Brain Dev. 2005 Dec 20; [Epub ahead of print]
MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients
Moog U, Roozendaal KV, Smeets E, Tserpelis D, Devriendt K, Buggenhout GV, Frijns JP, Schrander-Stumpel C.
Department of Clinical Genetics, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands; Research Institute Growth and Development (GROW), Maastricht University, Maastricht, The Netherlands.
Abstract
Mutations in the methyl-CpG-binding protein 2 (MECP2) gene located on Xq28, cause Rett syndrome (RTT) in female patients. Meanwhile, nonmosaic MECP2 mutations unknown in girls have been found in an increasing number of male patients with a normal 46, XY karyotype. They can cause a broad spectrum of neurodevelopmental disorders which often show a combination of mental retardation (MR) with neurological symptoms. We present the results of MECP2 analysis in a group of 72 male patients with an unexplained combination of MR and neurological features, and review the mutational reports published on male patients since the discovery of the MECP2 gene. Analysis included sequencing of exon 1 which thus far was mostly omitted from DNA screening. One pathogenic mutation has been found in a patient with Rett variant, in addition to an unclassified variant and a series of nonpathogenic changes. No changes have been found in exon 1. Criteria for testing of male patients are classic RTT, severe neonatal encephalopathy, and RTT variant which may be clinically underrecognized. Testing can also be considered in males with a combination of unexplained MR and (progressive) neurological manifestations although the yield of MECP2 analysis is probably low in this situation. Based on the literature, MECP2 testing in males with MR only is debatable.
Lay Summary
In the last few years, MeCP2 mutations have been reported in an increasing number of male patients. The aim of this study was to examine the MeCP2 gene sequence in 72 male patients with unexplained mental retardation and neurological conditions, to attempt to link any previously unexamined MeCP2 mutations to their condition. Interestingly, the authors found seven individuals with MeCP2 gene sequence changes within this cohort. However, only one of the MeCP2 mutations was considered to be causative of his Rett variant disease state. The majority of the other mutations were benign - that is, the same mutations were also detected in control populations or in non-affected relatives, and thus not considered to play a role in the development of their neurological conditions. These finding should have an impact on whether MeCP2 mutation testing should be performed on males with a combination of unexplained mental retardation and progressive neurological deteriorations (yes, but low probability of finding a MeCP2 link), versus males displaying only mental retardation (probably not).