Varghaei Parizad, Yoon Grace, Estiar Mehrdad A, Veyron Simon, Leveille Etienne, Dupré Nicolas, Trempe Jean-François, Rouleau Guy A, Gan-Or Ziv
Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Clin Genet. 2021 Jul;100(1):51-58. doi: 10.1111/cge.13955. Epub 2021 Mar 18.
GCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson's disease (PD) and tetrahydrobiopterin (BH )-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have been reported in five patients with hereditary spastic paraplegia (HSP). Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood-onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP-associated genes, and structural analysis of the variants indicated a disruptive effect. In conclusion, GCH1 mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.
GCH1基因突变与多巴反应性肌张力障碍（DRD）、帕金森病（PD）以及四氢生物蝶呤（BH4）缺乏性高苯丙氨酸血症B相关。最近，有报道称在5例遗传性痉挛性截瘫（HSP）患者中发现了GCH1基因突变。在此，我们通过全外显子组测序（WES）对来自加拿大不同中心的总共400例HSP患者（291个家系）进行了分析。鉴定出3例携带GCH1杂合变异的患者：一对携带p.(Ser77_Leu82del)变异的同卵双胞胎，以及1例携带p.(Val205Glu)变异的患者。前一种变异预计可能致病，后一种变异则为致病型。这3例患者均表现为儿童期起病的下肢痉挛、反射亢进和异常的足底反应。其中1例患者有日间波动，且均无帕金森综合征或肌张力障碍。观察到同卵双胞胎之间存在表型差异，他们对左旋多巴治疗反应良好。通路富集分析表明，GCH1与其他HSP相关基因具有共同的过程和通路，变异的结构分析显示有破坏作用。总之，GCH1基因突变可能导致HSP；因此，我们建议对HSP患者进行左旋多巴试验，并将GCH1纳入HSP基因筛查面板。同卵双胞胎之间的临床差异表明，环境因素、表观遗传学和随机性可能在临床表现中起作用。
