The aim of this study was to analyze well-characterized cases with MR and to clarify the role of the MECP2 gene in the etiology of MR and atypical Angelman syndrome.
Rett syndrome (RTT), the second most common cause of mental retardation in females, has been associated with mutations in MeCP2, the archetypical member of the methyl-CpG binding domain (MBD) family of proteins.
These findings suggest that mutations in ATRX may cause mental retardation in females, if the X chromosome carrying mutated ATRX is not properly inactivated.
The phenotypic spectrum of MECP2 mutations is broad and includes mental retardation with or without seizures, Angelman syndrome-like phenotype, and autism.
Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype.
We consider essential proceeding further screening in the whole extension of the MECP2 gene using clinically well-documented and larger sized sample to assure the overall contribution of MECP2 to mental retardation.
MECP2 gene mutations responsible for Rett syndrome have also been found in male patients with mental retardation, sometimes associated with different neurologic abnormalities.
In this study, the question was addressed as to whether implementation of systematic screening of MECP2 in patients with an unexplained mental retardation in DNA diagnostics would be reasonable, and the spectrum of phenotypes resulting from mutations in this gene was further explored.
Recently, mutations in the MECP2 gene were reported in males with non-specific mental retardation suggesting that defects in MECP2 could be responsible for up to 2% of X-linked mental retardation.
Mutations in the XNP gene have been reported in alpha thalassemia/mental retardation (MR) syndrome (ATR-X) and other severe X-linked MR conditions with facial dysmorphisms.
Numerous recent reports have proposed that mutations in the C-terminal domain of the MECP2 gene could be a frequent cause of mental retardation in males.
This case, as well as other published studies of males with MECP2 mutations, reveals that the clinical manifestations in viable males vary from neonates with severe encephalopathy to adults with mental retardation and demonstrate genotype-phenotype correlations.
To date, descriptions have been published of two patients with independent familial mental retardation (MR) and two patients with sporadic MR who harbor this specific mutation in the MECP2 gene.
Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females.
Given that molecular investigation of XNP/ATR-X mutations is made onerous by the length of the gene transcript, we carried out a prenatal diagnosis in a fetus at risk for ATR-X syndrome by initially determining the XNP/ATR-X gene haplotype before considering gene sequencing.
These alterations are comparable with those found in the partial trisomy chromosome 16 murine models of DS and suggest a causative role of DYRK1A in mental retardation and in motor anomalies of DS.
Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.
Only recently have mutations in MECP2 been found to be a cause of Rett Syndrome (RTT), a neuro-developmental disorder characterized by mental retardation, loss of expressive speech, deceleration of head growth and loss of acquired skills that almost exclusively affects females.
Since the identification of the ATRX gene (synonyms XNP, XH2) in 1995, it has been shown to be the disease gene for numerous forms of syndromal X-linked mental retardation [X-linked alpha thalassemia/mental retardation (ATR-X) syndrome, Carpenter syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, X-linked mental retardation with spastic paraplegia].