Data Sheet 1_Case report: LMNB1 duplication-mediated autosomal dominant adult leukodystrophy in a Chinese family and literature review of Chinese patients.docx

Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare, slowly progressive, and fatal neurodegenerative disorder characterized by central nervous system white matter loss due to LMNB1 gene abnormalities encoding laminB1. However, not all LMNB1 mutations lead to ADLD. Currently, two genetic alterations have been identified in association with the pathogenesis of ADLD: LMNB1 gene tandem duplication and LMNB1 gene upstream deletions. We report a case of a 60-year-old man diagnosed with ADLD, with pyramidal tract dysfunction and autonomic abnormalities as the main clinical manifestations. MRI revealed bilateral symmetric high signal intensities in the white matter of the medulla oblongata, middle cerebellar peduncles, cerebral peduncle, periventricular white matter, centrum semi vale, and the pressure region of the corpus callosum. Whole exome sequencing results indicated 73.6Kb duplicate copy number variation signals in the 5q23.2 region of the proband’s chromosome. The Multiplex ligation-dependent probe amplification (MLPA) experiment results indicate recurrent mutations across all exons (exon1–11) of the LMNB1 gene. This is the eighth ADLD pedigree from China. We conducted a literature review of all ADLD pedigrees in China and summarized the characteristics of Chinese patients with ADLD to raise awareness of ADLD disease.

成人起病常染色体显性遗传性脑白质营养不良（Adult-onset autosomal dominant leukodystrophy, ADLD）是一种罕见、缓慢进展且致命的神经退行性疾病，以编码核纤层蛋白B1（lamin B1）的LMNB1基因异常所致中枢神经系统白质脱失为特征。然而，并非所有LMNB1基因突变均可导致ADLD。目前已明确两种与ADLD发病机制相关的遗传变异：LMNB1基因串联重复与LMNB1基因上游缺失。本文报告1例确诊为ADLD的60岁男性患者，其主要临床表现为锥体束功能障碍与自主神经异常。磁共振成像（Magnetic Resonance Imaging, MRI）显示，患者延髓、小脑中脚、大脑脚、脑室周围白质、半卵圆中心及胼胝体压部白质区域均可见双侧对称性高信号。全外显子组测序（Whole exome sequencing）结果显示，该先证者（proband）染色体5q23.2区域存在73.6kb的重复型拷贝数变异信号。多重连接依赖性探针扩增（Multiplex ligation-dependent probe amplification, MLPA）实验结果表明，LMNB1基因所有外显子（外显子1~11）均存在复发性突变。本家系为我国第8个ADLD家系。我们对国内已报道的全部ADLD家系进行了文献复习，并总结了中国ADLD患者的临床特征，以期提升临床对ADLD疾病的认知水平。