Patterns of Neuronal Migration Abnormalities in Autism of Unknown Etiology and Autism Caused By Chromosome 15q11.2-q13 Duplications, and Their Contribution to Clinical Phenotype

Background: Our concepts of autism neuropathology have evolved over the past several decades from no abnormalities to a global encephalopathy with type, brain-region and age specific alterations. Abnormal neuronal migration resulting in ectopias, heterotopias and dysplasia appears to be evidence of abnormal germinal cell divisions and migration in autism. Depending on the type, size and topography, they are clinically silent or contribute to diverse clinical manifestations that can include epileptogenic activity, epilepsy and sudden unexpected death of subjects with known epilepsy (SUDEP). Interstitial duplications of maternal origin on chromosome 15q11.2-q13 (dup15) are one of the most prevalent cytogenetic aberrations associated with autism (Rineer et al 1998), epilepsy and SUDEP.  

Objectives: The first aim of this study was to identify patterns of neuronal migration in idiopathic autism, including heterotopias and dysplastic changes. The second aim was to study subjects with dup(15)/autism to establish how genetic duplications alter the type and topography of neuronal migration abnormalities and increase the prevalence of the early onset of seizures and SUDEP.  

Methods: One formalin-fixed brain hemisphere was examined from each of 23 individuals diagnosed with idiopathic autism (including 13 hemispheres embedded in celloidin and 10 in polyethylene glycol (PEG), nine subjects diagnosed with dup(15) (PEG) and 21-age-matched control brains (including 14 in celloidin and seven in PEG). The examination of cresyl violet stained hemispheric sections was designed to detect the global pattern of neuronal migration defects in cortical and subcortical structures including white matter. The aim of the study of 200-µm-thick (celloidin) and 50-µm-thick (PEG) serial sections was to maximize the detection of small alterations.  

Results: Different patterns of developmental changes distinguished idiopathic autism and the dup(15) cohorts. In the dup(15) cohort, the leading pathology was microcephaly with mean brain weights 300 g less than in idiopathic autism. Dysplasia in the dentate gyrus was observed in 89% of the dup(15) cases but in only 10% of idiopathic autism. However, cortical dysplastic changes that were absent in dup15 were present in 50% of the idiopathic autism cases. A comparable prevalence of neuronal heterotopias in the cerebellar white matter in idiopathic autism (60%) and dup(15) (56%) suggests that the mechanisms which control the abnormal migration of neurons in the cerebellum are similar in idiopathic autism and autism associated with dup(15). Infiltration of the cerebral and cerebellar subcortical white matter with a unique phenotype of FMRP-positive astrocytes suggested a response of glial cells to the defective migration of neurons in both idiopathic autism and dup(15). Neuronal deficits and severe dysplastic changes in the flocculus, which is known to be involved in eye movement control, coexisted with a disruption of the oculomotor system in 88% of individuals diagnosed with autism and atypical gaze.  

Conclusions: This study demonstrates abnormal neuronal migration in autism of unknown and known etiology but the prevalence of developmental alterations was higher in the dup(15)/autism cohort than in idiopathic autism and was associated with an increased risk of an early onset of intractable epilepsy and SUDEP.