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Annotation: what do we know about sensory dysfunction in autism? A critical review of the empirical evidence.

BACKGROUND: Unusual responses to sensory stimuli are seen in many children with autism. Their presence was highlighted both in early accounts of autism and in more recent first-person descriptions. There is a widespread belief that sensory symptoms characterize autism and differentiate it from other disorders. This paper examines the empirical evidence for this assumption. METHOD: All controlled experimental laboratory investigations published since 1960 were identified through systematic searches using Medline/PubMed and PsycInfo search engines. A total of 48 empirical papers and 27 theoretical or conceptual papers were reviewed. RESULTS: Sensory symptoms are more frequent and prominent in children with autism than in typically developing children, but there is not good evidence that these symptoms differentiate autism from other developmental disorders. Certain groups, including children with fragile X syndrome and those who are deaf-blind, appear to demonstrate higher rates of sensory symptoms than children with autism. In reviewing the evidence relevant to two theories of sensory dysfunction in autism, over- and under-arousal theory, we find that there is very little support for hyper-arousal and failure of habituation in autism. There is more evidence that children with autism, as a group, are hypo-responsive to sensory stimuli, but there are also multiple failures to replicate findings and studies that demonstrate lack of group differences. CONCLUSIONS: The use of different methods, the study of different sensory modalities, and the changing scientific standards across decades complicate interpretation of this body of work. We close with suggestions for future research in this area.

Arousal↗

Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism.

OBJECTIVE: The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype. METHOD: The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments. RESULTS: Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects. CONCLUSIONS: These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.

Adolescent↗

A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.

BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism.

Autistic Disorder↗

Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society [RETIRED].

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Asperger Syndrome↗

Understanding children with autism: exploding the myths.

The incidence of autism is increasing in both the USA and in Britain. There is still controversy over what causes autism and even greater controversy over selecting a preferred method of intervention and support (as there is no treatment for autism). Although there is now a general consensus that individuals may have a genetic predisposition to develop autism, it is also acknowledged that this may be off set by a range of environmental and/or biological factors. The understanding of the causation of autism is now considered in much the same way as we understand cerebral palsy, in that there can be a range of different reasons for causation and prevalence. This article, the first of two parts, will explore how an awareness and understanding of autism can enable nurses working with children with autism to provide more child-centred nursing care based on fact as opposed to stereotype and mythology surrounding autism. The second part will concentrate on adults with autism.

Autistic Disorder↗

The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages.

Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction, deficits in verbal and nonverbal communication, and a restricted repertoire of activities or interests. We performed a magnetic resonance imaging study to better define the neuropathology of autistic spectrum disorders. Here we report findings on the amygdala and the hippocampal formation. Borders of the amygdala, hippocampus, and cerebrum were defined, and their volumes were measured in male children (7.5-18.5 years of age) in four diagnostic groups: autism with mental retardation, autism without mental retardation, Asperger syndrome, and age-matched typically developing controls. Although there were no differences between groups in terms of total cerebral volume, children with autism (7.5-12.5 years of age) had larger right and left amygdala volumes than control children. There were no differences in amygdala volume between the adolescent groups (12.75-18.5 years of age). Interestingly, the amygdala in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. Thus, the amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children. Children with autism, with and without mental retardation, also had a larger right hippocampal volume than typically developing controls, even after controlling for total cerebral volume. Children with autism but without mental retardation also had a larger left hippocampal volume relative to controls. These cross-sectional findings indicate an abnormal program of early amygdala development in autism and an abnormal pattern of hippocampal development that persists through adolescence. The cause of amygdala and hippocampal abnormalities in autism is currently unknown.

Adolescent↗

Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation.

OBJECTIVE: This study determined the prevalence of autism for a defined community, Brick Township, New Jersey, using current diagnostic and epidemiologic methods. METHODS: The target population was children who were 3 to 10 years of age in 1998, who were residents of Brick Township at any point during that year, and who had an autism spectrum disorder. Autism spectrum disorder was defined as autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), and Asperger disorder. The study used 4 sources for active case finding: special education records, records from local clinicians providing diagnosis or treatment for developmental or behavioral disabilities, lists of children from community parent groups, and families who volunteered for participation in the study in response to media attention. The autism diagnosis was verified (or ruled out) for 71% of the children through clinical assessment. The assessment included medical and developmental history, physical and neurologic evaluation, assessment of intellectual and behavioral functioning, and administration of the Autism Diagnostic Observation Schedule-Generic. RESULTS: The prevalence of all autism spectrum disorders combined was 6.7 cases per 1000 children. The prevalence for children whose condition met full diagnostic criteria for autistic disorder was 4.0 cases per 1000 children, and the prevalence for PDD-NOS and Asperger disorder was 2.7 cases per 1000 children. Characteristics of children with autism in this study were similar to those in previous studies of autism. CONCLUSIONS: The prevalence of autism in Brick Township seems to be higher than that in other studies, particularly studies conducted in the United States, but within the range of a few recent studies in smaller populations that used more thorough case-finding methods.

