The Penn State Institute for Personalized Medicine (www.med.psu.edu/ipm) applies genomic tools to determine genetic factors contributing to disease onset and treatment response as a means of improving health outcomes.  One focus of the Institute is amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with a worldwide prevalence of 4-6 per 100,000 population.  ALS affects lower motor neurons in brainstem and spinal cord, upper motor neurons in motor cortex, and the corticospinal tract, resulting in progressive weakness and atrophy of skeletal muscles. Death results from respiratory failure within three years on average of initial diagnosis.  The majority of ALS cases are sporadic (SALS) with only 5-10% of patients having a family history of the disease (FALS).  Studies of FALS patients have identified a number of genes, mutation of which likely accounts for the onset of the disease.  However, twin studies have estimated ALS heritability at greater than 60%, strongly suggesting that a majority of SALS cases also have a genetic basis.  Accordingly, we have determined the genomic sequences of several hundred SALS patients and, when possible, the parents of those patients as well.  These studies demonstrate that patients often carry compound heterozygous mutations that potentially inactivate genes whose loss leads to ALS onset.  We are currently examining the functions of these genes in various model systems to assess their likely association with ALS and to provide a format for tailoring treatment options on the basis of the genetic underpinning of the disease.