Neuropathology of Idiopathic Autism and Autism Associated with Chromosome 15 Duplication

Background: Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. Duplication of chromosome 15 (Dup15), characterized by alterations of the multi-disorder critical region  (15q1-q13) is detected in from 1% to 4% of autism cases (Cook 1998, Gillberg, 1998). These genetic abnormalities are usually associated with autism, mental retardation (often profound), seizures, and increased risk of sudden death (Baker et al 1994, Bundey et al 1994). In idiopathic autism abnormalities of neurogenesis, neuronal migration and dysplastic changes were reported in 92% of brains (Wegiel et al 2010) but neuropathology of Dup15 is not known. One may speculate that neuropathological studies of brains of subjects with autism and related disorders will help to identify common forms of pathology with major contribution to autism phenotype and comorbidity-associated modifications. 

Objectives: The aim of this study is to detect differences between pattern of pathological changes in the brain of subjects with idiopathic autism and Dup15.

Methods: One brain hemisphere of 10 subjects diagnosed with idiopathic autism and 9 subjects with chromosome 15 duplication was fixed in formalin, dehydrated, embedded in polyethylene glycol (PEG) and cut into 50-μm thick serial hemispheric sections. In extended neuropathological protocol more than 220 serial hemispheric sections stained with cresyl violet or immunostained were examined in each case.

Results: Sudden unexpected death was more often in Dup15 cohort. Brain weight was lower by 295 g  (1,234 g versus 1,529 g) than in idiopathic autism. In both cohorts defects of neurogenesis (subependymal nodular dysplasia), neuronal migration (heterotopias) and dysplastic changes were observed. However, Dup15 cohort was affected by a broader spectrum of dysplastic changes in neocortex, hippocampus, amygdala and cerebellum, and focal abnormalities were more numerous. Significantly smaller volume of neurons and neuronal nuclei was another marker of developmental defects in Dup15. Numerous corpora amylacea, accumulation of Aβ-positive rod-like inclusions in neuronal processes in the stratum lacunosum moleculare, and excessive cytoplasmic accumulation of amino-terminally truncated Aβ appear to be the marker of metabolic alterations leading to neurodegeneration. Signs of glial proliferation and activation in the subependymal and in subpial zone indicate that glia are also involved in developmental alterations in Dup15.

Conclusions: Dup15 cohort is characterized by a high prevalence of sudden unexpected death, lower brain weight, broader spectrum and severity of developmental alterations, degenerative changes and glial proliferation and activation. Common defects of migration and dysplastic changes may contribute to high prevalence of epilepsy, including intractable seizures.