Sival Deborah A, Garofalo Martinica, Brandsma Rick, Bokkers Tom A, van den Berg Marloes, de Koning Tom J, Tijssen Marina A J, Verbeek Dineke S
Department of Paediatric Neurology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
Department of Neurology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
Diagnostics (Basel). 2020 Nov 24;10(12):997. doi: 10.3390/diagnostics10120997.
In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD), are still unclear. In 80 EOA-patients, we determined the EOAD-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus ( = 0.001)). Genetic network and functional enrichment analysis in EOAD-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.
在退行性成人起病性共济失调（AOA）中，肌张力障碍合并症被归因于一种疾病连续体。然而，在早发性成人起病性共济失调（EOA）中，肌张力障碍合并症（EOAD）的患病率和发病机制仍不清楚。在80例EOA患者中，我们确定了与MRI异常相关的EOAD患病率。随后，我们通过基因网络和功能富集分析探索潜在的生物学途径。我们通过将结果与最新的EOA、AOA和肌张力障碍基因面板中（可能同时导致共济失调和肌张力障碍）非特异性（计算机模拟确定）共享基因进行比较，来检查特定EOAD基因型中的途径结果。在大多数（65%）EOA患者中，轻度EOAD特征与小脑外MRI异常（在脑桥和/或基底神经节和/或丘脑）同时出现（p = 0.001）。EOAD基因型的基因网络和功能富集分析表明与细胞器和细胞成分组织有关（对能量产生和信号转导很重要）。在非特异性的、计算机模拟确定的共享EOA、AOA和肌张力障碍基因中，途径富集了三羧酸循环和脂肪酸/脂质代谢过程。在常见的EOAD表型中，临床、解剖和生物学途径分析揭示了共济失调和肌张力障碍之间的共同病理生理学，与细胞能量代谢和网络信号转导有关。深入了解异质性EOAD表型-基因型关系的潜在病理生理学支持了使用完整的、最新的运动障碍基因列表进行检测的基本原理，而不是单一的EOA基因面板。