Anthropometry↗

The contribution of diagnostic substitution to the growing administrative prevalence of autism in US special education.

OBJECTIVE: Growing administrative prevalence of autism has stirred public controversy and concern. The extent to which increases in the administrative prevalence of autism have been associated with corresponding decreases in the use of other diagnostic categories is unknown. The main objective of this study was to examine the relationship between the rising administrative prevalence of autism in US special education and changes in the use of other classification categories. METHODS: The main outcome measure was the administrative prevalence of autism among children ages 6 to 11 in US special education. Analysis involved estimating multilevel regression models of time-series data on the prevalence of disabilities among children in US special education from 1984 to 2003. RESULTS: The average administrative prevalence of autism among children increased from 0.6 to 3.1 per 1000 from 1994 to 2003. By 2003, only 17 states had a special education prevalence of autism that was within the range of recent epidemiological estimates. During the same period, the prevalence of mental retardation and learning disabilities declined by 2.8 and 8.3 per 1000, respectively. Higher autism prevalence was significantly associated with corresponding declines in the prevalence of mental retardation and learning disabilities. The declining prevalence of mental retardation and learning disabilities from 1994 to 2003 represented a significant downward deflection in their preexisting trajectories of prevalence from 1984 to 1993. California was one of a handful of states that did not clearly follow this pattern. CONCLUSIONS: Prevalence findings from special education data do not support the claim of an autism epidemic because the administrative prevalence figures for most states are well below epidemiological estimates. The growing administrative prevalence of autism from 1994 to 2003 was associated with corresponding declines in the usage of other diagnostic categories.

Autistic Disorder↗

Comparison of Sensory Profile scores of young children with and without autism spectrum disorders.

OBJECTIVES: The purpose of this study was to describe the sensory-based behaviors of young children with autism as reported by their parents on the Sensory Profile. Factor scores of children with autism were compared with those of children without autism. METHOD: The Sensory Profile questionnaire was completed by parents of 40 children with autism 3 through 6 years of age and parents of 40 children without autism 3 through 6 years of age. RESULTS: The performance of children with autism was significantly different from that of children without autism on 8 of 10 factors. Factors where differences were found included Sensory Seeking, Emotionally Reactive, Low Endurance/Tone, Oral Sensitivity, Inattention/Distractibility, Poor Registration, Fine Motor/Perceptual, and Other. CONCLUSION: Findings from the study suggest that young children with autism have deficits in a variety of sensory processing abilities as measured by the Sensory Profile. Further research is needed to replicate these findings, to examine the possibility of subgroups on the basis of sensory processing, and to contrast the sensory processing abilities of children with other disabilities to those of children with autism.

Autistic Disorder↗

Etiology of infantile autism: a review of recent advances in genetic and neurobiological research.

The etiology of autism is complex, and in most cases the underlying pathologic mechanisms are unknown. Autism is a hetereogeneous disorder, diagnosed subjectively on the basis of a large number of criteria. Recent research has investigated genetics, in utero insults and brain function as well as neurochemical and immunological factors. On the basis of family and twin studies, there appears to be a genetic basis for a wide "autistic syndrome." About a quarter of cases of autism are associated with genetic disorders such as fragile X syndrome or with infectious diseases such as congenital rubella. Genetic studies have shown an association between autism markers of brain development such as 3 markers of the c-Harvey-ros oncogene and the homeobox gene EN2. In some cases, autism is associated with insults early in gestation, including thalidomide embryopathy. Autism may arise from abnormal central nervous system functioning, since most autistic patients have indications of brain dysfunction, and about half of them have abnormal electroencephalograms. Similarly, the pattern of evoked response potentials and conduction time is altered in autistic children. There is substantial evidence from neuroimaging studies that dysfunctions in the cerebellum and possibly the temporal lobe and association cortex occur in autistic symptoms. Neurochemical studies have investigated the role of serotonin, epinephrine and norepinephrine, since levels of these neurotransmitters are altered in autism, although other hypotheses implicate overactive brain opioid systems and changes in oxytocin neurotransmission. Autoimmunity may also play a role; antibodies against myelin basic protein are often found in children with autism, who also have increased eosinophil and basophil response to IgE-mediated reactions. In summary, the prevailing view is that autism is caused by a pathophysiologic process arising from the interaction of an early environmental insult and a genetic predisposition.

Autistic Disorder↗

[The dynamics of infantile autism. The longitudinal studies].

