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1.  Developing a Predictive Gene Classifier for Autism Spectrum Disorders Based upon Differential Gene Expression Profiles of Phenotypic Subgroups 
North American journal of medicine & science  2013;6(3):10.7156/najms.2013.0603107.
Autism spectrum disorders (ASD) are neurodevelopmental disorders which are currently diagnosed solely on the basis of abnormal stereotyped behavior as well as observable deficits in communication and social functioning. Although a variety of candidate genes have been identified on the basis of genetic analyses and up to 20% of ASD cases can be collectively associated with a genetic abnormality, no single gene or genetic variant is applicable to more than 1–2 percent of the general ASD population. In this report, we apply class prediction algorithms to gene expression profiles of lymphoblastoid cell lines (LCL) from several phenotypic subgroups of idiopathic autism defined by cluster analyses of behavioral severity scores on the Autism Diagnostic Interview-Revised diagnostic instrument for ASD. We further demonstrate that individuals from these ASD subgroups can be distinguished from nonautistic controls on the basis of limited sets of differentially expressed genes with a predicted classification accuracy of up to 94% and sensitivities and specificities of ~90% or better, based on support vector machine analyses with leave-one-out validation. Validation of a subset of the “classifier” genes by high-throughput quantitative nuclease protection assays with a new set of LCL samples derived from individuals in one of the phenotypic subgroups and from a new set of controls resulted in an overall class prediction accuracy of ~82%, with ~90% sensitivity and 75% specificity. Although additional validation with a larger cohort is needed, and effective clinical translation must include confirmation of the differentially expressed genes in primary cells from cases earlier in development, we suggest that such panels of genes, based on expression analyses of phenotypically more homogeneous subgroups of individuals with ASD, may be useful biomarkers for diagnosis of subtypes of idiopathic autism.
PMCID: PMC3867975  PMID: 24363828
Autism; subphenotypes; gene expression; class prediction; blood biomarkers
2.  Studying Autism in Rodent Models: Reconciling Endophenotypes with Comorbidities 
Autism spectrum disorder (ASD) patients commonly exhibit a variety of comorbid traits including seizures, anxiety, aggressive behavior, gastrointestinal problems, motor deficits, abnormal sensory processing, and sleep disturbances for which the cause is unknown. These features impact negatively on daily life and can exaggerate the effects of the core diagnostic traits (social communication deficits and repetitive behaviors). Studying endophenotypes relevant to both core and comorbid features of ASD in rodent models can provide insight into biological mechanisms underlying these disorders. Here we review the characterization of endophenotypes in a selection of environmental, genetic, and behavioral rodent models of ASD. In addition to exhibiting core ASD-like behaviors, each of these animal models display one or more endophenotypes relevant to comorbid features including altered sensory processing, seizure susceptibility, anxiety-like behavior, and disturbed motor functions, suggesting that these traits are indicators of altered biological pathways in ASD. However, the study of behaviors paralleling comorbid traits in animal models of ASD is an emerging field and further research is needed to assess altered gastrointestinal function, aggression, and disorders of sleep onset across models. Future studies should include investigation of these endophenotypes in order to advance our understanding of the etiology of this complex disorder.
PMCID: PMC3722572  PMID: 23898259
autism; epilepsy; sleep; motor deficits; aggression; sensory; gastrointestinal function; anxiety
3.  Mutant Mouse Models of Autism Spectrum Disorders 
Disease markers  2012;33(5):225-239.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental diseases characterized by a triad of specific behavioral traits: abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Several recent studies showed that ASDs have a strong genetic basis, contributing to the discovery of a number of ASD-associated genes. Due to the genetic complexity of these disorders, mouse strains with targeted deletion of ASD genes have become an essential tool to investigate the molecular and neurodevelopmental mechanisms underlying ASD. Here we will review the most relevant genetic mouse models developed by targeted inactivation of ASD-associated genes, and discuss their importance for the development of novel pharmacological therapies of these disorders.
