Etiology and pathophysiology
Initially considered a consequence of psychosocial phenomena, ASDs are now understood to be brain-based biological disorders, although no clear universal cause has been revealed. Medical conditions, such as aminoaciduria and ligamentous laxity, and perinatal difficulties have been reported to co-occur with AD, but robust correlations have not been documented across studies.5,33,34 Increased rates of epilepsy have been observed in persons with AD.35 Neurochemical studies of ASDs have produced inconsistent results; the most common finding suggests elevated blood serotonin levels.36
The most consistent neuroanatomical findings in ASD reflect rapid brain growth in early childhood. This leads to increased brain volume that normalizes in mid-childhood and results in a relatively small corpus callosum.37 Several studies that have focused specifically on AD have shown associated abnormalities, including left frontal macrogyria and bilateral opercular polymicrogyria, gray tissue anomalies, left temporal lobe damage, left occipital hypoperfusion, and dysmorphology superior to the ascending ramus of the Sylvian fissure proximal to the intersection of the mid frontal gyrus and the precentral sulcus.38,39 Replication is required to determine whether distinct brain regions are implicated in AD.
Similar brain regions may be involved in ASDs, with quantitative differences in functioning that lead to the observed phenotypic heterogeneity and variation in severity.40 Functional imaging has revealed abnormalities in brain activity associated with social information processing and social cognition as well as problems with functional connectivity among separate brain regions.41-44 Research has not yet identified the brain regions implicated in AD or in the broader autism spectrum.
Genetic factors have been considered since Asperger’s original account.45 Case series have reported AD, ASD, or autistic-like traits in family members, particularly among fathers. Also, the rate of autistic-like traits in siblings of children with an ASD is considerably higher than that in the general population.10,46-48 Some family history studies also indicate associations with other psychiatric disorders, including depression, schizophrenia, and schizoid personality disorders.49
Although AD may have stronger heritability than autism, most evidence indicates shared genetic mechanisms common to all ASDs.50,51 No consistent genetic etiology has been established for AD, and the ASDs probably feature a polygenetic etiology with as-yet-unspecified epigenetic gene-environment interactions.52 Individual studies have reported specific genetic abnormalities, including balanced translocations, and de novo translocations—chromosomes 1, 5, 11, 13, 14, 15, 17, autosomal fragile site, fragile X syndrome, fragile Y, and 21p+.35,53-57
Diagnostic assessment of AD entails a comprehensive developmental history, including early social development. The individual’s social and communicative characteristics should be assessed by direct observation in multiple contexts; social difficulties are often most pronounced during unstructured periods without clear social expectations or adult-directed interactions. Psychiatric interviewers should observe social behaviors, such as use of eye contact, gesture, and social reciprocity. Social communicative competency can be assessed by making leading conversational bids, asking open-ended questions, and forcing the interviewee to sustain the burden of maintaining the conversation. The interview should elicit details about social relationships, circumscribed interests, self-awareness, and insight into others. Input from teachers and parents about the child’s behavior with peers is also important. The assessment should address obsessions and compulsions, ritualized behaviors, depression and panic attacks, and integrity of thought processes and should include reality testing.