28 children diagnosed to be autistic were involved in the longitudinal studies. The criteria were taken from DSM-III-R. 18 children in the early stage of autism were chosen. The development of disorders has been observed since the period infancy among these children. The other group consisted of 10 children in the late stage of autism. The development of autism in the group was followed by normal development of the child until the 12-18 month of life. The research was conducted in the 3rd, 5th and 7th year of life. 3 areas of developments were taken under consideration: social relations (A), verbal vs. non-verbal communication (B), activity and interests (C). In the estimated group (A, B, C) 5 criteria were achieved, each in a 5-grade scale, 1 meaning the lack of symptom and 5 meaning the higher intensity. At the age of 3 the intensity of disorders on the three evaluated areas of development did not differentiate children in early and late stage of autism. The future development of children in the early stage of autism was not successful. A visible difference was seen at the age of 5. Children in the late stage of autism developed in all 3 areas of investigation. At the age of 7, children in the late stage of autism seemed to gradually "withdraw from autism". Longitudinal studies conducted on autistic children confirmed the hypothesis about the age of child's life, when the first symptoms of disorders showed, as being an important predictor of the autism development dynamic.

Activities of Daily Living↗

Autism and specific language impairment: categorical distinction or continuum?

Traditionally, autism and specific language impairment (SLI) are regarded as distinct disorders, with differential diagnosis hinging on two features. First, in SLI one sees isolated language impairments in the context of otherwise normal development, whereas in autism a triad of impairments is seen, affecting communication, social interaction and behavioural repertoire. Second, there are different communication problems in these two conditions. Children with SLI have particular difficulty with structural aspects of language (phonology and syntax). In contrast, abnormal use of language (pragmatics) is the most striking feature of autism. However, recently, this conventional view has been challenged on three counts. First, children with autism have structural language impairments similar to those in SLI. Second, some children have symptoms intermediate between autism and SLT. Third, there is a high rate of language impairments in relatives of people with autism, suggesting aetiological continuities between SLI and autism. One interpretation of these findings is to regard autism as 'SLI plus', i.e. to assume that the only factor differentiating the disorders is the presence of additional impairments in autism. It is suggested that a more plausible interpretation is to regard structural and pragmatic language impairments as correlated but separable consequences of common underlying risk factors.

Autistic Disorder↗

An autosomal genomic screen for autism.

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions.

Adolescent↗

The incidence of autism in Olmsted County, Minnesota, 1976-1997: results from a population-based study.

OBJECTIVE: To determine the incidence of autism among children in Olmsted County, Minnesota. DESIGN: Through the Rochester Epidemiology Project, all inpatient and outpatient diagnoses are indexed for computerized retrieval. This computerized diagnostic index was used to identify children with any developmental disorder. A glossary of symptoms of autism was used to review medical and school records of these children for symptoms consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for autistic disorder. SETTING: Olmsted County, Minnesota. Subjects All residents of Olmsted County 21 years or younger between 1976 and 1997. Main Outcome Measure The incidence of research-identified autism based on DSM-IV criteria for autistic disorder. RESULTS: The age-adjusted incidence of research-identified autism was 5.5 (95% confidence interval, 1.4-9.5) per 100 000 children from 1980 to 1983 and 44.9 (95% confidence interval, 32.9-56.9) from 1995 to 1997 (8.2-fold increase). This increase was confined to children younger than 10 years who were born after 1987. CONCLUSIONS: The incidence of research-identified autism increased in Olmsted County from 1976 to 1997, with the increase occurring among young children after the introduction of broader, more precise diagnostic criteria, increased availability of services, and increased awareness of autism. Although it is possible that unidentified environmental factors have contributed to an increase in autism, the timing of the increase suggests that it may be due to improved awareness, changes in diagnostic criteria, and availability of services, leading to identification of previously unrecognized young children with autism.

Adolescent↗

Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome.

BACKGROUND: Recognition of individual faces is an integral part of both interpersonal interactions and successful functioning within a social group. Therefore, it is of considerable interest that individuals with autism and related conditions have selective deficits in face recognition (sparing nonface object recognition). METHOD: We used functional magnetic resonance imaging (fMRI) to study face and subordinate-level object perception in 14 high-functioning individuals with autism or Asperger syndrome (the autism group), in comparison with 2 groups of matched normal controls (normal control group ] [NC1] and normal control group 2 [NC2]) (n = 14 for each). Regions of interest (ROIs) were defined in NC1 and then applied in comparisons between NC2 and the autism group. Regions of interest were also defined in NC2 and then applied to comparisons between NC1 and the autism group as a replication study. RESULTS: In the first set of comparisons, we found significant task x group interactions for the size of activation in the right fusiform gyrus (FG) and right inferior temporal gyri (ITG). Post hoc analyses showed that during face (but not object) discrimination, the autism group had significantly greater activation than controls in the right ITG and less activation of the right FG. The replication study showed again that the autism group used the ITG significantly more for processing faces than the control groups, but for these analyses, the effect was now on the left side. Greater ITG activation was the pattern found in both control groups during object processing. CONCLUSIONS: Individuals with autism spectrum disorders demonstrate a pattern of brain activity during face discrimination that is consistent with feature-based strategies that are more typical of nonface object perception.

