A homozygous nonsense mutation in the <i>Fukutin</i> gene causes a Walker-Warburg syndrome phenotype

Abstract

Neuronal migration is a key process in the development of the cerebral cortex. During neocortex lamination new sets of neurones proliferate at the subventricular zone and migrate alongside specialised radial glial fibres to occupy their final destinations in an “inside-out” fashion.1 More than 25 neuronal migration disorders resulting in death or improper positioning of the cortical neurones have been described in humans.2 In the cobblestone neocortex the postmitotic neurones do not respond to their stop signals, and, crossing through the neocortex, bypass the glia limitans and invade the subarachnoid space. The resulting cortex is chaotically structured, consisting of an irregular lissencephalic surface and absence of lamination. Cobblestone lissencephalies are often seen in association with additional features, such as eye malformations and congenital muscular dystrophy. Walker-Warburg syndrome (WWS, OMIM:236670), muscle-eye-brain (MEB, OMIM:253280), and Fukuyama congenital muscular dystrophy (FCMD, OMIM:253800) are the three major entities of this group. Patients are classified into these three entities on the basis of the severity of the phenotype and the presence of syndrome specific symptoms (table 1). WWS is the most severe syndrome of the group, especially with regard to the brain phenotype. The WWS brain manifests cobblestone lissencephaly with agenesis of the corpus callosum, fusion of hemispheres, hydrocephalus, dilatation of the fourth ventricle, cerebellar hypoplasia, hydrocephalus, and sometimes encephalocele.3,4 View this table: Table 1 Clinical features of patient 1 compared with cobblestone lissencephalies ### Key points