Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome

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ett syndrome is an X linked mental retardation syndrome almost exclusively affecting girls, and has long been regarded as an X linked dominant condition lethal in hemizygous males. 1 Mutations in the gene encoding the methyl-CpG binding protein 2 (MECP2) were demonstrated as the cause of Rett syndrome, 2 and confirmed by a number of studies.The vast majority (95%) of MECP2 mutations occurs de novo.Girls affected by ''classic'' Rett syndrome show mental retardation and regression, with a typical pattern of symptoms including initially normal development, stagnation, loss of acquired abilities, stereotypic hand movements, regression of speech, profound psychomotor retardation, epilepsy, and autism, although molecular diagnostics has proven that variant clinical forms exist.3 4 It has recently been shown that missense mutations in MECP2 can cause severe neonatal encephalopathy in boys.5 Classic Rett phenotypes in boys have so far only been reported in rare cases of somatic mosaicism or XXY karyotypes.6-11 In girls, larger intragenic deletions are responsible for about 11-16% of typical Rett syndrome without point mutations in the coding exons.12 13 Larger deletions have not yet been found in boys, and duplications of MECP2 have not yet been reported as a cause for typical Rett syndrome at all.We have established quantitative PCR for diagnosis of deletions affecting MECP2, and in this paper, we report a boy manifesting clinical features of Rett syndrome and a submicroscopic duplication within the cytogenetic band Xq28 encompassing the entire MECP2 gene. CLINICAL FEATURESThe boy is the second child of healthy, unrelated parents, whose older brother had developed normally.There is no family history of mental retardation or developmental disorders.The patient was born in the 41st week after an uneventful pregnancy.Birth was spontaneous but with protracted labour (birth weight 3940 g, length 54 cm, head circumference 36.2 cm).Head growth was normal and did not decelerate (head circumference 54.5 cm at 7.5 years), but growth of length was retarded (length 117 cm at 7.5 years).Psychomotor development was retarded from birth.Initially, reduced movements, muscular hypotonia, and insufficient weight gain were noticed.The patient could not turn at the age of 15 months, and could not sit up until the age of 4 years.The first stereotypic hand movements were noticed at the age of 4 years.At the age of 6 years, he was crawling and able to walk a few steps with assistance.He was able to hold things and play with toys, but showed gradual loss of purposeful hand use around the same age.There was no spasticity or fixed scoliosis.The patient never learned to speak, but made babbling sounds to communicate basic needs.During the first hospitalisation at the age of 10 months, magnetic resonance imaging (MRI) showed mildly enlarged inner and outer liquor spaces, but no retardation of myelination.In the following years, thorough screening for metabolic disorders including liquor tests revealed normal results.No signs of energy metabolism disorders, organoacidopathies, aminoacidopathies, peroxisomal or lysosomal disorders, or storage disorders were detected.There was no organomegaly.Ophthalmological examination showed mild Key points N Rett syndrome has been recognised as one of the major

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