Elliott H. Sherr, MD, PhD
The genetics of autism and epilepsy: studies in cerebral development and connectivity

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Background: The causes of autism, cognitive disabilities and epilepsy are generally poorly understood, current therapeutic approaches are not sufficient, nor is early identification feasible.

Major Goals: We are interested in understanding the genetic causes of autism and severe childhood epilepsies, both as a means to better understand the principles of cerebral development and to devise novel therapeutic approaches.

Ongoing Research:
De novo copy number variation and gene discovery in human brain malformations: Our lab and others have shown that de novo genetic events play an important role in causing disorders of cerebral development. We are using high density SNP arrays to identify de novo deletions, duplications and translocations in a large cohort of patients with three malformations of brain development that frequently have overlapping presentations: agenesis of the corpus callosum (ACC), polymicrogyria (PMG) and Dandy Walker malformation (DWM). ACC in particular has a strong association with autism, as many patients meet ADI /ADOS criteria or have clinical symptoms within the autistic spectrum, as exemplified by Kim Peek, whose life was fictionalized in the movie, Rain Man. When candidate genes are identified, we are developing animal models (in mouse in our lab and in zebrafish in collaboration), to investigate the implications on cerebral development.

Cerebral Connectivity in ACC: ACC is a radiological finding and not a single diagnosis. Moreover, surgical transection of the corpus callosum does not recapitulate the clinical findings of patients with congenital ACC. This suggests that other non-obvious changes in cerebral connectivity may account for these autistic behaviors. We are using diffusion tensor imaging and magnetoencephalography (in collaboration with Drs. Mukherjee and Nagarajan in the department of radiology) to probe anatomic and functional cerebral connectivity in ACC patients. We have shown that the cingulum bundle, (the major white matter tract that connects the limbic system to the prefrontal cortex), is severely diminished in ACC patients. Additionally, we have shown that ACC patients have heterotopic cortico-cortical connections that were unappreciated on conventional imaging, suggesting a more global disruption in cerebral development.

Gene discovery and neurodevelopmental analysis in a mouse model of autism: We are investigating the mouse strain, BTBR T+tf/J (BTBR), that has both AgCC and behaviors with face validity to autism. BTBR mice display multiple social deficits as juveniles and adults, unusual vocalizations as infants and high levels of repetitive behaviors, representing the first, second and third diagnostic symptoms of autism, respectively. These mice also have cerebral wiring deficits, the most obvious being AgCC and probst bundles. We are investigating the hypothesis that AgCC and other disruptions of cerebral connectivity and development in BTBR mice are intimately related to the observed autistic symptomatology. We have identified two loci that are the major contributors to the lack of the corpus callosum and are working aggressively to identify the causative genes. In collaboration with Jacki Crawley at the NIH and Ralph Adolphs at Caltech, we are investigating the interaction between the autistic behavior and genetics and also using advanced imaging and detailed histological analyses to begin to bridge the brain/behavior/gene interface.

Gene Discovery in Aicardi Syndrome: A Special Case of Callosal Agenesis: In 1965 Dr. Jean Aicardi first described a syndrome of infantile spasms, chorioretinal lacunae and ACC. This disorder presents sporadically and only in females and XXY (Klinefelter) males, strongly suggesting that it is caused by de novo X chromosome mutations, which would be lethal in hemizygous males. Imaging studies demonstrate a unique cerebral malformation complex that includes callosal agenesis and other characteristic findings: polymicrogyria, heterotopia, cysts and a marked asymmetry of the cerebral hemispheres and microscopic evaluation of brain has demonstrated disruption of normal cortical layering and cerebral perinuclear inclusions that contain cytoskeletal elements. These findings suggest that the causative gene may be critical to establishing neuronal and overall cerebral patterning during development. We have recruited a large cohort of these patients and are using a novel genetic approach, array capture, followed by high throughput sequencing to identify the gene in these patients and develop a model to study how this gene regulates cerebral development.

