1. Akins RS, Angkustsiri K, Hansen RL. {{Complementary and alternative medicine in autism: an evidence-based approach to negotiating safe and efficacious interventions with families}}. {Neurotherapeutics} (Jul);7(3):307-319.
This review focuses on helping clinicians identify resources and develop strategies they may use to effectively negotiate safe and effective use of complementary and alternative medicine (CAM) treatments with families of children with autism spectrum disorders (ASD), as well as other neurodevelopmental disorders. Since new types of CAM continue to be introduced into the autism community, emphasis is placed on providing clinicians with tools to help families negotiate the myriad of available treatments and make decisions based on current safety and efficacy data, while remaining mindful of the reasons families may be considering these treatments. We familiarize readers with high-quality, evidence-based resources that providers and families may use to ascertain current information about specific types of CAM, verify the content of biologically-based treatments, identify ongoing CAM research and obtain toolkits designed to help healthcare providers raise the topic of CAM usage and facilitate disclosure and discussion of CAM use with patients and their families.
2. Bauman ML. {{Medical Comorbidities in Autism: Challenges to Diagnosis and Treatment}}. {Neurotherapeutics} (Jul);7(3):320-327.
Ever since its original description by Leo Kanner in l943, autism has been generally defined by its clinical characteristics and core symptoms that include impaired social skills, isolated areas of interest, and delayed and disordered language. Over time, it has become apparent that autism is a heterogeneous disorder with regard to its clinical presentation, etiology, underlying neurobiology, and degree of severity. As a result, the termed diagnosis of autism spectrum disorders (ASDs) has come into common usage. With advancements in clinical care, there has come the appreciation that many ASD children, adolescents, and adults may have medically relevant disorders that may negatively impact their developmental progress and behavior, but which frequently go undetected. Many of these medical conditions are treatable, often resulting in improved developmental gains and quality of life for the patient and family. In addition, the possibility exists that some of these medical conditions may suggest the presence of important genetic and/or biologic markers, which, if identified, can refine our ability to be more precise in categorizing clinical and genetic subtypes within the autism spectrum.
3. Bent S, Hendren RL. {{Improving the Prediction of Response to Therapy in Autism}}. {Neurotherapeutics} (Jul);7(3):232-240.
Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.
4. Careaga M, Van de Water J, Ashwood P. {{Immune Dysfunction in Autism: A Pathway to Treatment}}. {Neurotherapeutics} (Jul);7(3):283-292.
Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.
5. Chez MG, Guido-Estrada N. {{Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy}}. {Neurotherapeutics} (Jul);7(3):293-301.
Autism affects 1 in 110 new births, and it has no single etiology with uniform agreement. This has a significant impact on the quality of life for individuals who have been diagnosed with autism. Although autism has a spectrum quality with a shared diagnosis, it presents a uniquely different clinical appearance in each individual. Recent research of suspected immunological factors have provided more support for a probable immunological process or for processes that may play a role in the acquisition of an autistic condition. These factors include prenatal, genetic, and postnatal findings, as well as the discovery of a dysfunctional chronic pro-inflammatory state in brain tissue and cerebrospinal fluid in subsets of autistic patients. These findings offer new theories that may lead to the development of disease modification or preventative therapeutic options in the near future. This article reviews prenatal, genetic, and observed immune aspects of the autism condition that may be risk factors in the presentation of the autistic clinical phenotype. Historical immune interventions in autism are reviewed and potential new therapies and interventions are discussed.
6. Ebisch SJ, Gallese V, Willems RM, Mantini D, Groen WB, Romani GL, Buitelaar JK, Bekkering H. {{Altered intrinsic functional connectivity of anterior and posterior insula regions in high-functioning participants with autism spectrum disorder}}. {Hum Brain Mapp} (Jul 19)
Impaired understanding of others’ sensations and emotions as well as abnormal experience of their own emotions and sensations is frequently reported in individuals with Autism Spectrum Disorder (ASD). It is hypothesized that these abnormalities are based on altered connectivity within « shared » neural networks involved in emotional awareness of self and others. The insula is considered a central brain region in a network underlying these functions, being located at the transition of information about bodily arousal and the physiological state of the body to subjective feelings. The present study investigated the intrinsic functional connectivity properties of the insula in 14 high-functioning participants with ASD (HF-ASD) and 15 typically developing (TD) participants in the age range between 12 and 20 years by means of « resting state » or « nontask » functional magnetic resonance imaging. Essentially, a distinction was made between anterior and posterior regions of the insular cortex. The results show a reduced functional connectivity in the HF-ASD group, compared with the TD group, between anterior as well as posterior insula and specific brain regions involved in emotional and sensory processing. It is suggested that functional abnormalities in a network involved in emotional and interoceptive awareness might be at the basis of altered emotional experiences and impaired social abilities in ASD, and that these abnormalities are partly based on the intrinsic functional connectivity properties of such a network. Hum Brain Mapp, 2010. (c) 2010 Wiley-Liss, Inc.
