Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease

Background: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuron al migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrom e (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, oc ular abnormalities are a constant feature in MEB and WWS. Lack of consisten t ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has r emained controversial. The MEB gene is located on chromosome 1p32-p34. Obje ctives: To establish distinguishing diagnostic criteria for MEB and WWS;VS and to determine whether MEB and WWS are allelic disorders, Methods: The au thors undertook clinical characterization followed by linkage analysis in 1 9 MEB/WWS families with 29 affected individuals. With use of clinical diagn ostic criteria based on Finnish patients with MEB! each patient was categor ized as having either MEB or WWS. 4 linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource . Results: Patients in 11 families were classified as having MEB and in 8 f amilies as WWS. Strong evidence in favor of genetic heterogeneity was obtai ned in the 19 families. There was evidence for linkage to 1p32-p34 in all b ut 1 of the II pedigrees segregating the MEB phenotype. In contrast, linkag e to the MEB locus was excluded in seven of eight of the WSI'S families. Co nclusion: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).