HEREDITARY SPASTIC PARAPLEGIA - LOD-SCORE CONSIDERATIONS FOR CONFIRMATION OF LINKAGE IN A HETEROGENEOUS TRAIT

Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lo wer limbs. HSP may be inherited as an autosomal dominant (AD), autosom al recessive, or an X-linked trait. AD HSP is genetically heterogeneou s, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysi s with 21 uncomplicated AD families to the three AD HSP loci. We repor t significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage inform ation from several different research teams to evaluate the statistica l probability of linkage to the SPG4 locus for uncomplicated AD HSP fa milies and established the critical LOD-score value necessary for conf irmation of linkage to the SPG4 locus from Bayesian statistics. In add ition, we calculated the empirical P-values for the LOD scores obtaine d with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evalu ated. This combined analytical approach permitted conclusive linkage a nalyses on small to medium-size families, under the restrictions of ge netic heterogeneity.