Rett syndrome: New progress towards the molecular basis of an enigmatic disorder

Abstract

One meets little resistance when stating that dysfunction (both hyperventilation and periodic clinical neurology has been transformed by apnoea) in most patients, and, finally, the fact that ‘neurogenetics’, where disease after disease has the disease occurs nearly exclusively in girls.* surrendered their genes to the allied forces of The fact that the disorder affected girls indicated neurologists and geneticists. Over the last 10 a ‘genetic’ origin, perhaps involving the Xyears, most of the major inherited neurological chromosome. However, the majority ( > 99.5%) disorders have been conquered, at least with were isolated patients, with no family history of regards to molecular diagnosis and aetiology. Rett syndrome, or any other neurological disorder. This golden age of neurogenetics should continue Thus, finding the extensive families that serve as as knowledge of the underlying pathogenesis and the crucial tool for the geneticist’s assault on the cloned genes eventually leads to molecular causative gene seemed impossible. With concerted therapeutics. efforts at patient diagnosis and recruitment, Despite the dramatic advances in dozens of particularly the efforts of the Kennedy-Krieger common neurological disorders, Rett syndrome Institute at Johns Hopkins (Drs Hugo Moser and had successfully remained elusive until quite Sakkubai Naidu), rare multiplex families began to recently. For years, patients were assigned to the emerge.4-7 Some of these families again hinted at an repository of ‘idiopathic developmental neurologi- X-linked gene; affected step-sisters with different cal defects’. First recognized by Andreas Rett in fathers, and affected girls with affected maternal 1966,l Rett syndrome has become increasingly aunts. The most likely model for Rett syndrome accepted as a discrete entity with characteristic emerged as an X-linked dominant disorder, where clinical features2r3 Classical Rett syndrome patients the guilty gene caused early embryonic or fetal show a normal prenatal and perinatal period, with lethality in a hemizygous male, and Rett syndrome a deceleration of head growth between 5 months in a carrier female. and 4 years of age. The failure of brain growth is This model began to be bolstered by Xaccompanied by loss of acquired purposeful hand inactivation studies. It is well established that all skills, loss of learned words or nuanced babble, females of all placental mammals must shut down derangement of contact and communication, fol- (inactivate) either the maternal or paternal Xlowed by apparent mental retardation. There are chromosome in each cell of the body. The key clinical features which seem to set Rett X-inactivation patterns are established very early in syndrome patients apart from all other develop- development (-100 cell stage embryo), and the mental neurological disorders; the stereotypical majority of normal girls and women show an hand washing or hand wringing, marked breathing admixture of cells with the paternally derived