DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families.

BACKGROUND: The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males. METHODS: We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility. RESULTS: There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children (P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing. CONCLUSION: Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.

The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes.

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4-60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-mum-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.

Triggers of Aggressive Behaviors in Intellectually Disabled Adults and Their Association with Autism, Medical Conditions, Psychiatric Disorders, Age and Sex: A Large-Scale Study.

Aggressive behaviors in those with intellectual disability (ID) and autism (ASD) have been linked to a variety of factors including ID level, age, sex, psychiatric disorders, and medical conditions but these factors have not been studied, in large samples, in terms of how they affect the stimuli that trigger aggression. In this survey of 2243 adults, four triggers of aggression associated with frustration, discomfort, change in the physical/social environment, and defensive reactions were analyzed for their relation to ID level, ASD, age, sex, number of psychiatric diagnoses, sleeping problems, seizures, visual impairment, ear infections and gastrointestinal problems. All four triggers were associated with increasing number of psychiatric disorders, with frustration, discomfort, and change intolerance commonly linked to sleeping problems and ASD. Implications for assessment and intervention are discussed.

Autism Spectrum Disorder Decision Tree Subgroups Predict Adaptive Behavior and Autism Severity Trajectories in Children with ASD.

A recent cross-sectional analysis of PDD Behavior Inventory (PDDBI) data, analyzed with a classification and regression tree algorithm, yielded a decision tree (the Autism Spectrum Disorder-Decision Tree or ASD-DT) that detected three behaviorally distinct ASD subgroups: minimally verbal, verbal, and atypical. These subgroups differed in PDDBI profiles and in factors previously reported to be predictors of autism severity and adaptive behavior trajectories. We retrospectively analyzed trajectories of adaptive skills and autism severity in these subgroups, defined by ASD-DTs calculated from initial evaluation PDDBIs. Results confirmed predictions that each subgroup had distinct trajectories that varied with the type of adaptive behavior assessed suggesting that the ASD-DT has prognostic value that could be helpful for both clinical and research applications.

Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents.

Folate deficiency can affect fetal and neonatal brain development Considering the reported association of Folate receptor alpha (FRα) autoantibodies (Abs) with autism and developmental disorders, we sought to confirm this in families of 82 children with ASD, 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated normal controls. Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%. The Ab was highly prevalent in affected families including unaffected siblings. The appearance of these antibodies may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected. The antibody response appears heritable with the blocking autoantibody in the parents and affected child increasing the risk of ASD. Autism Res 2018, 11: 707-712. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Folate is an essential nutrient during fetal and infant development. Autoantibodies against the folate receptor alpha can block folate transport from the mother to the fetus and to the brain in infants. Children diagnosed with autism and their immediate family members were evaluated for the prevalence of folate receptor autoantibodies. The autoantibody was highly prevalent in affected families with similar distribution in parents, normal siblings and affected children. The presence of these antibodies appears to have a familial origin and may contribute to developmental deficits when combined with other factors.

Altered development of neuronal progenitor cells after stimulation with autistic blood sera.

Changes of brain structure and functions in people with autism may result from altered neuronal development, however, no adequate cellular or animal models are available to study neurogenesis in autism. Neuronal development can be modeled in culture of neuronal progenitor cells (NPCs) stimulated with serum to differentiate into neurons. Because sera from people with autism and age-matched controls contain different levels of numerous biologically active factors, we hypothesized that development of human NPCs induced to differentiate into neurons with sera from children with autism reflects the altered early neuronal development that leads to autism. The control and autistic sera were collected from siblings aged below 6 years that lived in the same environment. The effect of sera on differentiation of NPC neurospheres into neuronal colonies was tested in 72-h-long cultures by morphometry, immunocytochemistry and immunoblotting. We found that sera from children with autism significantly reduced NPCs' proliferation, but stimulated cell migration, development of small neurons with processes, length of processes and synaptogenesis. These results suggest that development of network of processes and synaptogenesis--the specific events in the brain during postnatal ontogenesis--are altered in autism. Further studies in this cell culture model may explain some of the cellular alterations described in autistic patients.

Maternal recurrent mood disorders and high-functioning autism.

A quantitative examination was made of the association of parental mood and anxiety disorders with severity of disability within a large sample of young children with Pervasive Developmental Disorder (PDD). Maternal recurrent mood disorders were associated with elevated cognitive and adaptive functioning in their affected children, parent reports of increased behavior problems and teacher reports of an internalizing behavioral style. Maternal histories of anxiety disorders and paternal depression or anxiety disorders were not associated with levels of adaptive/cognitive functioning or levels of maladaptive behaviors in the children. Various genetic models are discussed. It is hypothesized that genes associated with recurrent depression in women may exert a "protective" effect on cognition and adaptive functioning in children with PDD.

