Original ArticleNeurologic Aspects of MECP2 Gene Duplication in Male Patients
Introduction
Mutations in the methyl CpG binding protein 2 gene (MECP2) are found in more than 95% of patients with typical Rett syndrome (OMIM 300005), a progressive neurodegenerative disorder that affects almost exclusively females [1], [2]. Point mutations in MECP2 behave similarly to a complete deletion of the coding sequence of MECP2, indicating that there is complete or partial loss of functional alleles [3]. These point mutations cause features characteristic of Rett syndrome in females; in males, however, the same point mutations may result in severe encephalopathy and early death. The phenotype of MECP2 mutations in males covers a larger spectrum of neurodevelopmental disorders than would expected based on the female phenotype, varying from severe early-onset encephalopathy to moderate and isolated mental retardation [4], [5], [6], [7], [8], [9], [10], [11], [12]. Large cohort studies have demonstrated that these mutations in males are far more rare than initially thought [13].
Array comparative genomic hybridization has become the method of choice for the detection of microdeletions and more specifically for microduplications that were previously undiagnosed by classical polymerase chain reaction and Southern blot techniques [14], [15], [16], [17]. MECP2 gene duplications that were undiagnosed until recently seem to correspond to an important cause of X-linked mental disability in males, and they seem to have a phenotype different from those with MECP2 deletion.
Described here are the clinical aspects of these gene duplications in five patients from two families, with particular attention to epilepsy and neuroimaging abnormalities observed in most of these patients, especially over a long period of follow-up.
Section snippets
Case Reports
In the first four cases presented, the patients are related: an uncle and three nephews. The fifth case is from an unrelated family. In all five cases, no respiratory infection or serious infectious disease was observed during the period of follow-up.
Genetic Studies
For the first four patients, a commercially available multiplex ligation-dependent probe amplification kit was used (MRC Holland, Amsterdam, Netherlands), with methods as reported by Lugtenberg et al. [19]. The Xq28 duplication in this family had a minimum size of 260 kb including the L1CAM, IRAK1, and MECP2 genes. The grandmother and her three daughters (one of whom had three miscarriages) had the MECP2 duplication, as did all four patients. Patient 5 was investigated in another laboratory,
Discussion
In 1997, Pai et al. [20] described a large, four-generation family with five affected males and 10 carrier females with linkage to Xq28. The affected males all presented with severe mental retardation. Seizure activity occurred in four of the five affected boys, but no specific electroencephalographic pattern was noted. Subsequently, a second family with linkage to Xq28 was reported by Lubs et al. [21]. This three-generation family had five affected males presenting with severe mental
Conclusion
Some studies indicate that MECP2 duplication in males could correspond to approximately 2% of the etiologies of X-linked mental disabilities [20]. In these cases, some nonconstant but important signs that can evoke the possibility of a MECP2 gene duplication include the clinical and electroencephalographic characteristics of epilepsy when seizures occur and the frequency of nonspecific cerebral MRI abnormalities. Because the extent of MECP2 duplication varies from one patient to another, and
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