PMCID: PMC3810701  PMID: 22960336
Autism; brain development; knockout mouse; animal model
4.  Mouse Models of Mutations and Variations in Autism Spectrum Disorder-Associated Genes: Mice Expressing Caps2/Cadps2 Copy Number and Alternative Splicing Variants 
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disturbances in interpersonal relationships and behavior. Although the prevalence of autism is high, effective treatments have not yet been identified. Recently, genome-wide association studies have identified many mutations or variations associated with ASD risk on many chromosome loci and genes. Identification of the biological roles of these mutations or variations is necessary to identify the mechanisms underlying ASD pathogenesis and to develop clinical treatments. At present, mice harboring genetic modifications of ASD-associated gene candidates are the best animal models to analyze hereditary factors involved in autism. In this report, the biological significance of ASD-associated genes is discussed by examining the phenotypes of mouse models with ASD-associated mutations or variations in mouse homologs, with a focus on mice harboring genetic modifications of the Caps2/Cadps2 (Ca2+-dependent activator protein for secretion 2) gene.
PMCID: PMC3881117  PMID: 24287856
CAPS2/CADPS2; dense-core vesicle; BDNF; GABAergic interneurons; CNV; ASD mouse model; social interaction; anxiety; maternal behavior
5.  Genetics and Mitochondrial Abnormalities in Autism Spectrum Disorders: A Review 
Current Genomics  2011;12(5):322-332.
We review the current status of the role and function of the mitochondrial DNA (mtDNA) in the etiology of autism spectrum disorders (ASD) and the interaction of nuclear and mitochondrial genes. High lactate levels reported in about one in five children with ASD may indicate involvement of the mitochondria in energy metabolism and brain development. Mitochondrial disturbances include depletion, decreased quantity or mutations of mtDNA producing defects in biochemical reactions within the mitochondria. A subset of individuals with ASD manifests copy number variation or small DNA deletions/duplications, but fewer than 20 percent are diagnosed with a single gene condition such as fragile X syndrome. The remaining individuals with ASD have chromosomal abnormalities (e.g., 15q11-q13 duplications), other genetic or multigenic causes or epigenetic defects. Next generation DNA sequencing techniques will enable better characterization of genetic and molecular anomalies in ASD, including defects in the mitochondrial genome particularly in younger children.
PMCID: PMC3145262  PMID: 22294875
Autism spectrum disorders (ASD); mitochondrial DNA (mtDNA) mutations and depletion; oxidative stress; nuclear genes; lactate/pyruvate ratios; genetic causation.
6.  Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder 
Translational Psychiatry  2013;3(1):e220-.
Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels—a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction. Future studies need to identify additional parallels between the PPA rodent model of ASD and this subset of ASD individuals with this unique pattern of acyl-carnitine abnormalities. A better understanding of this animal model and subset of children with ASD should lead to better insight in mechanisms behind environmentally induced ASD pathophysiology and should provide guidance for developing preventive and symptomatic treatments.
PMCID: PMC3566723  PMID: 23340503
acyl-carnitines; autism spectrum disorder; clostridia; microbiome; mitochondrial disease; propionic acid
7.  Multiple rare variants in the etiology of autism spectrum disorders 
Recent studies in autism spectrum disorders (ASDs) support an important role for multiple rare variants in these conditions. This is a clinically important finding, as, with the demonstration that a significant proportion of ASDs are the result of rare, etiological genetic variants, it becomes possible to make use of genetic testing to supplement behavioral analyses for an earlier diagnosis. As it appears that earlier interventions in ASDs will produce better outcomes, the development of genetic testing to augment behaviorally based evaluations in ASDs holds promise for improved treatment. Furthermore, these rare variants involve synaptic and neuronal genes that implicate specific paihvi/ays, cells, and subcellular compartments in ASDs, which in turn will suggest novel therapeutic approaches in ASDs, Of particular recent interest are the synaptic cell adhesion and associated molecules, including neurexin 1, neuroligin 3 and 4, and SHANK3, which implicate glutamatergic synapse abnormalities in ASDs, In the current review we will overview the evidence for a genetic etiology for ASDs, and summarize recent genetic findings in these disorders.
