Cormand B, Pihko H, Bayés M, Valanne L, Santavuori P, Talim B, Gershoni-Baruch R, Ahmad A, van Bokhoven H, Brunner H G, Voit T, Topaloglu H, Dobyns W B, Lehesjoki A E
Department of Medical Genetics, University of Helsinki, Finland.
Neurology. 2001 Apr 24;56(8):1059-69. doi: 10.1212/wnl.56.8.1059.
Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34.
To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders.
The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource.
Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families.
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).
三种罕见的常染色体隐性疾病都表现为先天性肌营养不良和脑畸形，包括神经元迁移缺陷，即肌肉-眼-脑疾病（MEB）、沃克-沃尔堡综合征（WWS）和福山先天性肌营养不良（FCMD）。此外，眼部异常是MEB和WWS的一个常见特征。FCMD缺乏一致的眼部异常表现，使得该综合征在临床上有明确的界定，而MEB和WWS之间的表型区分仍存在争议。MEB基因位于1号染色体的1p32 - p34区域。
建立MEB和WWS的鉴别诊断标准，并确定MEB和WWS是否为等位基因疾病。
作者对19个MEB/WWS家庭中的29名患者进行了临床特征分析，随后进行连锁分析。根据芬兰MEB患者的临床诊断标准，将每位患者分类为患有MEB或WWS。使用跨越MEB基因座的10个标记对整个家系资源进行连锁和单倍型分析。
11个家庭的患者被分类为患有MEB，8个家庭的患者被分类为患有WWS。在这19个家庭中获得了支持基因异质性的有力证据。在11个分离MEB表型的家系中，除1个家系外，所有家系均有证据表明与1p32 - p34连锁。相比之下，在8个WWS家庭中的7个家庭中排除了与MEB基因座的连锁。
这些结果从临床和遗传学角度将MEB和WWS分类为不同的疾病，并为WWS基因的定位提供了基础。
