Many sporadic and familial neurodegenerative diseases are associated with neural protein deposits. We have recently reported (Griffin et al, SFN Abs 2001) that familial prion diseases appear to respect an allele barrier, such that conservativeness of missense substitutions governs whether multimer accretion of PrP is restricted to mutant protein only (slowly progressive disease), or from protein encoded by both the mutant and wild-type alleles (rapidly progressive disease). We now investigate if a similar model might apply to other neurodegenerative diseases characterized by protein aggregation, such as amyotrophic lateral sclerosis (ALS) and familial amyloidotic polyneuropathy (FAP), associated with mutations in superoxide (SOD1) and transthyretin (TTR) genes respectively. Using the Bacon and BLOSUM 62 indices of amino acid similarity (Bacon and Anderson, 1986; Henikoff and Henikoff, 1992) we evaluated the pathogenic missense mutations in SOD1 and TTR and compared these to the clinical data. In both disea...