subjects (46%) met the Autism Diagnostic Interview-Revised (ADI-R) algorithm criteria (Lord et al. [1993] Infant Mental Health 14:234-252; Lord et al. [1994] J Autism Dev Disord 24:659-685) and the Diagnostic and Statistical Manual (APA [1994] DSM-IV) diagnostic criteria for autistic disorder. Smith-Lemli-Opitz syndrome is a metabolic disorder that is associated with autism. |