van der Zee Julie, Mariën Peter, Crols Roeland, Van Mossevelde Sara, Dillen Lubina, Perrone Federica, Engelborghs Sebastiaan, Verhoeven Jo, D'aes Tine, Ceuterick-De Groote Chantal, Sieben Anne, Versijpt Jan, Cras Patrick, Martin Jean-Jacques, Van Broeckhoven Christine
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Neurol Genet. 2016 Sep 16;2(5):e102. doi: 10.1212/NXG.0000000000000102. eCollection 2016 Oct.
To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD).
Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing.
We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype.
A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms.
研究一个比利时家族中常染色体隐性成人发病型神经元蜡样脂褐质沉积症（ANCL或库夫斯病[KD]）且额叶受累明显的分子基础，并将研究结果扩展至一组不相关的患有额颞叶痴呆（FTD）的比利时患者。
采用外显子组测序和靶向大规模平行重测序技术，对ANCL家族和FTD队列（n = 461）进行基因筛查。
我们在组织蛋白酶F（CTSF）基因中鉴定出一个纯合突变（p.Ile404Thr），该突变在ANCL家族中呈共分离现象。未发现其他能解释该家族疾病的突变。所有4名受影响的同胞均出现运动症状和具有明显额叶特征的早发性痴呆。其中2人发展为运动不能性缄默症。疾病表现出明显的表型变异，发病年龄在26至50岁之间。其中一名同胞出现肌阵挛性癫痫提示为A型KD，而其他表现为B型KD临床特征的同胞未出现癫痫。在一组不相关的患有FTD的比利时患者队列中，在2名具有共同单倍型的患者中鉴定出相同的杂合p.Arg245His突变。
在一个隐性ANCL家系中鉴定出一个纯合CTSF突变。与之前CTSF与B型KD的关联不同，我们的研究结果表明，对于A型KD患者以及具有明显额叶和运动症状的早发性痴呆患者，也应考虑进行CTSF基因检测。