7. Emond A, Emmett P, Steer C, Golding J. {{Feeding Symptoms, Dietary Patterns, and Growth in Young Children With Autism Spectrum Disorders}}. {Pediatrics} (Jul 19)
Objective: To investigate the feeding, diet and growth of young children with autism spectrum disorders (ASD). Method: Data on feeding and food frequency were collected by questionnaires completed at 6, 15, 24, 38 and 54 months by participants in the Avon Longitudinal Study of Parents and Children. A food variety score was created, and the content of the diet was calculated at 38 m. The feeding and dietary patterns of 79 children with ASD were compared with 12 901 controls. Results: The median ages of ASD children were 28 months at referral and 45 months at diagnosis. ASD infants showed late introduction of solids after 6 months (p = .004) and were described as « slow feeders » at 6 months (p = .04). From 15-54 months ASD children were consistently reported to be « difficult to feed » (p < .001) and « very choosy » (p < .001). From 15 months, the ASD group had a less varied diet than controls, were more likely to have different meals from their mother from 24 months, and by 54 months 8% of ASD children were taking a special diet for « allergy. » ASD children consumed less vegetables, salad and fresh fruit, but also less sweets and fizzy drinks. At 38 months intakes of energy, total fat, carbohydrate and protein were similar, but the ASD group consumed less vitamins C (p = .02) and D (p = .003). There were no differences in weight, height or BMI at 18 months and 7 years, or in hemoglobin concentrations at 7 years. Conclusions: ASD children showed feeding symptoms from infancy and had a less varied diet from 15 months, but energy intake and growth were not impaired.
8. Erickson CA, Stigler KA, Posey DJ, McDougle CJ. {{Aripiprazole in Autism Spectrum Disorders and Fragile X Syndrome}}. {Neurotherapeutics} (Jul);7(3):258-263.
Autism spectrum disorders (ASDs) are childhood onset developmental disorders characterized by impairment of social skills and repetitive behavior, and also for classic autistic disorder, a significant impairment of communication. In addition to these core symptom domains, persons with ASDs frequently exhibit interfering behavioral symptoms, including irritability marked by aggression, self-injurious behavior, and severe tantrums. Aripiprazole is an atypical or newer generation antipsychotic with a unique mechanism of action impacting dopaminergic and serotonergic neurotransmission. The drug has been found efficacious for several indications, including most recently for use targeting irritability associated with autistic disorder in youth. Fragile X syndrome is the most common inherited cause of developmental disability and the most common known single gene cause of ASDs. As in idiopathic ASDs, irritable behavior is often exhibited by persons with fragile X syndrome. However, research to date in this disorder has not focused on this target symptom cluster. An initial pilot study has begun to assess the impact of aripiprazole on irritability in youth with fragile X syndrome.
9. Frye RE, Huffman LC, Elliott GR. {{Tetrahydrobiopterin as a Novel Therapeutic Intervention for Autism}}. {Neurotherapeutics} (Jul);7(3):241-249.
