CEREBRAL AUTOSOMAL-DOMINANT ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, GENETIC HOMOGENEITY, AND MAPPING OF THE LOCUS WITHIN A 2-CM INTERVAL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal domi nant cerebral arteriopathy characterized by the recurrence of subcorti cal infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. I n the present study, these first 2 families and 13 additional ones, in cluding a total of 199 potentially informative meiosis, have been geno typed with eight polymorphic markers located between D19S221 and D19S2 15. All families were linked to chromosome 19. The highest combined lo d score (Z(max) = 37.24 at theta = .01) was obtained with marker D19S8 41, a new CA(n) microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families wer e used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S139 on 19p13.1. These data s trongly suggest the genetic homogeneity of this recently identified co ndition and establish the value of its clinical and neuroimaging diagn ostic criteria. Besides their importance for the ongoing positional cl oning of the CADASIL gene, these data help to refine the genetic mappi ng of CADASIL relative to familiar hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within th e same chromosome 19 region.