Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

Me screened 71 sporadic and 7 familiar Rett syndrome (RTT) patients for MEC P2 mutations by direct sequencing and determined the pattern of X chromosom e inactivation (XCI) in 39 RTT patients. We identified 23 different disease -causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. Me compared electrophysiological findings, cerebrospi nal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty -one of 34 patients (31%) with classic RTT had random XCI. Nonrandom XCI wa s associated with milder phenotypes, including a mitigated classic RTT caus ed by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels o f cerebrospinal fluid homovanillic acid. Scoliosis is more common in patien ts with missense mutations. These data indicate that different MECP2 mutati ons have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The associa tion of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function di e during embryogenesis, supports the notion that RTT is caused by partial l oss of MeCP2 function.