Using the PDD Behavior Inventory as a Level 2 Screener: A Classification and Regression Trees Analysis.

In order to improve discrimination accuracy between Autism Spectrum Disorder (ASD) and similar neurodevelopmental disorders, a data mining procedure, Classification and Regression Trees (CART), was used on a large multi-site sample of PDD Behavior Inventory (PDDBI) forms on children with and without ASD. Discrimination accuracy exceeded 80 %, generalized to an independent validation set, and generalized across age groups and sites, and agreed well with ADOS classifications. Parent PDDBIs yielded better results than teacher PDDBIs but, when CART predictions agreed across informants, sensitivity increased. Results also revealed three subtypes of ASD: minimally verbal, verbal, and atypical; and two, relatively common subtypes of non-ASD children: social pragmatic problems and good social skills. These subgroups corresponded to differences in behavior profiles and associated bio-medical findings.

Treatment of previously undiagnosed psychiatric disorders in persons with developmental disabilities decreased or eliminated self-injurious behavior.

BACKGROUND: Self-injurious behavior (SIB) is one of the most common challenging behaviors in persons with autistic disorder or severe/profound mental retardation. Many psychotropic drugs have been evaluated for their effectiveness in SIB. Results have varied, and no one psychotropic drug has been indicated for SIB. In this prospective, open clinical study, psychotropic drugs were used to treat the previously undiagnosed psychiatric disorder in persons exhibiting SIB. METHOD: Data were collected from 26 individuals with mental retardation (14 males, 12 females), 7 to 45 years of age (mean = 30.3 years), who exhibited SIB. Psychiatric diagnosis was made according to DSM-III-R and DSM-IV criteria. The Behavior Problem Inventory, Yudofsky's Overt Aggression Scale, repeated direct observation, and information on use of protective devices and Likert scales from log books were used to evaluate degree of SIB. Most of the patients were treated with different psychotropic drugs and behavior modification before they were evaluated for this study, but only 7 of them carried a psychiatric diagnosis. Data were collected between 1987 and 1997. RESULTS: Depressive disorders, impulse-control disorder, and anxiety disorder were the most common final diagnoses. Neuroleptics were discontinued in 5 patients and tapered by 50% to 75% in 14 patients. Antidepressants were added in 12 patients. Treatment of psychiatric disorders produced significant (p < .001) decrease in the severity of SIB in the 26 patients, and SIB was eliminated in 12 patients. The severity of SIB decreased to mild from a moderate, severe, or extreme degree in 11 patients and from an extreme to a severe degree in 3 patients. CONCLUSION: The most effective treatment for SIB that is resistant to environment changes and behavior modification in persons with developmental disabilities is the treatment of their psychiatric disorders with the appropriate psychotropics.

Alteration in amino-glycerophospholipids levels in the plasma of children with autism: a potential biochemical diagnostic marker.

Currently, there is no biochemical test to assist in the behavioral diagnosis of autism. We observed that levels of phosphatidylethanolamine (PE) were decreased while phosphatidylserine (PS) were increased in the erythrocyte membranes of children with autism as compared to their non-autistic developmentally normal siblings. A new method using Trinitrobenezene sulfonic acid (TNBS) for the quantification of PE and PS (amino-glycerophospholipids, i.e., AGP) in the plasma of children was developed and standardized. Wavelength scans of TNBS-PE and TNBS-PS complexes gave two peaks at 320 nm and 410 nm. When varying concentrations of PS and PE were used, a linear regression line was observed at 410 nm with TNBS. Using this assay, the levels of AGP were found to be significantly increased in the plasma of children with autism as compared to their non-autistic normal siblings. It is proposed that plasma AGP levels may function as a potential diagnostic marker for autism.

Criterion-related validity of the PDD Behavior Inventory.

The PDD Behavior Inventory (PDDBI) is a rating scale filled out by parents and teachers that is designed to assess response to intervention in children with PDD. It consists of subscales that measure both maladaptive and adaptive behaviors and also provides a summary "Autism Score" reflective of the severity of the condition. The scale has been shown to have very good internal consistency as well as developmental and construct validity. In this study, the PDDBI's criterion-related validity was assessed. Correlations with the Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised were good. Selected maladaptive scales from the PDDBI correlated well with comparable factors of the Nisonger Child Behavior Rating Form. The adaptive sections of the PDDBI correlated highly with the Griffiths Mental Development Scales and with the Vineland Adaptive Behavior Scales. These results confirm the validity of the PDDBI and suggest that the scale will have value in assessing treatment-related changes in maladaptive and adaptive behaviors associated with PDD.

The PDD Behavior Inventory: a rating scale for assessing response to intervention in children with pervasive developmental disorder.

