Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
Lancet Neurol. 2014 May;13(5):482-9. doi: 10.1016/S1474-4422(14)70027-4. Epub 2014 Mar 20.
The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2).
We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments.
We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively).
Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease.
Cuban Ministry of Public Health.
在小脑综合征能够被诊断之前，ATXN2 扩增对神经系统的影响就已经出现了；然而，潜在的早期临床表现的进展情况尚不清楚。我们的目的是评估脊髓小脑性共济失调 2 型（SCA2）早期的主要临床特征的进展情况。
我们在 1986 年 8 月 12 日至 2013 年 9 月 3 日期间，在 SCA2 突变的携带者和非携带者之间进行了这项纵向研究。我们招募了年龄在 6 至 60 岁之间、无症状的 SCA2 患者的后代或兄弟姐妹。参与者接受了重复评估（两次至七次），直到他们出现明确的小脑综合征。所有参与者都接受了标准的神经学检查和电生理学（神经传导测试和体感诱发电位）以及遗传评估。
我们招募了 55 名符合条件的参与者中的 40 名（73%）进行基线评估，其中 21 名（13 名女性和 8 名男性）是 SCA2 突变的携带者，19 名（14 名女性和 5 名男性）是非携带者。肌肉痉挛和感觉异常是携带者中最常见的临床特征（均为 17 例[81%]），而对照组中分别为 3 例（16%）和 4 例（21%）（χ²=84.58；p<0.0001 和 χ²=72.03；p<0.0001）。这两种特征都随着时间的推移明显恶化，在 17 名（81%）携带者中，发病年龄与 CAG 重复呈负相关（痉挛：r=-0.76，p=0.0004；感觉异常：r=-0.77，p=0.0004）。反射亢进与共济失调发病时间的延长有关（平均 5.71 年[SD 5.03]），而反射减退与发病时间的缩短有关（中位数 1.29 年[范围 1-3]）。在 11 名（52%）携带者中，在共济失调发生前 5 至 8 年进行的电生理记录显示，正中神经的感觉幅度降低（10.34 uV[SD 5.07]），平均 P40 潜伏期延长（39.31 ms[2.40]），与年龄和性别匹配的对照组相比（20.72 uV[9.08 uV]；p=0.0085，和 35.60 ms[2.05]；p=0.0023）。
SCA2 的早期特征在小脑综合征发病之前就可以检测到，并且与扩展的 CAG 重复和小脑综合征发病时间有关。这些发现可以帮助早期诊断和遗传咨询，也提供了病理生理学方面的见解，有助于在疾病的早期阶段进行临床试验。
古巴公共卫生部。
