Sorbonne Universités (P. Caroppo, A.C., L.G.-N., M.T., S.L., S.M., B.D., A.B., I.L.B.), UPMC Univ Paris 06, UMR S 1127, France; Inserm (P. Caroppo, A.C., L.G.-N., M.T., S.L., S.M., B.D., A.B., I.L.B.), U 1127, Paris, France; CNRS (P. Caroppo, A.C., L.G.-N., S.L., S.M., B.D., A.B., I.L.B.), UMR 7225, Paris, France; ICM (P. Caroppo, A.C., L.G.-N., M.T., S.L., S.M., B.D., A.B., I.L.B.), Paris, France; IRCCS Foundation "Carlo Besta" Neurological Institute, (P. Caroppo), Milan, Italy; Plein Ciel (C.T.-A.), Lyon; EA3082 Labo EMC (C.T.-A.), Université Lyon 2; Service de Neurologie (P. Couratier), Centre Hospitalo-Universitaire Dupuytren, Limoges, France; Department of Neurology (T.H.W., J.C.v.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Centre de Référence des Démences Rares (M.T., F.C., B.D., I.L.B.), AP-HP Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France; Service de Neurologie (V.G.), Centre Hospitalier de Saint-Brieuc, Saint-Brieuc, France; CMRR (V.G., S.B.), Centre Hospitalo-Universitaire, Rennes, France; Service de Neurologie (S.A.), Centre Hospitalo-Universitaire Pellegrin, Bordeaux, France; Inserm-EPHE-Université de Caen/Basse-Normandie (S.B.), Unité U1077, GIP Cyceron, Caen, France; Neurology/Neuropsychology CMRR Unit (B.L.), CHU Nord, France; Institute of Medical Genetics (S.L.), Catholic University, University Hospital A. Gemelli, Roma, Italy; Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire (F.C.), Unité Fonctionnelle de Génétique Clinique (A.B.), Département de Génétique et Cytogénétique, and Département de Neurologie (B.D., A.B., I.L.B.), AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France.
Neurol Genet. 2016 May 26;2(3):e80. doi: 10.1212/NXG.0000000000000080. eCollection 2016 Jun.
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.
我们描述了一组最大的 TARDBP 突变患者，这些患者表现为额颞叶痴呆（FTD），并回顾了文献中的病例，以准确描述与这种基因型相关的 FTD 疾病。
评估了 29 名 TARDBP 患者的表型特征，包括 10 名新的法国和荷兰病例以及 19 名从文献中回顾的病例。
最常见的表型是行为变异型额颞叶痴呆（bvFTD），但我们患者中有相当比例（40%）在发病时存在语义性（svFTD）或非流利性变异型（nfvFTD）；并且在 TARDBP 携带者中，svFTD 明显比其他 FTD 基因型更为常见（p<0.001）。值得注意的是，只有少数（40%）患者随后发展为肌萎缩侧索硬化症（ALS）。两名患者携带纯合突变，但表现出明显不同的表型（bvFTD 和 ALS），表明纯合性不会导致特定表型。大多数家族中，儿童的发病年龄比父母代更早，类似于明显的“预期”（21.8±9.3 岁，p=0.001），并且可能存在较低的外显率。
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提示特定的基因型；（3）即使在患者或家族史中没有 ALS，在排除主要基因后，也应在所有 FTD 表型中搜索突变；（4）应考虑降低的外显率和临床变异性，以提供适当的遗传咨询。
