The discovery of the mutations of methyl-CpG-binding protein 2 (MECP2) gene as the causative gene of RTT is an epoch helping not only to understand the pathophysiology of RTT but also various neurodevelopmental disorders.
With the recent identification of MECP2 mutations in Rett syndrome it is quite likely that genetic factors not only play a major role in brain development but may also influence other organ growth including bone formation.
We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females.
Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified.
It is the cluster of functionally defective nerve cells lacking fully functional MeCP2 generated by inactivation of normal MECP2 allele that causes the wide spectrum of RTT symptoms.
Among 60 patients 57 girls with a clinical picture of RTT had normal female karyotype (46,XX), one boy had normal male karyotype in peripheral lymphocytes (46,XY) and two boys had a mosaic form of Kleinfelter's syndrome (47,XXY/46,XY) in peripheral lymphocytes or muscle cells (with MeCP2 mutation R270X).
The patient presented here was clinically diagnosed with RTT at the age of 66 years and now the presence of one of the common missense mutations in MECP2 has been demonstrated.
MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.
Preliminary evidence suggests that MECP2 may be involved in a broader phenotype than classical Rett syndrome including preserved speech variants (PSV).
These results indicate that a MECP2 mutation associated with Rett syndrome in females could lead to a similar phenotype in males as a result of somatic mosaicism.
With the recent discovery that the MECP2 gene is responsible for most cases of Rett syndrome, it is possible to molecularly assess cases of affected males by direct sequencing analysis.