The PDD Behavior Inventory (PDDBI) is a rating scale filled out by caregivers or teachers that was designed to assess children having a Pervasive Developmental Disorder (PDD; autism, Asperger disorder, PDD-NOS, or childhood disintegrative disorder). Both adaptive and maladaptive behaviors are assessed in the scale, making it useful for treatment studies in which decreases in maladaptive behaviors and improvements in adaptive social and language skills relevant to PDD are expected. The adaptive behaviors assessed include core features of the disorder such as joint attention skills, pretend play, and referential gesture. The maladaptive behaviors sample a wide variety of behaviors observed in both lower- and higher-functioning individuals and include stereotyped behaviors, fears, aggression, social interaction deficits, and aberrant language. The inventory was found to have a high degree of internal consistency. Inter-rater reliability was better for adaptive behaviors than for maladaptive behaviors. Factor analyses confirmed the structure of the PDDBI and indicated good construct validity. In a subsample of children between 3 and 6 years of age, raw scores for adaptive behaviors increased with age in the parent and teacher versions, as did measures of social pragmatic problems. It was concluded that the PDDBI is both reliable and valid and is useful in providing information not typically available in most instruments used to assess children with PDD.

Rating scale measures are associated with Noldus EthoVision-XT video tracking of behaviors of children on the autism spectrum.

BACKGROUND: Children with Autism Spectrum Disorder (ASD) show unusual social behaviors and repetitive behaviors. Some of these behaviors, e.g., time spent in an area or turning rate/direction, can be automatically tracked. Automated tracking has several advantages over subjective ratings including reliability, amount of information provided, and consistency across laboratories, and is potentially of importance for diagnosis, animal models and objective assessment of treatment efficacy. However, its validity for ASD has not been examined. In this exploratory study, we examined associations between rating scale data with automated tracking of children's movements using the Noldus EthoVision XT system; i.e., tracking not involving a human observer. Based on our observations and previous research, we predicted that time spent in the periphery of the room would be associated with autism severity and that rate and direction of turning would be associated with stereotypies. METHODS: Children with and without ASD were observed in a free-play situation for 3 min before and 3 min after Autism Diagnostic Observation Scale - Generic (ADOS-G) testing. The Noldus system provided measures of the rate and direction of turning, latency to approach and time spend near the periphery or the parent. RESULTS: Ratings of the severity of maladaptive social behaviors, stereotypies, autism severity, and arousal problems were positively correlated with increases in percent time spent in the periphery in the total sample and in the ASD subset. Adaptive social communication skills decreased with increases in the percentage of time spent in the periphery and increases in the latency to approach the parent in the ASD group. The rate and direction of turning was linked with stereotypies only in the group without ASD (the faster the rate of a turn to the left, the worse the rating). In the ASD group, there was a shift from a neutral turning bias prior to the ADOS assessment to a strong left turn bias after the ADOS assessment. In the entire sample, this left turn bias was associated with measures of autism severity. CONCLUSION: Results suggest that automated tracking yields valid and unbiased information for assessing children with autism. Turning bias is an interesting and unexplored measure related to autism.

Stereological study of the neuronal number and volume of 38 brain subdivisions of subjects diagnosed with autism reveals significant alterations restricted to the striatum, amygdala and cerebellum.

INTRODUCTION: A total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods. RESULTS: The study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively. CONCLUSIONS: The observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.

Brain-region-specific alterations of the trajectories of neuronal volume growth throughout the lifespan in autism.

Several morphometric studies have revealed smaller than normal neurons in the neocortex of autistic subjects. To test the hypothesis that abnormal neuronal growth is a marker of an autism-associated global encephalopathy, neuronal volumes were estimated in 16 brain regions, including various subcortical structures, Ammon's horn, archicortex, cerebellum, and brainstem in 14 brains from individuals with autism 4 to 60 years of age and 14 age-matched control brains. This stereological study showed a significantly smaller volume of neuronal soma in 14 of 16 regions in the 4- to 8-year-old autistic brains than in the controls. Arbitrary classification revealed a very severe neuronal volume deficit in 14.3% of significantly altered structures, severe in 50%, moderate in 21.4%, and mild in 14.3% structures. This pattern suggests desynchronized neuronal growth in the interacting neuronal networks involved in the autistic phenotype. The comparative study of the autistic and control subject brains revealed that the number of structures with a significant volume deficit decreased from 14 in the 4- to 8-year-old autistic subjects to 4 in the 36- to 60-year-old. Neuronal volumes in 75% of the structures examined in the older adults with autism are comparable to neuronal volume in age-matched controls. This pattern suggests defects of neuronal growth in early childhood and delayed up-regulation of neuronal growth during adolescence and adulthood reducing neuron soma volume deficit in majority of examined regions. However, significant correction of neuron size but limited clinical improvements suggests that delayed correction does not restore functional deficits.