The genetics of epilepsy: We have studied a mouse model of generalized epilepsy, called audiogenic seizures. These are present in the mouse strain, Black Swiss, and we have cloned the causative gene (GIPC3). This gene is localized to the plasma membrane and to rab5 positive endocytic vesicles. We are currently investigating how mutation of that gene affects neuronal excitability. We are part of a large multi-center epilepsy research consortium (EPGP; www.epgp.com). Through this group, we are studying the genetics of two types of severe childhood epilepsies, infantile spasms and Lennox Gastaut.

Selected Publications

Misawa H # , Sherr E.H. # , Lee DJ, Chetkovich DM, Tan A, Schreiner CE, Bredt DS. Identification of a Monogenic Locus (jams1) Causing Juvenile Audiogenic Seizures in Mice J Neurosci Dec 1;22(23):10088-10093, 2002. ( #these authors contributed equally to this work).

Sherr, E.H. The ARX story: one gene leads to many phenotypes. Current Opinion in Pediatrics, 2003 Dec;15(6):567-71.

Hetts, S. Chao, S. Barkovich, A.J. and Sherr, E.H. Anomalies of the corpus callosum: an MR analysis of the phenotypic spectrum of associated malformations. AJR Am J Roentgenol. 2006 Nov;187(5):1343-8.

Sherr EH, Owen R, Albertson DG, Pinkel D, Cotter PD, Slavotinek AM, Hetts SW, Jeremy RJ, Schilmoeller G, Schilmoeller K, Wakahiro M, Barkovich AJ. Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies. Neurology. 2005 Nov 8;65(9):1496-8.

L.K. Paul, W.S. Brown, R. Adolphs, J.M. Tyszka, L.J. Richards, P. Mukherjee, and E.H. Sherr. Agenesis of the Corpus Callosum: A Model for Genetic, Developmental and Functional Aspects of Connectivity. Nature Review Neuroscience. 2007, 8(4): 287-299.

Boland, E., J. Clayton-Smith, S. McKee, L. Medne, E. Zackai, E. Swanson, K.J. Millen, E.H. Sherr, W.B. Dobyns, and G.C.M. Black, Deletion and translocation breakpoint mapping in 1q44 implicates disruption of the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. American Journal of Human Genetics, 2007, 81(2): 292-303.

Li, J., Shivakumar, S., Wakahiro, M, Mukherjee, P., Barkovich, A.J., Slavotinek, A. and E. H. Sherr.Agenesis of the Corpus Callosum, Optic Coloboma, Intractable Seizures, Craniofacial and Skeletal Dysmorphisms: an autosomal recessive disorder similar to Temtamy Syndrome.American Journal of Medical Genetics, 2007, 143(16): 1900-1905.

Marco, E., F.E. Abidi, J. Bristow, W.B. Dean, P.D. Cotter, R.J. Jeremy, C.E. Schwartz, and E.H. Sherr, ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal. J Med Genet, 2007 Sept 24. (epub).

Maccotta, L. and E.H. Sherr.Hematopoeitic stem cell transplantation for the treatment of childhood cerebral X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2008 Jan 22 (epub).

Glass, H., Shaw, G, Ma, C. and E.H. Sherr. Agenesis of the Corpus Callosum in California 1983-2003: A Population-Based Study. American Journal of Medical Genetics, 2008, In press.

Mueller, S. and E.H. Sherr. The Importance of Metabolic Testing in the Evaluation of Intellectual Disability. Annals of Neurology. 2008 In press.

Glenn, O. Sherr, E.H. Norton, M. and A.J. Barkovich. Agenesis of the Corpus Callosum: An MR Analysis of Associated Abnormalities in the Fetus. AJNR, 2008 In press.

Wahl, M., Strominger, Z., Jeremy, R.J., Barkovich, A.J., Wakahiro, M., Sherr, E.H. and P. Mukherjee. Variability of Homotopic and Heterotopic Callosal Connectivity in Partial Agenesis of the Corpus Callosum: A3T DTI and q-ball Tractography Study. AJNR, 2008 In press.