Garofalo M, Vansenne F, Verbeek D S, Sival D A
Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Eur J Paediatr Neurol. 2023 Mar;43:44-51. doi: 10.1016/j.ejpn.2023.02.005. Epub 2023 Feb 28.
Genetically inherited ataxic disorders are classified by their age of disease presentation into early- and late-onset ataxia (EOA and LOA, presenting before or after the 25th year-of-life). In both disease groups, comorbid dystonia co-occurs frequently. Despite overlapping genes and pathogenetic features, EOA, LOA and dystonia are considered as different genetic entities with a separate diagnostic approach. This often leads to diagnostic delay. So far, the possibility of a disease continuum between EOA, LOA and mixed ataxia-dystonia has not been explored in silico. In the present study, we analyzed the pathogenetic mechanisms underlying EOA, LOA and mixed ataxia-dystonia.
We analyzed the association of 267 ataxia genes with comorbid dystonia and anatomical MRI lesions in literature. We compared anatomical damage, biological pathways, and temporal cerebellar gene expression between EOA, LOA and mixed ataxia-dystonia.
The majority (≈65%) of ataxia genes were associated with comorbid dystonia in literature. Both EOA and LOA gene groups with comorbid dystonia were significantly associated with lesions in the cortico-basal-ganglia-pontocerebellar network. EOA, LOA and mixed ataxia-dystonia gene groups were enriched for biological pathways related to nervous system development, neural signaling and cellular processes. All genes revealed similar cerebellar gene expression levels before and after 25 years of age and during cerebellar development.
In EOA, LOA and mixed ataxia-dystonia gene groups, our findings show similar anatomical damage, underlying biological pathways and temporal cerebellar gene expression patterns. These findings may suggest the existence of a disease continuum, supporting the diagnostic use of a unified genetic approach.
遗传性共济失调疾病根据发病年龄分为早发性共济失调和晚发性共济失调（早发性共济失调和晚发性共济失调分别指在25岁之前或之后发病）。在这两组疾病中，共病性肌张力障碍经常同时出现。尽管存在重叠的基因和致病特征，但早发性共济失调、晚发性共济失调和肌张力障碍被视为不同的遗传实体，有各自独立的诊断方法。这往往导致诊断延迟。到目前为止，尚未在计算机模拟中探索早发性共济失调、晚发性共济失调和混合型共济失调-肌张力障碍之间存在疾病连续体的可能性。在本研究中，我们分析了早发性共济失调、晚发性共济失调和混合型共济失调-肌张力障碍的致病机制。
我们分析了文献中267个共济失调基因与共病性肌张力障碍和解剖学MRI病变之间的关联。我们比较了早发性共济失调、晚发性共济失调和混合型共济失调-肌张力障碍之间的解剖学损伤、生物学途径和小脑基因表达随时间的变化。
文献中大多数（约65%）共济失调基因与共病性肌张力障碍有关。伴有共病性肌张力障碍的早发性共济失调和晚发性共济失调基因组均与皮质-基底神经节-脑桥小脑网络的病变显著相关。早发性共济失调、晚发性共济失调和混合型共济失调-肌张力障碍基因组在与神经系统发育、神经信号传导和细胞过程相关的生物学途径中富集。所有基因在25岁之前和之后以及小脑发育过程中均显示出相似的小脑基因表达水平。
在早发性共济失调、晚发性共济失调和混合型共济失调-肌张力障碍基因组中，我们的研究结果显示出相似的解剖学损伤、潜在生物学途径和小脑基因表达模式。这些发现可能提示存在疾病连续体，支持采用统一的遗传学方法进行诊断。
