STUDIES OF X-INACTIVATION AND ISODISOMY IN TWINS PROVIDE FURTHER EVIDENCE THAT THE X-CHROMOSOME IS NOT INVOLVED IN RETT-SYNDROME

Rett syndrome (RS), a progressive encephalopathy with onset in infancy , has been attributed to an X-linked mutation, mainly on the basis of its occurrence almost exclusively in females and its concordance in fe male MZ twins. The underlying mechanisms proposed are an X-linked domi nant mutation with male lethality, uniparental disomy of the X chromos ome, and/or some disturbance in the process of X inactivation leading to unequal distributions of cells expressing maternal or paternal alle les (referred to as a ''nonrandom'' or ''skewed'' pattern of X inactiv ation). To determine if the X chromosome is in fact involved in RS, we studied a group of affected females including three pairs of MZ twins , two concordant for RS and one uniquely discordant for RS. Analysis o f X-inactivation patterns confirms the frequent nonrandom X inactivati on previously observed in MZ twins but indicates that this is independ ent of RS. Analysis of 29 RS females reveals not one instance of unipa rental X disomy, extending the observations previously reported. There fore, our findings contribute no support for the hypothesis that RS is an X-linked disorder. Furthermore, the concordant phenotype in most M Z female twins with RS, which has not been observed in female twins wi th known X-linked mutations, argues against an X mutation.