Globas Christoph, du Montcel Sophie Tezenas, Baliko Laslo, Boesch Syliva, Depondt Chantal, DiDonato Stefano, Durr Alexandra, Filla Alessandro, Klockgether Thomas, Mariotti Caterina, Melegh Bela, Rakowicz Maryla, Ribai Pascale, Rola Rafal, Schmitz-Hubsch Tanja, Szymanski Sandra, Timmann Dagmar, Van de Warrenburg Bart P, Bauer Peter, Schols Ludger
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Mov Disord. 2008 Nov 15;23(15):2232-8. doi: 10.1002/mds.22288.
Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two-thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA.
由于具有隐匿性和缓慢进展的特性，基因决定的神经退行性疾病的发病时间很难确定。对于脊髓小脑共济失调（SCA）来说尤其如此，因为其会影响神经系统的多个部位，且症状具有极大的变异性。我们调查了287例SCA1、SCA2、SCA3或SCA6患者的早期症状，并根据以下因素计算CAG重复序列长度对发病年龄的影响：（1）疾病发作的定义；（2）确定发作的人员；（3）症状持续时间。三分之二的患者最初症状为步态困难。4%的患者分别在共济失调之前出现复视、构音障碍、书写障碍和发作性眩晕。其他早期症状的发生率与对照组无差异，被认为是非特异性的。在44%的病例中，患者和亲属之间关于疾病发作的数据相差1年或更长时间。当将发作定义为永久性步态障碍开始且排除症状持续超过10年的病例时，重复序列长度对发病年龄的影响最大。在这些条件下，CAG重复序列长度在SCA1中决定了64%的发作变异性，在SCA2中为67%，在SCA3中为46%，在SCA6中为41%，这表明在所有SCA亚型中，非重复因素对疾病发作有重大影响。识别这些因素作为疾病修饰化合物的潜在靶点具有重要意义。在这方面，识别共济失调发作前出现的早期症状对于确定SCA从症状前状态向患病状态的转变至关重要。