Tetrahydrobiopterin (BH(4)) is an essential cofactor for several critical metabolic pathways that have been reported to be abnormal in autism spectrum disorder (ASD). In addition, the cerebrospinal fluid concentration of BH(4) is reported to be depressed in children with ASD. Over the past 25 years, several clinical trials have suggested that treatment with BH(4) improves ASD symptomatology in some individuals. Two ongoing clinical protocols may help further define the efficacy of BH(4) treatment in children with ASD. First, children with ASD who had low concentrations of cerebrospinal fluid or urine pterins were treated in an open-label manner with 20 mg/kg per day of BH(4). The majority of children (63%) responded positively to treatment, with minimal adverse events (AEs). Second, a double-blind placebo-controlled study examining the efficacy of 20 mg/kg per day of BH(4) treatment in children with ASD is currently underway. Safety studies from the commercially available forms of BH(4) document the low incidence of AEs, particularly serious AEs. Studies have also documented the ability of BH(4) to cross the blood-brain barrier. Based on the importance of BH(4) in neurodevelopmental metabolic pathways, the safety of BH(4) treatment, and the evidence for a therapeutic benefit of BH(4) treatment in children with ASD, we conclude that BH(4) represents a novel therapy for ASD, one that may gain wider use after further clinical studies have established efficacy and treatment guidelines.
10. Grafodatskaya D, Chung B, Szatmari P, Weksberg R. {{Autism Spectrum Disorders and Epigenetics}}. {J Am Acad Child Adolesc Psychiatry} (Aug);49(8):794-809.
OBJECTIVE: Current research suggests that the causes of autism spectrum disorders (ASD) are multifactorial and include both genetic and environmental factors. Several lines of evidence suggest that epigenetics also plays an important role in ASD etiology and that it might, in fact, integrate genetic and environmental influences to dysregulate neurodevelopmental processes. The objective of this review is to illustrate how epigenetic modifications that are known to alter gene expression without changing primary DNA sequence may play a role in the etiology of ASD. METHOD: In this review, we summarize current knowledge about epigenetic modifications to genes and genomic regions possibly involved in the etiology of ASD. RESULTS: Several genetic syndromes comorbid with ASD, which include Rett, Fragile X, Prader-Willi, Angelman, and CHARGE (Coloboma of the eye, Heart defects, Atresia of the nasal choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness), all demonstrate dysregulation of epigenetic marks or epigenetic mechanisms. We report also on genes or genomic regions exhibiting abnormal epigenetic regulation in association with either syndromic (15q11-13 maternal duplication) or nonsyndromic forms of ASD. Finally, we discuss the state of current knowledge regarding the etiologic role of environmental factors linked to both the development of ASD and epigenetic dysregulation. CONCLUSION: Data reviewed in this article highlight a variety of situations in which epigenetic dysregulation is associated with the development of ASD, thereby supporting a role for epigenetics in the multifactorial etiologies of ASD.
11. Green JJ, Hollander E. {{Autism and Oxytocin: New Developments in Translational Approaches to Therapeutics}}. {Neurotherapeutics} (Jul);7(3):250-257.
Autism is a neurodevelopmental disorder characterized by dysfunction in three core symptom domains: speech and communication deficits, repetitive or compulsive behaviors with restricted interests, and social impairment. The neuropeptide oxytocin, along with the structurally similar peptide arginine vasopressin, may play a role in the etiology of autism, and especially in the social impairment domain. Oxytocin is a nonapeptide (i.e., it has nine amino acids). It is synthesized in magnocellular neurons in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus and is released into the bloodstream by way of axon terminals in the posterior pituitary. Oxytocin is released both peripherally, where it is involved in milk letdown and the facilitation of uterine contractions, and centrally, where it acts as a neuromodulator along with arginine vasopressin. Here, we discuss relevant translational research pertaining to the role of oxytocin in social and repetitive behaviors and consider clinical implications. We also discuss current research limitations, review recent preliminary findings from studies involving oxytocin in autism spectrum disorder patient populations, and point to possible directions for future research.
12. Hagerman RJ, Hendren RL. {{Shifting the paradigm for autism treatments}}. {Neurotherapeutics} (Jul);7(3):230-231.
13. Hesling I, Dilharreguy B, Peppe S, Amirault M, Bouvard M, Allard M. {{The integration of prosodic speech in high functioning autism: a preliminary FMRI study}}. {PLoS One};5(7):e11571.