PMCID: PMC3181906  PMID: 19432386
pervasive developmental disorder; autism spectrum disorder; genetics; association; susceptibility locus
8.  Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses 
Autism spectrum disorder (ASD) is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and repetitive interests/behaviors. Advances in human genomics have identified a large number of genetic variations associated with ASD. These associations are being rapidly verified by a growing number of studies using a variety of approaches, including mouse genetics. These studies have also identified key mechanisms underlying the pathogenesis of ASD, many of which involve synaptic dysfunctions, and have investigated novel, mechanism-based therapeutic strategies. This review will try to integrate these three key aspects of ASD research: human genetics, animal models, and potential treatments. Continued efforts in this direction should ultimately reveal core mechanisms that account for a larger fraction of ASD cases and identify neural mechanisms associated with specific ASD symptoms, providing important clues to efficient ASD treatment.
PMCID: PMC3733014  PMID: 23935565
autism spectrum disorder; therapeutics; genetics; animal model; synapse; synaptopathy
9.  Macrophage Migration Inhibitory Factor and Stereotypical Behavior in Autism Spectrum Disorders 
Pediatrics  2008;122(2):10.1542/peds.2007-3604.
Autism-spectrum disorders (ASD) are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. Based on results of prior genetic linkage studies and reported altered innate immune response in ASD, we hypothesized that MIF could represent a candidate gene for ASD or its diagnostic components.
Genetic association between ASD and MIF was investigated in two independent sets of families of probands with ASD, from USA (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for ASD diagnoses. Genotyping was performed for two polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were carried out in a subset of Dutch patients from whom plasma was available.
There were genetic associations between known functional polymorphisms in the promoter for MIF and ASD-related behaviors. Also, probands with ASD exhibited higher circulating MIF levels than did their unaffected siblings; the amount of MIF in the plasma correlated with the severity of multiple ASD symptoms.
These results identify MIF as a susceptibility gene for ASD. Further research is warranted on the precise relationship between MIF and the behavioral components of ASD, the mechanism by which MIF contributes to ASD pathogenesis, and the clinical utility of MIF genotyping.
PMCID: PMC3816765  PMID: 18676531
10.  Enriched rearing improves behavioral responses of an animal model for CNV-based autistic-like traits 
Human Molecular Genetics  2012;21(14):3083-3096.
Potocki–Lupski syndrome (PTLS; MIM #610883), characterized by neurobehavioral abnormalities, intellectual disability and congenital anomalies, is caused by a 3.7-Mb duplication in 17p11.2. Neurobehavioral studies determined that ∼70–90% of PTLS subjects tested positive for autism or autism spectrum disorder (ASD). We previously chromosomally engineered a mouse model for PTLS (Dp(11)17/+) with a duplication of a 2-Mb genomic interval syntenic to the PTLS region and identified consistent behavioral abnormalities in this mouse model. We now report extensive phenotyping with behavioral assays established to evaluate core and associated autistic-like traits, including tests for social abnormalities, ultrasonic vocalizations, perseverative and stereotypic behaviors, anxiety, learning and memory deficits and motor defects. Alterations were identified in both core and associated ASD-like traits. Rearing this animal model in an enriched environment mitigated some, and even rescued selected, neurobehavioral abnormalities, suggesting a role for gene-environment interactions in the determination of copy number variation-mediated autism severity.
PMCID: PMC3384379  PMID: 22492990
11.  Modeling Autistic Features in Animals 
Pediatric research  2011;69(5 Pt 2):34R-40R.
