Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark.
J Neurol Sci. 2012 Oct 15;321(1-2):100-2. doi: 10.1016/j.jns.2012.07.036. Epub 2012 Aug 3.
Hereditary spastic paraplegia (HSP) confines a group of heterogeneous neurodegenerative disorders characterized by progressive spasticity and lower limb weakness. Age of onset is highly variable even in familial cases with known mutations suggesting that the disease is modulated by other yet unknown parameters. Although progressive gait disturbances, lower limb spasticity and extensor plantar responses are hallmarks of HSP these characteristics are also found in other neurodegenerative disorders, e.g. amytrophic lateral sclerosis (ALS). HSP has been linked to ALS and frontotemporal degeneration with motor neuron disease (FTD-MND), since TDP-43 positive inclusions have recently been found in an HSP subtype, and TDP-43 are found in abundance in pathological inclusions of both ALS and FTD-MND. Furthermore, ataxin-2 (encoded by the gene ATXN2), a polyglutamine containing protein elongated in spinocerebellar ataxia type 2, has been shown to be a modulator of TDP-43 induced toxicity in ALS animal and cell models. Finally, it has been shown that ATXN2 with non-pathogenic intermediate-length CAG/CAA repeat elongations (encoding the polyglutamine tract) is a genetic risk factor of ALS. Considering the similarities in the disease phenotype and the neuropathological link between ALS and HSP we hypothesized that intermediate-length CAG/CAA repeats in ATXN2 could be a modulator of HSP. We show that in a cohort of 181 HSP patients 4.9 % of the patients had intermediate-length CAG/CAA repeats in ATXN2 which was not significantly different from the frequencies in a Danish control cohort or in American and European control populations. However, the mean age of onset was significantly lower in HSP patients with intermediate-length CAG/CAA repeats in ATXN2 compared to patients with normal length repeats. Based on these results we conclude that ATXN2 is most likely not a risk factor of HSP, whereas it might serve as a modulator of age of onset.
遗传性痉挛性截瘫（HSP）是一组异质性神经退行性疾病，其特征为进行性痉挛和下肢无力。即使在具有已知突变的家族病例中，发病年龄也高度可变，这表明该疾病受到其他未知参数的调节。尽管进行性步态障碍、下肢痉挛和伸肌跖反射是 HSP 的标志，但这些特征也存在于其他神经退行性疾病中，例如肌萎缩侧索硬化症（ALS）。HSP 与 ALS 和额颞叶变性伴运动神经元病（FTD-MND）有关，因为最近在 HSP 亚型中发现 TDP-43 阳性包涵体，并且在 ALS 和 FTD-MND 的病理包涵体中均发现大量 TDP-43。此外，富含多聚谷氨酰胺的蛋白，脊髓小脑性共济失调 2 型的延长，已被证明是 ALS 动物和细胞模型中 TDP-43 诱导毒性的调节剂。最后，已经表明 ATXN2 与非致病性中间长度 CAG/CAA 重复伸长（编码多聚谷氨酰胺片段）是 ALS 的遗传风险因素。鉴于 ALS 和 HSP 之间在疾病表型和神经病理学方面的相似性，我们假设 ATXN2 中的中间长度 CAG/CAA 重复可能是 HSP 的调节剂。我们表明，在 181 名 HSP 患者的队列中，4.9%的患者 ATXN2 中存在中间长度的 CAG/CAA 重复，这与丹麦对照组或美国和欧洲对照组的频率没有显著差异。然而，与具有正常长度重复的患者相比，ATXN2 中具有中间长度 CAG/CAA 重复的 HSP 患者的发病年龄明显较低。基于这些结果，我们得出结论，ATXN2 不太可能是 HSP 的风险因素，而可能是发病年龄的调节剂。
