Craig Bennett, Ph.D. Research Assistant Professor of Pediatrics Research Affiliate, Center on Human Development and Disability cbenet@u.washington.edu 206-616-3788 University of Washington, Box 356320 Seattle, WA 98195-6320

Dr. Bennett's research focuses on genetic diseases of the peripheral nervous system including inherited forms of motor neuron disease. Rare point mutations in the SIMPLE gene were identified as the cause of a dominantly inherited, demyelinating peripheral neuropathy, Charcot Marie Tooth type 1C (CMT1C). Similarly, dominantly inherited point mutations were found in the Senataxin gene as the cause of a juvenile-onset form of motor neuron disease characterized by prominent lower motor neuron pathology with less prominent pyramidal tract signs and absence of bulbar involvement (ALS4).

Current research activity focuses on defining the role of these novel proteins "simple" and "senataxin" in the nervous system and determining how disease-associated mutations induce pathology. While mutations associated with ALS4 likely represent gain-of-toxic function, recessive mutations that represent loss-of-function have been reported associated with a type 2, severe cerebellar ataxia with oculomotor apraxia (AOA2). In many respects, ALS4 and AOA2 represent either ends of the phenotypic spectrum resulting from senataxin mutations. While ALS4 affects motor neurons almost exclusively, the effects of AOA2-associated mutations are more diffuse. AOA2 is characterized by cerebellar atrophy, oculomotor apraxia, early loss of reflexes, late peripheral neuropathy, and slow progression leading to severe motor disability. The majority of AOA2 patients also show elevated alpha-fetoprotein, which is somewhat diagnostic. For either condition, pathological material has been scarce. Two ALS4 autopsies showed characteristic ALS features such as significant anterior horn cell loss. No material has been obtained from AOA2 patients but magnetic resonance imaging shows significant cerebellar atrophy, particularly of the vermis. A common feature of the study of each of disorder has been the development of murine models, cell models, and the utilization of standard biochemistry techniques.