A variety of features of autism can be simulated in rodents, including the core behavioral hallmarks of stereotyped and repetitive behaviors, and deficits in social interaction and communication. Other behaviors frequently found in autism spectrum disorders (ASD) such as neophobia, enhanced anxiety, abnormal pain sensitivity and eye blink conditioning, disturbed sleep patterns, seizures, and deficits in sensorimotor gating are also present in some of the animal models. Neuropathology and some characteristic neurochemical changes that are frequently seen in autism, as well as alterations in the immune status in the brain and periphery are also found in some of the models. Several known environmental risk factors for autism have been successfully established in rodents, including maternal infection and maternal valproate administration. Also under investigation are a number of mouse models based on genetic variants associated with autism or on syndromic disorders with autistic features. This review briefly summarizes recent developments in this field, highlighting models with face and/or construct validity, and noting the potential for investigation of pathogenesis and early progress towards clinical testing of potential therapeutics. Wherever possible, reference is made to reviews rather than primary articles.
PMCID: PMC3088489  PMID: 21289542
12.  Channelopathy pathogenesis in autism spectrum disorders 
Frontiers in Genetics  2013;4:222.
Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.
PMCID: PMC3817418  PMID: 24204377
calcium; mTOR; Fragile X syndrome; tuberous sclerosis; Rett syndrome; Prader-Willi syndrome; Angelman syndrome
13.  Prader–Willi syndrome and autism spectrum disorders: an evolving story 
Prader–Willi syndrome (PWS) is well-known for its genetic and phenotypic complexities. Caused by a lack of paternally derived imprinted material on chromosome 15q11–q13, individuals with PWS have mild to moderate intellectual disabilities, repetitive and compulsive behaviors, skin picking, tantrums, irritability, hyperphagia, and increased risks of obesity. Many individuals also have co-occurring autism spectrum disorders (ASDs), psychosis, and mood disorders. Although the PWS 15q11–q13 region confers risks for autism, relatively few studies have assessed autism symptoms in PWS or directly compared social, behavioral, and cognitive functioning across groups with autism or PWS. This article identifies areas of phenotypic overlap and difference between PWS and ASD in core autism symptoms and in such comorbidities as psychiatric disorders, and dysregulated sleep and eating. Though future studies are needed, PWS provides a promising alternative lens into specific symptoms and comorbidities of autism.
PMCID: PMC3261277  PMID: 21858456
Prader–Willi syndrome; Chromosome 15q11–q13; Autism; Psychosis
14.  Multiple autism-like behaviors in a novel transgenic mouse model 
Behavioural brain research  2010;218(1):29-41.
Autism spectrum disorder (ASD) diagnoses are behaviorally-based with no defined universal biomarkers, occur at a 1:110 ratio in the population, and predominantly affect males compared to females at approximately a 4:1 ratio. One approach to investigate and identify causes of ASD is to use organisms that display abnormal behavioral responses that model ASD-related impairments. This study describes a novel transgenic mouse, MALTT, which was generated using a forward genetics approach. It was determined that the transgene integrated within a noncoding region on the X chromosome. The MALTT line exhibited a complete repertoire of ASD-like behavioral deficits in all three domains required for an ASD diagnosis: reciprocal social interaction, communication, and repetitive or inflexible behaviors. Specifically, MALTT male mice showed deficits in social interaction and interest, abnormalities in pup and juvenile ultrasonic vocalization communications, and exhibited a repetitive stereotypy. Abnormalities were also observed in the domain of sensory function, a secondary phenotype prevalently associated with ASD. Mapping and expression studies suggested that the Fam46 gene family may be linked to the observed ASD-related behaviors. The MALTT line provides a unique genetic model for examining the underlying biological mechanisms involved in ASD-related behaviors.
PMCID: PMC3022332  PMID: 21093492
social behavior; mouse model; ultrasonic vocalization; autism; gene expression
15.  Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments 
Neuropsychopharmacology  2011;37(1):196-212.
