Neuropathologic changes in subjects with chromosome 15 duplication and autism

Background: Duplications of the proximal long arm of chromosome 15 cause autistic features, mental retardation, seizures, functional deterioration with age and increased risk of sudden death. The pattern of neuropathological changes caused by this genetic defect is not known.

Objectives: Detection of (a) developmental changes contributing to mental retardation, (b) markers of neuronal degeneration contributing to clinical deterioration, and (c) pathology contributing to sudden death. 

Methods: Brains of four subjects (11, 15, 20, and 25 yrs) with chromosome 15 duplications, and four age-matched controls were examined by light and electron microscopy.

Results: The most consistent findings were a reduced size of the brain, and reduced volume of neurons and neuronal nuclei in the amygdala, accumbens, entorhinal cortex and Purkinje cells, indicating a delay in neuronal development. Microdysgenesis in the hippocampus represented by hyperconvolution and duplication of the granule cell layer in the dentate gyrus observed in two subjects may have contributed to seizures and sudden death. Enhanced accumulation of amyloid beta protein in phagosomes/dense bodies in all four subjects was a marker of modified APP processing, trafficking and deposition. Amyloid beta positive inclusions in dendrites in the CA1 sector were another marker of neuronal deterioration. Osmophilic inclusions in the mitochondrial matrix suggested mitochondrial degeneration. Chaslin’s gliosis observed in one subject may reflect epilepsy-related brain damage.

Conclusions: In subjects with chromosome 15 duplications, reduced size of the brain and delayed growth of neurons appear to be the main contributors to developmental deficits, whereas behavioral worsening could be the result of early neurodegeneration.  Sponsors: Autism Speaks and the NYS Office of Mental Retardation and Developmental Disabilities. The Harvard Brain Tissue Resource Center (R24-MH 068855), and Brain and Tissue Bank at the University of Maryland, Baltimore provided tissue. Autism Tissue Program coordinated tissue acquisition.