Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia
Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia
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DOI：
10.1093/brain/awp084
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发表时间：
2009-07-01
期刊：
影响因子：
14.5
通讯作者：
Brice, Alexis
中科院分区：
文献类型：
--
作者：
Clot, Fabienne;Grabli, David;Brice, Alexis
多巴反应性肌张力障碍是一种儿童期发病的肌张力障碍，其特征是对低剂量左旋多巴的剧烈反应。多巴反应性肌张力障碍主要由GCH1基因（GTP环水解酶1）的常染色体显性突变引起，较少由TH（酪氨酸羟化酶）或SPR （sepapterin还原酶）基因的常染色体隐性突变引起。此外，引起常染色体隐性青少年帕金森病的PARK2基因（parkin）突变可能表现为多巴反应性肌张力障碍。为了评估这些基因的相对突变频率，以及参与BH4生物合成和再循环的基因的突变频率，并评估相关的临床谱，我们研究了大量多巴反应性肌张力障碍患者（n 64），其中左旋多巴治疗后肌张力障碍改善至少50%。其中57例为纯多巴反应性肌张力障碍，7例为多巴反应性肌张力障碍加综合征。筛选所有患者GCH1基因的点突变和大重排，然后对TH和SPR基因进行测序，然后对PTS（丙酮酰四氢蝶呤合成酶）、PCBD（蝶呤-4a-碳醇胺脱水酶）、QDPR（二氢蝶呤还原酶）和PARK2 （parkin）基因进行测序。我们在40例患者中发现了34种不同的杂合点突变，在7例患者中发现了6种不同的GCH1基因大缺失。除了一名智力低下患者和包含10个基因的2.3 Mb大缺失外，所有患者都具有刻板的临床特征，其特征是纯粹的多巴反应性肌张力障碍，发病于下肢，对低剂量的左旋多巴有良好的反应。40例患者（85例）在10岁前开始肌张力障碍，1例患者（2.2例）在1岁前开始肌张力障碍。17例GCH1阴性患者中有3例TH基因突变，2例SPR基因突变，1例PARK2基因突变。参与BH4生物合成和循环的三个基因未发现突变。TH和SPR基因突变患者的临床表现异常复杂，表现为智力低下、眼功能危象和帕金森病，均属于多巴反应性肌张力障碍综合征。PARK2基因突变的患者有多巴反应性肌张力障碍，左旋多巴治疗改善良好，类似于GCH1突变继发的多巴反应性肌张力障碍。虽然纯多巴反应性肌张力障碍和多巴反应性肌张力障碍综合征组的突变量超过80，但所涉及的基因明显不同：前者为GCH1，后者为TH和SPR。
Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50 after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85) and before the age of 1 year in one patient (2.2). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80 in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.