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder affecting approximately 1% of children. ASD is defined by core symptoms in two domains: negative symptoms of impairment in social and communication function, and positive symptoms of restricted and repetitive behaviors. Available treatments are inadequate for treating both core symptoms and associated conditions. Twin studies indicate that ASD susceptibility has a large heritable component. Genetic studies have identified promising leads, with converging insights emerging from single-gene disorders that bear ASD features, with particular interest in mammalian target of rapamycin (mTOR)-linked synaptic plasticity mechanisms. Mouse models of these disorders are revealing not only opportunities to model behavioral perturbations across species, but also evidence of postnatal rescue of brain and behavioral phenotypes. An intense search for ASD biomarkers has consistently pointed to elevated platelet serotonin (5-HT) levels and a surge in brain growth in the first 2 years of life. Following a review of the diversity of ASD phenotypes and its genetic origins and biomarkers, we discuss opportunities for translation of these findings into novel ASD treatments, focusing on mTor- and 5-HT-signaling pathways, and their possible intersection. Paralleling the progress made in understanding the root causes of rare genetic syndromes that affect cognitive development, we anticipate progress in models systems using bona fide ASD-associated molecular changes that have the potential to accelerate the development of ASD diagnostics and therapeutics.
PMCID: PMC3238072  PMID: 21937981
translation; mGluR5; FMR1; glutamate; serotonin transporter; genetics; development; developmental disorders; serotonin; animal models; signal transduction; autism; translation; mTor; mGluR5; fragile X
16.  Rhythm, movement, and autism: using rhythmic rehabilitation research as a model for autism 
Recently, there has been increased focus on movement and sensory abnormalities in autism spectrum disorders (ASD). This has come from research demonstrating cortical and cerebellar differences in autism, with suggestion of early cerebellar dysfunction. As evidence for an extended profile of ASD grows, there are vast implications for treatment and therapy for individuals with autism. Persons with autism are often provided behavioral or cognitive strategies for navigating their environment; however, these strategies do not consider differences in motor functioning. One accommodation that has not yet been explored in the literature is the use of auditory rhythmic cueing to improve motor functioning in ASD. The purpose of this paper is to illustrate the potential impact of auditory rhythmic cueing for motor functioning in persons with ASD. To this effect, we review research on rhythm in motor rehabilitation, draw parallels to motor dysfunction in ASD, and propose a rationale for how rhythmic input can improve sensorimotor functioning, thereby allowing individuals with autism to demonstrate their full cognitive, behavioral, social, and communicative potential.
PMCID: PMC3610079  PMID: 23543915
autism spectrum disorders; synchronization; movement regulation; neurologic music therapy; rhythm
17.  The effectiveness of hydrotherapy in the treatment of social and behavioral aspects of children with autism spectrum disorders: a systematic review 
Autism spectrum disorders (ASDs) are increasing in prevalence. Children with ASDs present with impairments in social interactions; communication; restricted, repetitive, and stereotyped patterns of behavior, interests, or activities; as well as motor delays. Hydrotherapy is used as a treatment for children with disabilities and motor delays. There have been no systematic reviews conducted on the effectiveness of hydrotherapy in children with ASDs.
We aimed to examine the effectiveness of hydrotherapy on social interactions and behaviors in the treatment of children with ASDs.
A systematic search of Cochrane, CINAHL, PsycINFO, Embase, MEDLINE®, and Academic Search Premier was conducted. Studies of participants, aged 3–18 years, with ASDs at a high-functioning level were included if they utilized outcome measures assessing social interactions and behaviors through questionnaire or observation. A critical appraisal, using the McMaster Critical Review Form for Quantitative Studies, was performed to assess methodological quality.
Four studies of varying research design and quality met the inclusion criteria. The participants in these studies were aged between 3–12 years of age. The duration of the intervention ranged from 10–14 weeks, and each study used varied measures of outcome. Overall, all the studies showed some improvements in social interactions or behaviors following a Halliwick-based hydrotherapy intervention.
Few studies have investigated the effect of hydrotherapy on the social interactions and behaviors of children with ASDs. While there is an increasing body of evidence for hydrotherapy for children with ASDs, this is constrained by small sample size, lack of comparator, crude sampling methods, and the lack of standardized outcome measures. Hydrotherapy shows potential as a treatment method for social interactions and behaviors in children with ASDs.
PMCID: PMC3917923  PMID: 24520196
evidence-based practice; aquatic therapy; pediatrics; secondary research
18.  The Effects of Birth Order and Birth Interval on the Phenotypic Expression of Autism Spectrum Disorder 
PLoS ONE  2012;7(11):e51049.