Autoantibodies against neuronal progenitors in sera from children with autism.

The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55 kDa, 105 kDa, 150 kDa, and 210 kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150 kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism.

18-month predictors of later outcomes in younger siblings of children with autism spectrum disorder: a baby siblings research consortium study.

OBJECTIVE: Younger siblings of children with autism spectrum disorder (ASD) are at high risk (HR) for developing ASD as well as features of the broader autism phenotype. Although this complicates early diagnostic considerations in this cohort, it also provides an opportunity to examine patterns of behavior associated specifically with ASD compared to other developmental outcomes. METHOD: We applied Classification and Regression Trees (CART) analysis to individual items of the Autism Diagnostic Observation Schedule (ADOS) in 719 HR siblings to identify behavioral features at 18 months that were predictive of diagnostic outcomes (ASD, atypical development, and typical development) at 36 months. RESULTS: Three distinct combinations of features at 18 months were predictive of ASD outcome: poor eye contact combined with lack of communicative gestures and giving; poor eye contact combined with a lack of imaginative play; and lack of giving and presence of repetitive behaviors, but with intact eye contact. These 18-month behavioral profiles predicted ASD versus non-ASD status at 36 months with 82.7% accuracy in an initial test sample and 77.3% accuracy in a validation sample. Clinical features at age 3 years among children with ASD varied as a function of their 18-month symptom profiles. Children with ASD who were misclassified at 18 months were higher functioning, and their autism symptoms increased between 18 and 36 months. CONCLUSION: These findings suggest the presence of different developmental pathways to ASD in HR siblings. Understanding such pathways will provide clearer targets for neural and genetic research and identification of developmentally specific treatments for ASD.

Prevalence of psychotropic drug use in adults with intellectual disability: positive and negative findings from a large scale study.

The use of psychotropics by categories and the reason for their prescription was investigated in a large scale study of 4,069 adults with ID, including those with autism spectrum disorder, in New York State. Similar to other studies it was found that 58 % (2,361/4,069) received one or more psychotropics. Six percent received typical, while 39 % received atypical antipsychotics [corrected]. There was greater use of antidepressants (23 %), mood stabilizers (19 %), and antianxiety agents (16 %) relative to other studies. The use of anti-impulsives, stimulants and hypnotics was rare (1-2 %). Half of the psychotropics were prescribed for treatment of major psychiatric disorders, 13 % for control of challenging behaviors, and 38 % for both. Results indicated that the major psychiatric disorders, except anxiety disorder and autism, influenced the use of psychotropics and the number of medication used. These findings imply that although practitioners still rely too heavily on the use of antipsychotics in this population, there is a welcome shift in the prescription patterns relative to other studies. The practitioners appeared to use psychotropics primarily to treat diagnosed psychiatric disorders and not just to control aggressive behavior which suggests that evidence-based practice of psychiatry is playing an increasing role in the ID population.

Neonatal brainstem function and 4-month arousal-modulated attention are jointly associated with autism.

The authors evaluated the contribution of initially abnormal neonatal auditory brainstem responses (ABRs) and 4-month arousal-modulated attention visual preference to later autism spectrum disorder (ASD) behaviors in neonatal intensive care unit (NICU) graduates. A longitudinal study design was used to compare NICU graduates with normal ABRs (n = 28) to those with initially abnormal ABRs (n = 46) that later resolved. At 4 months postterm age, visual preference (measured after feeding) for a random check pattern flashing at 1, 3, or 8 Hz and gestational age (GA) served as additional predictors. Outcome measures were PDD Behavior Inventory (PDDBI) scores at 3.4 years (standard deviation = 1.2), and developmental quotients (DQ) obtained around the same age with the Griffiths Mental Development Scales (GMDS). Preferences for higher rates of stimulation at 4 months were highly correlated with PDDBI scores (all P-values < 0.01) and the GMDS Hearing and Speech DQ, but only in those with initially abnormal ABRs. Effects were strongest for a PDDBI social competence measure most associated with a diagnosis of autism. For those with abnormal ABRs, increases in preference for higher rates of stimulation as infants were linked to nonlinear increases in severity of ASD at 3 years and to an ASD diagnosis. Abnormal ABRs were associated with later reports of repetitive and ritualistic behaviors irrespective of 4-month preference for stimulation. The joint occurrence of initially abnormal neonatal ABRs and preference for more stimulation at 4 months, both indices of early brainstem dysfunction, may be a marker for the development of autism in this cohort.

Contribution of olivofloccular circuitry developmental defects to atypical gaze in autism.

Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivofloccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects.