Biomarker of Children With Familial Autoimmune History

Purpose: To identify biomarkers in this subset of autism patients, design a protein based
assay system for screening serum for these biomarkers and confirm that these serum
antibodies are still present at one year's time.

Rationale: Autistic spectrum disorders (ASD), are an increasingly important public health
concern. Estimates of prevalence of ASDs range from 1/500 to 1/150 children. Retrospective
data points to immune dysfunction in some of these children and increased frequency of
familial autoimmune history (FAH) has been reported in children with autism. Behavioral
responses to immune modulating therapy, though in uncontrolled studies, indicate a role for
autoimmunity in the pathogenesis. Preliminary prospective work has suggested an immune
etiology in autism based on the high frequency of brain endothelial antibodies (BEA) in
children with language regression, 2/3 of whom are on the autistic spectrum and with autism
without language regression. Follow up studies in a small number of patients showed
persistence of BEA after at least a year. The specific nervous system epitopes have not been
identified.

Population: Approximately 15 children with clinically diagnosed autism who have first degree
relatives (parents, brothers, sisters, or children) with autoimmune disorders listed on a
questionnaire. Children on the autism spectrum without autoimmune history and sibling
matched controls without an ASD from the Simons Foundation Autism Research Initiative
(SFARI) with deidentified data in the SFARI database will be matched for age, sex and
ethnicity. Plasma samples and psychometric data from the database will be provided through
the database for analysis in the laboratory of Dr. Reiter.

Design: The investigators seek to identify protein biomarkers in the serum of children with
carefully characterized autism who have a familial autoimmune history in first degree
relatives (FAH). Cognitive defects in the mouse model of the autism spectrum disorder
tuberous sclerosis complex can be ameliorated by rapamycin, an immune suppressant drug
indicating the likelihood that auto-immunity plays a role in autism pathogenesis. To
expedite the identification of these biomarkers the investigators will use proteomic
profiling in Drosophila melanogaster. The Drosophila (fly) nervous system is highly
homologous to humans at the molecular level and genetic pathways for synaptic development
and function are highly conserved. Several human neurogenetic diseases including Huntington,
Alzheimer, fragile X, spinal cerebellar ataxia and Parkinson disease have been successfully
studied using fly genetic models. Monoclonal antibodies generated against total fly brain
homogenate cross react with human neuronal tissue and are highly specific for the
recognition of particular subsets of neurons in the human nervous system. Our goal is to
identify biomarkers in this group of autism patients, design a protein based assay system
for screening serum for these biomarkers and confirm that these serum antibodies are
persistent. A similar approach was taken by Dr. Levin to identify the central nervous system
(CNS) autoantigen in the human T-lymphotropic virus type 1 disease associated
myelopathy/tropical spastic. Dr. Reiter's group currently uses proteomic profiling in
Drosophila to identify the protein targets of the Angelman syndrome gene, UBE3A.

Inclusion Criteria:

- 4-17 years of age

- male or female

- autistic subjects must have a diagnosis of autism spectrum disorder

Exclusion Criteria:

- Controls must have no diagnosis of autism spectrum disorder.

- controls must be typically developing children without behavioral deviations.