5个基因(GCH1,TH,PTS,SPR,和QDPR),参与多巴胺/四氢生物蝶呤的生物合成或再循环,与多巴反应性肌张力障碍(DRD)有关。由于组间和组内的高变异性,诊断和治疗通常会延迟。
全面分析个体基因型,表型,治疗反应,和生物化学信息。
使用MDSGene系统文献综述和自动分类方法区分不同形式的单基因DRDs,纳入734名DRD患者和151名无症状GCH1突变携带者。
而肌张力障碍,左旋多巴反应性,发病年龄较早,昼夜波动被确定为危险信号,没有肌张力障碍的帕金森综合征很少报道(11%),只有18%的患者合并肌张力障碍.虽然常染色体隐性遗传DRD的性别分布相等,与男性相比,常染色体显性遗传的DYT/PARK-GCH1患者以女性为主,同时女性的发病中位年龄较低,肌张力障碍较多.因此,大多数无症状杂合子GCH1突变携带者(>8岁)为男性.确定了多个其他亚组特异性特征,在自动分类方法中显示出较高的准确性:癫痫发作和小头畸形主要见于DYT/PARK-PTS,植物神经症状常见于DYT/PARK-TH和DYT/PARK-PTS,DYT/PARK-SPR中的睡眠障碍和眼病危机。生物化学,脑脊液中高香草酸和5-羟基吲哚乙酸在大多数DRDs中减少,但新蝶呤和生物蝶呤仅在DYT/PARK-PTS和DYT/PARK-SPR中增加。高苯丙氨酸血症见于DYT/PARK-PTS,DYT/PARK-QDPR,在常染色体隐性DYT/PARK-GCH1中很少报道。
我们的指标将有助于明确诊断并加速治疗的开始。©2021作者由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability.
Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information.
734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an
MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs.
Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1.
Our indicators will help to specify diagnosis and accelerate start of treatment. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.