Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein

Angelman syndrome (AS) is a neurodevelopmental disorder characterised by se vere mental retardation, absent speech, ataxia, sociable affect, and dysmor phic facial features. Eighty five percent of patients with AS have an ident ifiable genetic abnormality of chromosome 15q11-13. Mutations within the X linked MECP2 gene have been identified in patients with Rett syndrome (RTT) , a neurodevelopmental disorder which affects females almost exclusively an d which shares phenotypic overlap with AS. RTT is usually associated with n ormal development in infancy followed by loss of acquired skills and evolut ion of characteristic hand wringing movements and episodes of hyperventilat ion. A panel of 25 female and 22 male patients with a clinical diagnosis of AS a nd no molecular abnormality of 15q11-13 were screened for MECP2 mutations a nd these were identified in four females and one male. Following the diagno sis, it was possible to elicit a history of regression in three of these pa tients, who by then were showing features suggestive of Rett syndrome. In t he remaining two subjects the clinical phenotype was still considered to be Angelman-like. These findings illustrate the phenotypic overlap between the two conditions and suggest that screening for MECP2 mutations should be considered in AS patients without a demonstrable molecular or cytogenetic abnormality of 15q 11-13. Since MECP2 mutations almost always occur de novo, their identificat ion will substantially affect genetic counselling for the families concerne d.