Clinical and molecular characterization of genetically determined unclear white matter disorders

白质障碍，又称白质脑病或白质营养不良，是一组不断增长的遗传性和获得性神经疾病，主要影响中枢神经系统的白质。早期诊断很重要，特别是在那些可以治疗的情况下。这些疾病通常在婴儿期表现出来，可以是进行性的，也可以是静止性的。例如球状细胞白质营养不良症(Krabbe病)、异色性白质营养不良症(MLD)、X连锁肾上腺脑白质营养不良症(X-ALD)、Pelizaeus-Merzbacher病(PMD)和亚历山大病。虽然白质脑病的诊断和分类包括致病基因的鉴定在过去十年中有所改善，但在这些患者中，有一半以上的潜在主要遗传原因仍有待阐明。在这个三方项目中，我们将招募患有不明白质脑病的德国、以色列和巴勒斯坦患者。来自血亲和无血缘关系家庭的患者将通过全基因组纯合性图谱以及下一代测序技术进行调查，以确定这些疾病的新致病基因。新疾病基因的功能将在细胞和动物模型中进一步表征。该项目代表了一种综合协调的方法，以早期诊断受影响的儿童，了解不同种族白质脑病的初始症状和病程，识别新的疾病基因，并分析它们在人类髓鞘形成和大脑发育中的作用。

White matter disorders also known as leukoencephalopathies or leukodystrophies are a constantly growing heterogeneous group of genetic and acquired neurological disorders predominantly affecting the white matter of the central nervous system. Early diagnosis is important especially in those instances when treatment is possible. The disorders normally manifest in infancy and can be progressive or static. Examples include globoid-cell leukodystrophy (Krabbe’s disease), metachromatic leukodystrophy (MLD), X-linked adrenoleukodystrophy (X-ALD), Pelizaeus-Merzbacher disease (PMD), and Alexander’s disease. Although the diagnosis and classification of leukoencephalopathies including the identification of the causative genes have improved in the past decade, in more than half of these patients the underlying primary genetic cause remains to be elucidated. Within this trilateral project we will recruit German, Israeli and Palestinian patients with unclear leukoencephalopathies. Patients from consanguineous and unrelated families will be investigated by genome-wide homozygosity mapping as well as by next generation sequencing techniques to identify novel causative genes for these disorders. The function of new disease genes will be further characterized in cell and animal models. The project represents an integrated coordinated approach to early diagnose affected children, learn about the initial symptoms and course of leukoencephalopathies in different ethnic groups, identify new disease genes and analyze their role in human myelin formation and brain development.