Gene Transfer Technology Group, EGA UCL Institute for Women's Health, University College London, London WC1E 6HX, UK.
Genetic Therapy Accelerator Centre, Queens Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Cells. 2023 Jun 28;12(13):1737. doi: 10.3390/cells12131737.
Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the gene. Advances in genomic analysis have revealed an evolving spectrum of -related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy.
多巴胺转运体缺陷综合征（DTDS）所致婴儿帕金森-肌张力障碍是一种超罕见的儿童运动障碍疾病，由 基因的双等位基因失活突变引起。基因组分析的进展揭示了一系列与多巴胺转运体相关的神经和神经精神疾病。自 2009 年首次对 DTDS 进行临床和遗传特征描述以来，已有 31 例发表病例，涉及多种蛋白截断变异（无义变异、剪接位点改变和缺失）和错义改变。氨基酸取代导致突变蛋白的多巴胺转运体功能受损，原因是转运体活性降低、多巴胺结合减少、细胞表面表达减少以及异常的翻译后蛋白修饰，导致糖基化受损。在这篇综述中，我们概述了 DTDS 不断扩展的临床表型和正在开发的精准治疗方法，包括药物伴侣和基因治疗。
