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Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34
Neurology Genetics ( IF 3.1 ) Pub Date : 2020-04-01 , DOI: 10.1212/nxg.0000000000000403
Marie Beaudin 1 , Leila Sellami 1 , Christian Martel 1 , Lydia Touzel-Deschênes 1 , Gabrielle Houle 1 , Laurence Martineau 1 , Kevin Lacroix 1 , Andréane Lavallée 1 , Nicolas Chrestian 1 , Guy A Rouleau 1 , François Gros-Louis 1 , Robert Laforce 1 , Nicolas Dupré 1
Affiliation  

Objective

To better characterize the neurologic and cognitive profile of patients with spinocerebellar ataxia 34 (SCA34) caused by ELOVL4 mutations and to demonstrate the presence of ELOVL4 cellular localization and distribution abnormalities in skin-derived fibroblasts.

Methods

We investigated a 5-generation French-Canadian kindred presenting with a late-onset cerebellar ataxia and recruited age- and education-matched controls to evaluate the presence of neurocognitive impairment. Immunohistochemistry of dermal fibroblasts derived from a patient's skin biopsy was performed.

Results

Patients had a late-onset slowly progressive cerebellar syndrome (mean age at onset 47 years; range 32–60 years) characterized by truncal and limb ataxia, dysarthria, hypometric saccades, and saccadic pursuits. No patient had past or current signs of erythrokeratodermia variabilis, which had previously been reported. MRI revealed cerebellar atrophy, with pontine atrophy (4 of 6 patients), and cruciform hypersignal in the pons (2 of 6 patients). Fluorodeoxyglucose-PET showed diffuse cerebellar hypometabolism in all 5 tested patients with subtle parietal hypometabolism in 3. Significant cognitive deficits were found in executive functioning, along with apparent visuospatial, attention, and psychiatric involvement. Immunohistochemistry of dermal fibroblasts showed mislocalization of the ELOVL4 protein, which appeared punctate and aggregated, supporting a dominant negative effect of the mutation on protein localization.

Conclusions

Our findings support the pathogenicity of ELOVL4 mutations in cerebellar dysfunction and provide a detailed characterization of the SCA34 phenotype, with neurocognitive changes typical of the cerebellar cognitive-affective syndrome.



中文翻译:

SCA34 中具有认知障碍和蛋白质错误定位的表型特征

客观的

为了更好地表征由ELOVL4突变引起的脊髓小脑性共济失调 34 (SCA34) 患者的神经和认知特征,并证明皮肤源性成纤维细胞中存在 ELOVL4 细胞定位和分布异常。

方法

我们调查了一个患有迟发性小脑共济失调的 5 代法裔加拿大亲属,并招募了年龄和教育程度匹配的对照来评估神经认知障碍的存在。对源自患者皮肤活检的真皮成纤维细胞进行免疫组织化学分析。

结果

Patients had a late-onset slowly progressive cerebellar syndrome (mean age at onset 47 years; range 32–60 years) characterized by truncal and limb ataxia, dysarthria, hypometric saccades, and saccadic pursuits. No patient had past or current signs of erythrokeratodermia variabilis, which had previously been reported. MRI revealed cerebellar atrophy, with pontine atrophy (4 of 6 patients), and cruciform hypersignal in the pons (2 of 6 patients). Fluorodeoxyglucose-PET showed diffuse cerebellar hypometabolism in all 5 tested patients with subtle parietal hypometabolism in 3. Significant cognitive deficits were found in executive functioning, along with apparent visuospatial, attention, and psychiatric involvement. Immunohistochemistry of dermal fibroblasts showed mislocalization of the ELOVL4 protein, which appeared punctate and aggregated, supporting a dominant negative effect of the mutation on protein localization.

结论

我们的研究结果支持ELOVL4突变在小脑功能障碍中的致病性,并提供了 SCA34 表型的详细表征,以及小脑认知-情感综合征典型的神经认知变化。

更新日期:2020-04-01
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