Trender-Gerhard I, Sweeney M G, Schwingenschuh P, Mir P, Edwards M J, Gerhard A, Polke J M, Hanna M G, Davis M B, Wood N W, Bhatia K P
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK.
J Neurol Neurosurg Psychiatry. 2009 Aug;80(8):839-45. doi: 10.1136/jnnp.2008.155861. Epub 2009 Mar 29.
An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases.
A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented.
The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.
编码鸟苷三磷酸环化水解酶1（GTPCH1）的GCH1基因中的常染色体显性遗传缺陷是多巴反应性肌张力障碍（DRD）的最常见病因。与GCH1突变相关的年轻起病的下肢肌张力障碍、日间波动以及对左旋多巴的良好反应这一经典表型已得到充分认识，且已有罕见非典型表现的报道。然而，一些临床问题仍未解决，包括表型变异性、对左旋多巴的长期反应及相关非运动症状，并且关于基因确诊病例的长期随访数据有限。
对34例GCH1基因确诊突变患者（19例女性，15例男性）进行了详细的临床评估。
经典表型最为常见（n = 23），女性居多（女∶男 = 16∶7），起病早（平均4.5岁）且累及腿部。然而，数量惊人的患者出现了颅颈肌张力障碍，其中两名患者以痉挛性发声困难为主要症状。一部分患者，主要为男性，表现为年轻起病（平均6.8岁）的轻度DRD变异型，无需治疗（n = 4），或为成年起病（平均37岁）的帕金森病样表型（n = 4）。两名同胞受严重影响，早期出现肌张力减退及运动发育迟缓，与复合杂合GCH1基因突变有关。该研究还描述了一些补充特征，包括不宁腿样症状、女性性激素的影响、成年起病病例中震颤或帕金森症占优势、对左旋多巴的初始反向反应、抑郁症复发以及特定的左旋多巴抵抗症状（书写痉挛、发声困难、躯干肌张力障碍）。左旋多巴在20次妊娠中有效且安全使用，未导致任何胎儿异常。