Adult↗

Time trends in autism and in MMR immunization coverage in California.

CONTEXT: Considerable concern has been generated in the lay and medical communities by a theory that increased measles-mumps-rubella (MMR) immunization among young children may be the cause of an apparent marked increase in autism occurrence. OBJECTIVE: To determine if a correlation exists in secular trends of MMR immunization coverage among young children and autism occurrence. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analyses of MMR immunization coverage rates among children born in 1980-1994 who were enrolled in California kindergartens (survey samples of 600-1900 children each year) and whose school immunization records were reviewed to retrospectively determine the age at which they first received MMR immunization; and of autism caseloads among children born in these years who were diagnosed with autism and were enrolled in the California Department of Developmental Services regional service center system. MAIN OUTCOME MEASURES: Measles-mumps-rubella immunization coverage rates as of ages 17 months and 24 months and numbers of Department of Developmental Services system enrollees diagnosed with autism, grouped by year of birth. RESULTS: Essentially no correlation was observed between the secular trend of early childhood MMR immunization rates in California and the secular trend in numbers of children with autism enrolled in California's regional service center system. For the 1980-1994 birth cohorts, a marked, sustained increase in autism case numbers was noted, from 44 cases per 100 000 live births in the 1980 cohort to 208 cases per 100 000 live births in the 1994 cohort (a 373% relative increase), but changes in early childhood MMR immunization coverage over the same time period were much smaller and of shorter duration. Immunization coverage by the age of 24 months increased from 72% to 82%, a relative increase of only 14%, over the same time period. CONCLUSIONS: These data do not suggest an association between MMR immunization among young children and an increase in autism occurrence.

Autistic Disorder↗

Prevalence of autism in a US metropolitan area.

CONTEXT: Concern has been raised about possible increases in the prevalence of autism. However, few population-based studies have been conducted in the United States. OBJECTIVES: To determine the prevalence of autism among children in a major US metropolitan area and to describe characteristics of the study population. DESIGN, SETTING, AND POPULATION: Study of the prevalence of autism among children aged 3 to 10 years in the 5 counties of metropolitan Atlanta, Ga, in 1996. Cases were identified through screening and abstracting records at multiple medical and educational sources, with case status determined by expert review. MAIN OUTCOME MEASURES: Autism prevalence by demographic factors, levels of cognitive functioning, previous autism diagnoses, special education eligibility categories, and sources of identification. RESULTS: A total of 987 children displayed behaviors consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for autistic disorder, pervasive developmental disorder-not otherwise specified, or Asperger disorder. The prevalence for autism was 3.4 per 1000 (95% confidence interval [CI], 3.2-3.6) (male-female ratio, 4:1). Overall, the prevalence was comparable for black and white children (black, 3.4 per 1000 [95% CI, 3.0-3.7] and white, 3.4 per 1000 [95% CI, 3.2-3.7]). Sixty-eight percent of children with IQ or developmental test results (N = 880) had cognitive impairment. As severity of cognitive impairment increased from mild to profound, the male-female ratio decreased from 4.4 to 1.3. Forty percent of children with autism were identified only at educational sources. Schools were the most important source for information on black children, children of younger mothers, and children of mothers with less than 12 years of education. CONCLUSION: The rate of autism found in this study was higher than the rates from studies conducted in the United States during the 1980s and early 1990s, but it was consistent with those of more recent studies.

Black or African American↗

Minor malformations and physical measurements in autism: data from Nova Scotia.

In the context of an epidemiological study of autism in Nova Scotia, subjects were evaluated for minor physical anomalies and physical measurements. Normal control children, children with autism and their siblings, and children with developmental disabilities and their siblings were compared. Posterior rotation of the external ears was found to be a characteristic related to autism specifically, rather than to developmental disabilities in general. Small feet and normal-to-large hands also were observed in the autism group. Children with autism had a significant reduction in interpupillary distance, but not intercanthic distance or head circumference. In contrast, children with other developmental disabilities were notable for general small stature, which affected the hands, feet, eyes, and head size, as well as height. Abnormal ear configuration was the minor malformation most characteristic of the developmental disability group, and the subset of Down syndrome children had single transverse creases of the palm and epicanthic folds that resulted in significantly increased rates of these anomalies in the developmentally disabled controls. Siblings of the two disabled groups were not significantly different from normal controls on any of the measures that characterized children with autism or other developmental disabilities. The results agree with those of several previous studies, which have suggested that abnormalities of the ears are the general category of minor anomalies most associated with autism. Recent evidence regarding the embryological origin of autism suggests that the ear effects may be an important marker of the initiating events that lead to the disorder.

Abnormalities, Multiple↗