以共济失调为例的罕见病：诊断、遗传学与治疗

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中文摘要

背景： 共济失调是一组罕见疾病。在欧盟，如果一种疾病的患病率低于每1万人中5例，则被定义为罕见病。共济失调比这一阈值更为罕见，尽管可靠的患病率估计在很大程度上仍然缺乏。常染色体显性遗传性共济失调的全球平均患病率约为每10万人中2.7例（95%置信区间[1.5；4.0/10万]），常染色体隐性共济失调约为每10万人中3.3例[1.8；4.9/10万]。共济失调包括遗传性（基因性）、散发性退行性和获得性类型。
方法： 本叙述性综述基于德国神经病学学会（Deutsche Gesellschaft für Neurologie）的指南及其他当前综述，并补充了有针对性的PubMed检索结果。
结果： 在较常见的遗传性共济失调类型中，已经可以根据病史、神经系统检查和脑MRI发现作出推定诊断（即视诊诊断），然后通过基因检测加以确认。这些类型包括Friedreich共济失调、RFC1-CANVAS综合征（小脑性共济失调、神经病和前庭反射消失），以及脊髓小脑性共济失调3型和27B型（SCA3和SCA27B）。当无法进行视诊诊断时，通常可以通过基因检测（最好基于基因组）来确立诊断。小脑型多系统萎缩（MSA-C）为散发性。亚急性病程的共济失调提示获得性共济失调类型——特别是免疫介导的共济失调和维生素B1缺乏（Wernicke）脑病。Omaveloxolone已被批准用于治疗Friedreich共济失调。在一项纳入103例患者的2期试验中，治疗48周后临床严重程度评分（mFARS值，最高99分）平均改善1.55分，而安慰剂组则恶化0.85分。Fampridine被超说明书用于治疗发作性共济失调、下跳性眼震和SCA27B。随机试验已记录物理治疗和规律运动训练对共济失调患者的益处。
结论： 随着目前可用的遗传和免疫诊断技术的改进，越来越多的共济失调可以得到诊断。治疗机会仍然有限，但许多新疗法正在开发中，包括基因治疗。

英文摘要

BACKGROUND: Ataxias are a group of rare diseases. In the European Union, a disease is defined as rare if its prevalence is less than 5 per 10 000 people. Ataxias are rarer than this threshold, although reliable prevalence estimates are largely lacking. The worldwide mean prevalence of autosomal dominant hereditary ataxias is approximately 2.7 per 100 000 people (95% confidence interval [1.5; 4.0/100 000]), and that of autosomal-recessive ataxias is approximately 3.3 per 100 000 people [1.8; 4.9/100 000]. Ataxias include hereditary (genetic), sporadic degenerative, and acquired types.
METHODS: This narrative review is based on the guidelines of the German Society for Neurology (Deutsche Gesellschaft für Neurologie) and on other current reviews, supplemented by the findings of targeted PubMed searches.
RESULTS: In the more common types of hereditary ataxia, a presumptive diagnosis (spot diagnosis) can already be made on the basis of the history, neurological examination, and brain MRI findings and can then be confirmed by genetic testing. These include Friedreich ataxia, the RFC1-CANVAS syndrome (cerebellar ataxia, neuropathy, and vestibular areflexia), and spinocerebellar ataxia types 3 and 27B (SCA3 and SCA27B). When a spot diagnosis is not possible, the diagnosis can often be established by genetic testing (preferably genome-based). Multisystem atrophy of the cerebellar type (MSA-C) arises sporadically. Ataxia with a subacute course suggests an acquired type of ataxia-in particular, immune-mediated ataxias and vitamin B1 deficiency (Wernicke) encephalopathy. Omaveloxolone has been approved for the treatment of Friedreich ataxia. In a phase 2 trial with 103 patients, the clinical severity score (mFARS value, maximum 99 points) improved by a mean of 1.55 points after 48 weeks of treatment, compared with worsening by 0.85 points with placebo. Fampridine is used off-label to treat episodic ataxias, downbeat nystagmus, and SCA27B. Randomized trials have documented the benefit of physiotherapy and regular exercise training for patients with ataxia.
CONCLUSION: An increasing number of ataxias can be diagnosed with the improved genetic and immunological diagnostic techniques that are now available. Opportunities for treatment remain limited, but many new therapies are under development, including gene therapy.