Potential Contributions of Developmental and Epilepsy-Associated Neuropathological Changes to Sudden, Unexpected Death in Four People with Chromosome 15 Duplication and Autism

Background: The ~1% prevalence of epilepsy in the general population increases to ~33% in autism (Tuchman and Rapin, 2002). The interpretation of developmental changes in autism and in chromosome 15 duplication autism has been challenged by a need to separate lesions not associated with epilepsy from lesions that cause epilepsy or are produced by epilepsy (Sutula and Pitkanen, 2001). Epilepsy induces brain alterations that contribute to changes in circuitry, which potentiates seizure-genic foci (Armstrong 2005). Studies of epilepsy in non-autistic subjects have shown that epilepsy is associated with an elevation of APP expression (Shang et al., 1994) and diffuse nonfibrillar A beta plaque formation (Mackenzie et al., 1994, 1996). Defining the patterns of neuropathological changes caused by chromosome 15 duplications is in a very early stage, based on studies of only a few brains.

Objectives: Separation of developmental changes from those associated with epilepsy and those potentially increasing risk of sudden death.

Methods: Brains of four autistic subjects (11, 15, 20, and 25 years old) with chromosome 15 duplications, and four age-matched controls were examined by light microscopy including the unbiased morphometric method and immunocytochemistry, and by electron microscopy. Three affected subjects were previously diagnosed with epilepsy and all four died suddenly and unexpectedly.

Results: The study found reduced size of brain, and reduced volume of neurons and neuronal nuclei in the striatum, amygdala, entorhinal cortex and Purkinje cells, correspond to developmental abnormalities. Changes observed in two subjects, including hippocampal microdysgenesis with hyperconvolution and duplication of the granule cell layer in the dentate gyrus, would appear to be contributory to seizures and could be enhanced by seizures. Chaslin's gliosis, observed in one subject, and local neuronal loss may reflect epilepsy-related brain damage. Enhanced cytoplasmic accumulation of A beta protein in all four subjects may be a reflection of modified APP processing.

Conclusions: This neuropathological study of brains of four subjects with chromosome 15 duplications, showed developmental changes. In three subjects, changes associated with seizures and caused by seizures could have contributed to sudden death. However, central apnea, asphyxia and pulmonary oedema, as well as life threatening cardiac arrythmias during seizures (Earnest et al., 1992, Nashef et al., 1996, Reeves et al., 1996; Jallon 1997; Saussu et al., 1998, Thom et al., 1999) could not be excluded as a direct cause of sudden, unexpected death.                                                                                                                                Sponsors: Autism Speaks, the Department of Defense Autism Spectrum Disorders Research Program (AS073234), and the NYS Office of Mental Retardation and Developmental Disabilities. The Harvard Brain Tissue Resource Center (R24-MH 068855), and the Brain and Tissue Bank at the University of Maryland, Baltimore, provided tissue. The Autism Tissue Program coordinated tissue acquisition.