Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22

Context Occasionally, 2 or more major neurodegenerative diseases arise simu ltaneously, An understanding of the genetic bases of combined disorders, su ch as amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD ), will likely provide insight into mechanisms of these and related neurode generative diseases, Objective To identify loci that contain genes whose defects cause ALS. Design A genome-wide linkage analysis of 2 data sets from an ongoing study begun in the mid-1980s at 4 university research centers, Subjects An initial subset of 16 families (549 people) potentially informat ive for genetic analysis, in which 2 or more individuals were diagnosed as having ALS, identified from a Boston data set of 400 families and 4 familie s potentially informative (244 people) subsequently identified from a Chica go data set of more than 300 families to test a hypothesis based on finding s from the Boston families, Main Outcome Measures Linkage calculations assuming autosomal dominant inhe ritance with age-dependent penetrance (a parametric logarithm-of-odds [lod] score of 1.0 or greater required for further study of a potential locus); crossover analysis involving the ALS-FTD locus, Results In a set of families in which persons develop both ALS and FTD or e ither ALS or FTD alone, a genetic locus that is linked to ALS with FTD loca ted between markers D9S301 and D9S167 was identified on human chromosome 9q 21-q22, Families with ALS alone did not show linkage to this locus. Crossov er analysis indicates this region covers approximately 77 cM, Conclusion These data suggest that a defective gene located in the chromoso me 9q21-q22 region may be linked to ALS with FTD.