The heritability and genetics of frontotemporal lobar degeneration
The heritability and genetics of frontotemporal lobar degeneration
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DOI：
10.1212/wnl.0b013e3181bf997a
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发表时间：
2009-11-03
期刊：
影响因子：
9.9
通讯作者：
Rossor, M. N.
中科院分区：
文献类型：
--
作者：
Rohrer, J. D.;Guerreiro, R.;Rossor, M. N.
背景资料：额颞叶变性（FTLD）是一种遗传和病理异质性的神经退行性disorder.Methods：我们收集了血液样本，从一个队列的225例患者的诊断范围内的FTLD频谱和检查遗传力的FTLD给每个患者的家族史评分，从1（明确的常染色体显性遗传史的FTLD）到4（无痴呆家族史）。我们还寻找突变的5个致病基因（MAPT，GRN，VCP，CHMP 2B，和TARDP）和FUS基因，已知引起运动神经元diseases.Results：共有41.8%的患者有一些家族史（得分为1，2，3，或3.5），虽然只有10.2%有明确的常染色体显性遗传史（得分为1）。FTLD的不同临床亚型的遗传性各不相同，其中行为变异是最可遗传的，额颞叶痴呆-运动神经元疾病和语言综合征（特别是语义痴呆）的遗传性最低。在MAPT（8.9%的队列）和GRN（8.4%）中发现了突变，但在其他任何基因中均未发现突变。在其余无突变但有家族史的患者中，7例经病理证实，分为2组：无GRN突变的3型FTLD-TDP（6例）和FTLD-UPS（1例）。结论：这些发现表明额颞叶变性（FTLD）是一种高度遗传性疾病，但不同综合征的遗传性不同。此外，虽然MAPT和GRN突变占家族性病例的很大比例，但还有其他基因尚未发现，特别是在没有GRN突变的3型FTLD-TDP患者中。神经病学（R）2009; 73：1451-1456
Background: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder.Methods: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease.Results: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1).Conclusion: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation. Neurology (R) 2009; 73:1451-1456