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

Abstract

We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome 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. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.

The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome

“…Three studies have found weak but inconsistent associations. Amir et al (2000) found that respiratory dysfunction was more common in patients with truncating mutations than in patients with missense mutations, but that the latter had higher levels of CSF HVA. Scoliosis was also more common in patients with missense than truncating mutations.…”

Annotation: Rett syndrome: recent progress and implications for research and clinical practice

“…Is it possible that some part of the function of MECP2 may be preserved while another part is disabled? Present evidence suggests that an early (truncating) mutation may indeed prove more damaging than a late one (Amir et al, 2000); however, some geneticists, including those working on the mouse model, have suggested that any MECP2 mutation will obliterate its action altogether.…”

The role of oxidative stress in Rett syndrome: an overview

“…23 Moreover, and likely most important, the type and location of the mutations are known to modulate clinical severity. [23][24][25][26][27][28][29][30][31][32][33][34] In addition, since the time of the discovery of the MeCP2 mutation as a cause of the disease, the geneticists have learned that mutations in MeCP2 do not always correspond with RTT. 35 In fact, besides RTT, mutations in MeCP2 have also been identified in individuals who do not show the clinical features of RTT (e.g., asymptomatic female carriers, boys with MeCP2 mutations known to cause typical RTT in girls, and rare individuals with mutations in MeCP2 who present with other neurodevelopmental conditions), collectively termed as MeCP2-pathies.…”