A rise in the prevalence of diagnosed cases of autism spectrum disorder (ASD) has been reported in several studies in recent years. While this rise in ASD prevalence is at least partially related to increased awareness and broadened diagnostic criteria, the role of environmental factors cannot be ruled out, especially considering that the cause of most cases of ASD remains unknown. The study of families with multiple affected children can provide clues about ASD etiology. While the majority of research on ASD multiplex families has focused on identifying genetic anomalies that may underlie the disorder, the study of symptom severity across ASD birth order may provide evidence for environmental factors in ASD. We compared social and cognitive measures of behavior between over 300 first and second affected siblings within multiplex autism families obtained from the Autism Genetic Resource Exchange dataset. Measures included nonverbal IQ assessed with the Ravens Colored Progressive Matrices, verbal IQ assessed with the Peabody Picture Vocabulary Test, and autism severity assessed with the Social Responsiveness Scale (SRS), an instrument established as a quantitative measure of autism. The results indicated that females were more severely impacted by ASD than males, especially first affected siblings. When first and second affected siblings were compared, significant declines in nonverbal and verbal IQ scores were observed. In addition, SRS results demonstrated a significant increase in autism severity between first and second affected siblings consistent with an overall decline in function as indicated by the IQ data. These results remained significant after controlling for the age and sex of the siblings. Surprisingly, the SRS scores were found to only be significant when the age difference between siblings was less than 2 years. These results suggest that some cases of ASD are influenced by a dosage effect involving unknown epigenetic, environmental, and/or immunological factors.
PMCID: PMC3511407  PMID: 23226454
19.  The Neurology of Autism Spectrum Disorders 
Current opinion in neurology  2011;24(2):132-139.
Purpose of review
Neurological comorbidities in autism spectrum disorders (ASD) are not only common, but they are also associated with more clinical severity. This review highlights the most recent literature on three of autism’s most prevalent neurological comorbidities: motor impairment, sleep disorders, and epilepsy.
Recent findings
Motor impairment in ASD manifests as both delays and deficits, with delays found in gross and fine motor domains and deficits found in praxis, coordination, and gait, all of which affect other cognitive and behavioral domains. Sleep disorders, especially insomnia, occur in up to 83% of children with ASD and recent studies have begun to explore the underlying biochemical and behavioral basis of the impairment, which has bolstered treatment studies. Epilepsy is reported in up to one-third of children with ASD, and new studies have focused on identifying the genetic causes of this association.
Better characterization of the phenotype, developmental trajectory, and underlying pathophysiology of these neurological comorbidities will enable us to define neurological endophenotypes within the autism spectrum. Future studies must investigate the emergence of these comorbidities prospectively in order to determine whether they lie on the causal pathway to ASD or whether they reflect epiphenomena of the disorder. Since epilepsy and sleep disorders can be treated and may contribute significantly to behavioral and cognitive abnormalities in ASD, their identification is of high clinical relevance.
PMCID: PMC3160764  PMID: 21293268
autism; neurology; motor; sleep; epilepsy; endophenotype
20.  Motor abnormalities as a putative endophenotype for Autism Spectrum Disorders 
Autism Spectrum Disorders (ASDs) represent a complex group of behaviorally defined conditions with core deficits in social communication and the presence of repetitive and restrictive behaviors. To date, neuropathological studies have failed to identify pathognomonic cellular features for ASDs and there remains a fundamental disconnection between the complex clinical aspects of ASDs and the underlying neurobiology. Although not listed among the core diagnostic domains of impairment in ASDs, motor abnormalities have been consistently reported across the spectrum. In this perspective article, we summarize the evidence that supports the use of motor abnormalities as a putative endophenotype for ASDs. We argue that because these motor abnormalities do not directly depend on social or linguistic development, they may serve as an early disease indicator. Furthermore, we propose that stratifying patients based on motor development could be useful not only as an outcome predictor and in identifying more specific treatments for different ASDs categories, but also in exposing neurobiological mechanisms.