BACKGROUND: Autism is a neurodevelopmental disorder characterized by a specific triad of symptoms such as abnormalities in social interaction, abnormalities in communication and restricted activities and interests. While verbal autistic subjects may present a correct mastery of the formal aspects of speech, they have difficulties in prosody (music of speech), leading to communication disorders. Few behavioural studies have revealed a prosodic impairment in children with autism, and among the few fMRI studies aiming at assessing the neural network involved in language, none has specifically studied prosodic speech. The aim of the present study was to characterize specific prosodic components such as linguistic prosody (intonation, rhythm and emphasis) and emotional prosody and to correlate them with the neural network underlying them. METHODOLOGY/PRINCIPAL FINDINGS: We used a behavioural test (Profiling Elements of the Prosodic System, PEPS) and fMRI to characterize prosodic deficits and investigate the neural network underlying prosodic processing. Results revealed the existence of a link between perceptive and productive prosodic deficits for some prosodic components (rhythm, emphasis and affect) in HFA and also revealed that the neural network involved in prosodic speech perception exhibits abnormal activation in the left SMG as compared to controls (activation positively correlated with intonation and emphasis) and an absence of deactivation patterns in regions involved in the default mode. CONCLUSIONS/SIGNIFICANCE: These prosodic impairments could not only result from activation patterns abnormalities but also from an inability to adequately use the strategy of the default network inhibition, both mechanisms that have to be considered for decreasing task performance in High Functioning Autism.
14. Oller DK, Niyogi P, Gray S, Richards JA, Gilkerson J, Xu D, Yapanel U, Warren SF. {{Automated vocal analysis of naturalistic recordings from children with autism, language delay, and typical development}}. {Proc Natl Acad Sci U S A} (Jul 19)
For generations the study of vocal development and its role in language has been conducted laboriously, with human transcribers and analysts coding and taking measurements from small recorded samples. Our research illustrates a method to obtain measures of early speech development through automated analysis of massive quantities of day-long audio recordings collected naturalistically in children’s homes. A primary goal is to provide insights into the development of infant control over infrastructural characteristics of speech through large-scale statistical analysis of strategically selected acoustic parameters. In pursuit of this goal we have discovered that the first automated approach we implemented is not only able to track children’s development on acoustic parameters known to play key roles in speech, but also is able to differentiate vocalizations from typically developing children and children with autism or language delay. The method is totally automated, with no human intervention, allowing efficient sampling and analysis at unprecedented scales. The work shows the potential to fundamentally enhance research in vocal development and to add a fully objective measure to the battery used to detect speech-related disorders in early childhood. Thus, automated analysis should soon be able to contribute to screening and diagnosis procedures for early disorders, and more generally, the findings suggest fundamental methods for the study of language in natural environments.
15. Reading R. {{Clinical genetic testing for patients with autism spectrum disorders}}. {Child Care Health Dev} (Jul);36(4):599.
16. Ronald A, Larsson H, Anckarsater H, Lichtenstein P. {{A twin study of autism symptoms in Sweden}}. {Mol Psychiatry} (Jul 20)
This study aimed to identify empirically the number of factors underlying autism symptoms-social impairments, communication impairments, and restricted repetitive behaviors and interests-when assessed in a general population sample. It also investigated to what extent these autism symptoms are caused by the same or different genetic and environmental influences. Autistic symptoms were assessed in a population-based twin cohort of >12 000 (9- and 12-year-old) children by parental interviews. Confirmatory factor analyses, principal component analyses and multivariate structural equation model fitting were carried out. A multiple factor solution was suggested, with nearly all analyses pointing to a three-factor model for both boys and girls and at both ages. A common pathway twin model fit the data best, which showed that there were some underlying common genetic and environmental influences across the different autism dimensions, but also significant specific genetic effects on each symptom type. These results suggest that the autism triad consists of three partly independent dimensions when assessed in the general population, and that these different autism symptoms, to a considerable extent, have partly separate genetic influences. These findings may explain the large number of children who do not meet current criteria for autism but who show some autism symptoms. Molecular genetic research may benefit from taking a symptom-specific approach to finding genes associated with autism.Molecular Psychiatry advance online publication, 20 July 2010; doi:10.1038/mp.2010.82.
17. Turlejski K. {{Focus on autism}}. {Acta Neurobiol Exp (Wars)};70(2):117-118.
18. Wang LW, Berry-Kravis E, Hagerman RJ. {{Fragile X: Leading the Way for Targeted Treatments in Autism}}. {Neurotherapeutics} (Jul);7(3):264-274.
Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5′ end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur.
