Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies.
Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies.
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DOI：
10.1093/brain/awx328
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发表时间：
2018-02-01
期刊：
影响因子：
--
通讯作者：
Halliday GM
中科院分区：
文献类型：
--
作者：
Forrest SL;Kril JJ;Stevens CH;Kwok JB;Hallupp M;Kim WS;Huang Y;McGinley CV;Werka H;Kiernan MC;Götz J;Spillantini MG;Hodges JR;Ittner LM;Halliday GM
请参阅Josephs （doi:）对本文的科学评论。17号染色体上的MAPT基因突变与额颞叶变性（FTLD）有关。突变相关的病例目前与散发的tau内含物病例（FTDP-17）分开分类，但Forrest等人提供的证据表明，这些病例实际上应该被认为是FTLD-tau亚型的家族性形式。请参阅Josephs （doi:）对本文的科学评论。在许多神经退行性疾病中，家族性形式为其相应的散发性形式的发病机制提供了重要的见解。在额颞叶变性和帕金森病（FTDP-17）家族中，在17号染色体上的微管相关蛋白tau （MAPT）基因中发现了与额颞叶变性（FTLD）相关的第一个突变。然而，人们很快发现，这些家庭中有50%的人在颗粒蛋白前有附近的突变。无论如何，原始的FTDP-17命名法被保留用于MAPT突变患者，这些患者目前独立于具有tau免疫反应性包涵体（FTLD-tau）的不同散发形式的FTLD。家族性FTLD与MAPT突变的单独分类表明，家族性FTLD-tau的不同散发形式的发病机制并不能说明家族性FTLD-tau的发病机制。为了验证这一假设，本研究对悉尼和剑桥脑库持有的所有已知MAPT突变的FTLD-tau病例进行了病理评估，并将其与散发的四种亚型FTLD-tau的四例病例进行了比较，此外还发表了病例报告。筛选10例伴有MAPT突变的FTLD-tau病例（K257T、S305S、P301L、IVS10+16、R406W），用于诊断不同散发性FTLD-tau亚型的核心鉴别神经病理特征，以确定MAPT突变与散发性FTLD-tau的分类分离是否有效。与散发性病例相比，MAPT突变的FTLD-tau病例的平均病程相似，但症状出现年龄较年轻（55±4年对70±6年）。有趣的是，MAPT突变的FTLD-tau病例与散发性FTLD-tau亚型具有相似的模式和严重程度的神经病理特征，可分为：Pick病（K257T），皮质基底变性（S305S, IVS10+16, R406W），进行性核上性麻痹（S305S）或球胶质tau病（P301L, IVS10+16）。发现S305S突变可以分为两种tau病，这表明存在其他修饰因素。对我们的病例和先前报告的评估表明，不同的MAPT突变导致特定的FTLD-tau亚型，支持这样的概念，即它们可能提供了与不同形式的散发性FTLD-tau相关的不同细胞机制。因此，具有MAPT突变的FTLD-tau病例应被视为FTLD-tau亚型的家族性形式，而不是单独的FTDP-17类别，并且继续研究不同突变的影响，更多地集中在模拟它们对动物和细胞模型中产生非常不同的散发性FTLD-tau病理的影响。
See Josephs (doi:) for a scientific commentary on this article. Mutations in the MAPT gene on chromosome 17 are associated with frontotemporal lobar degeneration (FTLD). Mutation-associated cases are currently classified separately from sporadic cases with tau inclusions, as FTDP-17, but Forrest et al. provide evidence that these cases should in fact be considered familial forms of FTLD-tau subtypes. See Josephs (doi:) for a scientific commentary on this article. In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD-tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10+16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 ± 4 years versus 70 ± 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick’s disease (K257T), corticobasal degeneration (S305S, IVS10+16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10+16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models.
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