J Med Genet 40:845-848 doi:10.1136/jmg.40.11.845
  • Letters to JMG

A homozygous nonsense mutation in the Fukutin gene causes a Walker-Warburg syndrome phenotype

  1. D Beltrán-Valero de Bernabé1,
  2. H van Bokhoven1,
  3. E van Beusekom1,
  4. W Van den Akker2,
  5. S Kant3,
  6. W B Dobyns4,
  7. B Cormand5,
  8. S Currier6,
  9. B Hamel1,
  10. B Talim7,
  11. H Topaloglu7,
  12. H G Brunner1
  1. 1Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, Netherlands
  2. 2Netherlands Institute for Developmental Biology/Hubrecht Laboratory, Utrecht, Netherlands
  3. 3Department of Clinical Genetics, University Medical Centre Leiden, Leiden, Netherlands
  4. 4Departments of Human Genetics, Neurology, and Pediatrics, The University of Chicago, Chicago, Illinois, USA
  5. 5Department of Genetics, University of Barcelona, Barcelona, Spain
  6. 6Division of Neurogenetics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
  7. 7Hacettepe Children’s Hospital, Ankara, Turkey
  1. Correspondence to:
 Dr Han G Brunner
 417 Department of Human Genetics, PO Box 9101, 6500 HB Nijmegen, Netherlands;

    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

    • Three rare autosomal recessive syndromes form a group of related diseases: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). All share the combination of congenital muscular dystrophy and brain malformations, including a neuronal migration defect.

    • The genes underlying these three disorders have been implicated in O-linked protein glycosylation: Fukutin (FCMD), POMGnT1 (MEB), and POMT1 (WWS). WWS is genetically heterogeneous, and mutations in the POMT1 gene account for …