PMCID: PMC3678087  PMID: 23781177
Autism Spectrum Disorders; motor abnormalities; endophenotype; early assessment; early screening
21.  Which DSM-IV-TR criteria best differentiate high-functioning autism spectrum disorder from ADHD and anxiety disorders in older children? 
Diagnosis of autism spectrum disorder (ASD) is often delayed in high-functioning children with milder and more varied forms of ASD. The substantial overlap between ASD and other psychiatric disorders is thought to contribute to this delay. This study examined the endorsement of DSM-IV-TR diagnostic criteria for ASD based on semi-structured parent interviews across three groups of older children referred to an ASD clinic: 55 children diagnosed with high-functioning ASD, 27 children diagnosed with attention-deficit/hyperactivity disorder (ADHD), and 23 children diagnosed with anxiety disorder. Results indicate that the criteria within the domains of communication and social relatedness were largely able to discriminate the high-functioning ASD group from the ADHD and anxiety disorder groups, but criteria within the domain of restricted/repetitive/stereotyped patterns were not.
PMCID: PMC3035910  PMID: 19759063
ADHD; anxiety disorder; autism; diagnostic differentiation
22.  Array‐based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders 
Journal of Medical Genetics  2006;43(11):843-849.
Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11–q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling.
Methods and results
29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2–19 clones). No recurrent abnormality was identified.
These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.
PMCID: PMC2563185  PMID: 16840569
23.  Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders 
Journal of medical genetics  2006;43(11):843-849.
Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11–q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling.
Methods and results:
29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2–19 clones). No recurrent abnormality was identified.
These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.
PMCID: PMC2563185  PMID: 16840569
24.  A prospective Cross-sectional Cohort Assessment of Health, Physical, and Behavioral Problems in Autism Spectrum Disorders 
Mædica  2012;7(3):193-200.
Objectives: Autism spectrum disorder (ASD) is diagnostically defined by impaired socialization/communication and stereotypical behaviors. Health, physical, and behavioral problems have also been described in subjects diagnosed with an ASD, but have usually been examined in isolation. The purpose of the present study was to for the first time, systematically and quantitatively, examines health, physical and behavioral problems in a cohort of subjects diagnosed with an ASD.
Materials and Methods: A prospective cross-sectional ASD cohort (n=54) was evaluated for health, physical, and behavioral symptoms derived from parentally completed Autism Treatment Evaluation Checklist (ATEC) forms. The study protocol received Institutional Review Board (IRB) approval from Liberty IRB, Inc (Deland, FL).
Outcomes: The results showed the following occurrence of symptoms among study participants: gastrointestinal disturbances=48%, incontinence=57%, sleep problems=57%, eating disorders=94%, hyperactivity=67%, lethargy=26%, sensory processing problems=85%, anxiety/fear=74%, behavioral problems=89%, and obsessive-compulsive behaviors=92%. Of all of the areas examined, eating problems, behavioral problems, and obsessive-compulsive behaviors, were reported by the parents to be the most serious and problematic.
Conclusions: The present findings, taken together with previous research, suggest that subjects diagnosed with an ASD have significant health, physical, and behavioral problems beyond the symptoms evaluated in the diagnostic criteria used to diagnosis an ASD. The present findings also suggest the ATEC provides an economical means for healthcare providers to identify health, physical, and behavioral problems in subjects diagnosed with an ASD.
PMCID: PMC3566881  PMID: 23400046
ASDs; Asperger's; autistic; PDD-NOS; CARS; ATEC
25.  Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders 
Molecular Autism  2010;1:3.
It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS) and 'repetitive sensory-motor actions' (RSMA) are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales.
A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees.
Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled.
The finding that IS and RSMA are linked to different regions that only partially overlap regions previously identified with ASD as the phenotype supports the value of including multiple, narrowly defined phenotypes in ASD genetic research. Further, we replicated previous reports indicating that RSMA is more strongly associated than IS with measures of ASD severity.
PMCID: PMC2907569  PMID: 20678246

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