Defining the spectrum of frontotemporal dementias associated with TARDBP mutations.
Defining the spectrum of frontotemporal dementias associated with TARDBP mutations.
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DOI：
10.1212/nxg.0000000000000080
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Le Ber I
中科院分区：
文献类型：
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作者：
Caroppo P;Camuzat A;Guillot-Noel L;Thomas-Antérion C;Couratier P;Wong TH;Teichmann M;Golfier V;Auriacombe S;Belliard S;Laurent B;Lattante S;Millecamps S;Clot F;Dubois B;van Swieten JC;Brice A;Le Ber I
我们描述了最大的一系列的患者与TARDBP突变提出额颞叶痴呆（FTD）和审查的情况下，在文献中，以准确地描述与这种基因型相关的FTD疾病。对29例TARDBP患者的表型特征进行了评价，其中包括10例新的法国和荷兰病例以及19例文献综述。最常见的表型是行为变异型额颞叶痴呆（bvFTD），但我们的患者中有显著比例（40%）在发病时具有语义（svFTD）或非流利变异型（nfvFTD）;并且在TARDBP携带者中svFTD的发生率显著高于其他FTD基因型（p < 0.001）。值得注意的是，我们的患者中只有少数（40%）继发肌萎缩侧索硬化症（ALS）。2例患者携带纯合突变，但表型显著不同（bvFTD和ALS），表明纯合性不会导致特定表型。儿童发病年龄早于父母一代，模仿明显的“预期”（21.8 ± 9.3岁，p = 0.001），大多数家庭中可能存在发病率降低。本研究扩大了TARDBP的表型谱，并将具有重要的临床意义：（1）FTD可能是TARDBP突变的唯一临床表现;（2）初始语言或语义障碍可能指示特定基因型;（3）排除主要基因后，应在所有FTD表型中搜索突变，即使先证者或家族史中没有ALS;（4）应考虑降低遗传易感性和临床变异性，提供适当的遗传咨询。
We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype. The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated. The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families. This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling.