Bianchi Silvia, Zicari Enza, Carluccio Alessandra, Di Donato Ilaria, Pescini Francesca, Nannucci Serena, Valenti Raffaella, Ragno Michele, Inzitari Domenico, Pantoni Leonardo, Federico Antonio, Dotti Maria Teresa
Department of Medical, Surgical and Neurological Sciences Medical School, University of Siena, Viale Bracci 2, Siena, Italy.
J Neurol. 2015 Jan;262(1):134-41. doi: 10.1007/s00415-014-7533-2. Epub 2014 Oct 26.
The objective of the study is to detail clinical and NOTCH3 gene mutational spectrum in a large group of Italian CADASIL patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial cerebral small vessels disease caused by mutations in the NOTCH3 gene on 19p13 usually presenting in young or middle adulthood. Characteristic features include migraine, recurrent lacunar stroke, subcortical dementia, mood disturbances and leukoencephalopathy. The disorder is often overlooked and misdiagnosed. CADASIL prevalence and disease burden is still undetermined. We retrospectively reviewed demographic, clinical, and mutational characteristic of all CADASIL patients diagnosed from January 2002 to December 2012 in three referral centers for neurogenetic and cerebrovascular diseases in central Italy. 229 NOTCH3 positive subjects were identified. Mean age at diagnosis was 57.8 ± 14.7 years, and 48.6 ± 17.1 years at first symptom onset. Most frequent clinical symptoms were ischemic events (59 %) and psychiatric disturbances (48 %). The highest percentage of mutations were found on exons 4 and 19 (20.6 and 17.6 % respectively), the remaining being dispersed over the entire EGF-like region of the NOTCH3 gene. 209 patients resided in a circumscribed geographic area which included three regions of the central Italy, yielding a minimum prevalence of 4.1 per 100.000 adult inhabitants. This is the most extensive study on CADASIL in Italy. Clinical phenotype showed several peculiarities in frequency and presentation of the main disease manifestations. Our study enlarges the number of pathogenic NOTCH3 mutations and due to the heterogeneous mutational spectrum observed suggests that full sequencing of exons 2-24 is mandatory for CADASIL screening in the Italian population.
本研究的目的是详细描述一大组意大利CADASIL患者的临床特征和NOTCH3基因突变谱。伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种家族性脑小血管疾病，由19p13上NOTCH3基因的突变引起，通常在青年或中年发病。其特征性表现包括偏头痛、复发性腔隙性卒中、皮质下痴呆、情绪障碍和白质脑病。该疾病常被忽视和误诊。CADASIL的患病率和疾病负担仍未确定。我们回顾性分析了2002年1月至2012年12月期间，意大利中部三个神经遗传学和脑血管疾病转诊中心确诊的所有CADASIL患者的人口统计学、临床和突变特征。共识别出229例NOTCH3基因阳性患者。诊断时的平均年龄为57.8±14.7岁，首次出现症状时的平均年龄为48.6±17.1岁。最常见的临床症状是缺血性事件（59%）和精神障碍（48%）。在外显子4和19上发现的突变比例最高（分别为20.6%和17.6%），其余突变则分散在NOTCH3基因的整个EGF样区域。209名患者居住在意大利中部三个地区的一个限定地理区域内，成年居民的最低患病率为每10万人4.1例。这是意大利对CADASIL进行的最广泛研究。临床表型在主要疾病表现的频率和呈现方式上显示出几个特点。我们的研究增加了致病性NOTCH3突变的数量，并且由于观察到的突变谱具有异质性，表明在意大利人群中进行CADASIL筛查时，对外显子2 - 24进行全测序是必要的。
