MeCP2 mutations in children with and without the phenotype of Rett syndrome

Abstract

Article abstract-Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Methods: One hundred sixteen patients with classical and atypical RTT were studied for mutations of the MeCP2 gene by using DHPLC and direct sequencing. Results: Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a duplication. The duplication was identical to a region within the 3Ј untranslated region (UTR), and represents the first report of involvement of the 3Ј UTR in RTT. The authors also report the identification of MeCP2 mutations in two males; a Klinefelter's male with classic RTT (T158M) and a hemizygous male infant with a Xq27-28 inversion and a novel 32 bp frameshift deletion [1154(del32)]. Studies examining the relationship between mutation type, X-inactivation status, and severity of clinical presentation found significant differences in clinical presentation between different types of mutations. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the carboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with either atypical or classical RTT. Conclusion: This patient series confirms the high frequency of MeCP2 gene mutations causative of RTT in females and provides data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).

Transcranial magnetic stimulation in children

“…Since CMCT is of normal latency in children who are in the pseudo-stationary stage of Rett Syndrome (15 years and older), it may reflect an underlying dynamic process which burns itself out over time. The CMCT abnormalities may not be of significant diagnostic use in most typical cases of Rett syndrome who all appear to have mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2) (Dunn, 2001;Hoffbuhr et al, 2001). However, they are likely to be of use in atypical cases or those children who present with the Rett phenotype but do not have the gene mutation.…”

Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy

“…10 ± 12 Several cases of 47,XXY males with a clinical diagnosis of Rett syndrome have been reported, although to our knowledge only one has been reported so far as having a MECP2 mutation. 13 In order to determine whether MECP2 is involved in the development of the disease phenotype in males, we performed mutation screening in a patient not reported before, and diagnosed as Rett syndrome.…”

Rett Syndrome: Reaching for Clinical Trials

“…Males with seemingly typical RTT have been reported in a small number under 2 scenarios: one being co-occurrence of Klinefelter syndrome (47 XXY) [51][52][53][54] and the other being somatic mosaicism [55]. In each instance, 2 populations of cells exist: 1 with a normal and 1 with a mutant X chromosome.…”