Original articleMECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients
Introduction
Rett syndrome (RTT, OMIM #312750) is a clinically defined neurodevelopmental entity occurring mainly in females. Diagnostic criteria have been established for classic RTT leaning upon a characteristic developmental profile, and for variant forms of RTT [1]. RTT is thought to be the second most common cause, after trisomy 21, of severe mental retardation (MR) in females [2]. In up to 90% of individuals with RTT, mutations in the MECP2 (methyl-CpG-binding protein 2) gene can be found [3], [4], [5]. For further review of the clinical and genetic aspects, the reader is referred to a recent publication by Weaving et al. [6].
In the last few years, the phenotypic spectrum of MECP2 mutations has expanded considerably and mutations have also been reported in an increasing number of male patients, reviewed by others and us [7], [8]. Apart from males with RTT caused by a MECP2 mutation and X-chromosome aneuploidy or somatic mosaicism of the mutation, and from male patients with severe neonatal encephalopathy due to a known MECP2 mutation, reported cases consist of a group of patients with a broad spectrum of neurodevelopmental disorders. They have MR of various degrees, mostly in combination with neurological features, sometimes associated with psychiatric disorders, up to mild MR only [8]. These individuals often have familial mutations, which are unknown to occur in females affected with RTT.
In order to study the phenotypic spectrum, the MECP2 gene has been screened for mutations in various cohorts of mentally retarded males. The initial suggestion that MECP2 mutations might be a significant cause of MR in males, comparable even to FMR1 mutations [9], could not be confirmed by further studies as reviewed in detail recently [10]. In the latter study, no pathogenic mutation was found in a group of 103 males with unspecific MR. Interestingly, however, the majority of published male patients with MECP2 mutations presented with MR in combination with various neurological signs. In addition, MECP2 studies in male patients did often not include analysis of exon 1. In this study, a group of 72 carefully examined male patients with an unexplained combination of MR and neurological symptoms were tested for MECP2 mutations, including exon 1 analysis. Aim of the study was to further elucidate the phenotype of disorders caused by MECP2 mutations in males and to reconsider the criteria for mutation analysis.
Section snippets
Patients
A group of 72 male patients with MR and various neurological symptoms aged 2–83 years, with a mean age of 29.8 years, was tested for mutations in the MECP2 gene. All patients had undergone a careful clinical evaluation by a pediatrician or a physician for persons with intellectual disabilities, and by a clinical geneticist trained in dysmorphology. Cytogenetic analysis was performed in all and additional investigations (e.g. FMR1 analysis) in most cases. Patients with known diagnoses, as well
Results
In total, seven sequence changes of the MECP2 gene were identified (see Table 1).
The c.674C>T mutation (p.P225L) occurred in a 22 year old male with RTT variant. He had an apparently normal early infantile development, showed hypotonia from 4 months of age emerging into severe spasticity, became severely retarded and lost his initial motor abilities. At age 22 years, he had severe MR, spastic tetraplegia, dystonia, complete apraxia, neurogenic scoliosis, breathing irregularities and a good
Discussion
In this paper, we report on the results of MECP2 analysis in 72 male patients with MR and associated neurological features. Adding to a previous review on MECP2 related disorders in males, we want to update the knowledge on the phenotypic spectrum of MECP2 mutations in males with MR, and we critically review clinical features thought to be suggestive for a MECP2 mutation in males.
In the reported cohort of 72 male patients with MR and neurological features, seven sequence changes have been
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