Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Curr Neurol Neurosci Rep. 2021 Feb 9;21(3):8. doi: 10.1007/s11910-021-01095-1.
Since the advent of next-generation sequencing, the number of genes associated with dystonia has been growing exponentially. We provide here a comprehensive review of the latest genetic discoveries in the field of dystonia and discuss how the growing knowledge of biology underlying monogenic dystonias may influence and challenge current classification systems.
Pathogenic variants in genes without previously confirmed roles in human disease have been identified in subjects affected by isolated or combined dystonia (KMT2B, VPS16, HPCA, KCTD17, DNAJC12, SLC18A2) and complex dystonia (SQSTM1, IRF2BPL, YY1, VPS41). Importantly, the classical distinction between isolated and combined dystonias has become harder to sustain since many genes have been shown to determine multiple dystonic presentations (e.g., ANO3, GNAL, ADCY5, and ATP1A3). In addition, a growing number of genes initially linked to other neurological phenotypes, such as developmental delay, epilepsy, or ataxia, are now recognized to cause prominent dystonia, occasionally in an isolated fashion (e.g., GNAO1, GNB1, SCN8A, RHOBTB2, and COQ8A). Finally, emerging analyses suggest biological convergence of genes linked to different dystonic phenotypes. While our knowledge on the genetic basis of monogenic dystonias has tremendously grown, their clinical boundaries are becoming increasingly blurry. The current phenotype-based classification may not reflect the molecular structure of the disease, urging the need for new systems based on shared biological pathways among dystonia-linked genes.
自下一代测序技术问世以来，与肌张力障碍相关的基因数量呈指数级增长。我们在这里对肌张力障碍领域的最新遗传发现进行了全面综述，并讨论了单基因肌张力障碍背后生物学知识的不断增加如何影响和挑战当前的分类系统。
在受孤立或合并性肌张力障碍（KMT2B、VPS16、HPCA、KCTD17、DNAJC12、SLC18A2）和复杂性肌张力障碍（SQSTM1、IRF2BPL、YY1、VPS41）影响的患者中，已鉴定出先前在人类疾病中未确认具有作用的基因中的致病变异。重要的是，由于许多基因已被证明决定多种肌张力障碍表现（例如，ANO3、GNAL、ADCY5 和 ATP1A3），因此孤立性和合并性肌张力障碍之间的经典区分变得更加困难。此外，越来越多的最初与其他神经表型（如发育迟缓、癫痫或共济失调）相关的基因，现在被认为会导致明显的肌张力障碍，偶尔以孤立的方式（例如，GNAO1、GNB1、SCN8A、RHOBTB2 和 COQ8A）。最后，新兴分析表明与不同肌张力障碍表型相关的基因存在生物学趋同。虽然我们对单基因肌张力障碍的遗传基础的了解有了极大的增长，但它们的临床界限变得越来越模糊。目前基于表型的分类可能无法反映疾病的分子结构，因此需要基于与肌张力障碍相关基因之间共享的生物学途径的新系统。
