Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations
Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations
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DOI：
10.1002/ana.410440107
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发表时间：
1998-07-01
影响因子：
11.2
通讯作者：
Trugman, JM
中科院分区：
文献类型：
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作者：
Furukawa, Y;Kish, SJ;Trugman, JM
GTP环水解酶I（GCH）基因突变已被确定为两种疾病的原因：常染色体显性遗传性进行性肌张力障碍/多巴反应性肌张力障碍（HPD/DRD）和常染色体隐性遗传性GCH缺陷型高苯丙氨酸血症（HPA）。尚未报道具有介于HPD/DRD（轻度）和GCH缺陷HPA（重度）之间的表型的患者的详细临床描述和遗传分析。我们对两名患者（病例1和2）的GCH基因进行了基因组DNA测序，这两名患者表现为对左旋多巴有反应的全身性肌张力障碍和严重的发育性运动延迟。在患者1的谱系中，在索引病例之前的三代中存在HPD/DRD患者。患者1和2是复合杂合子，在GCH基因的编码区具有母系和父系传递的突变。在两种复合杂合子中，脑脊液中四氢生物蝶呤（BH 4）水平低于HPD/DRD。除了左旋多巴之外，BH 4的施用进一步改善了患者1的泌尿学。我们的数据表明，一种新的表型GCH缺乏症与复合杂合性GCH基因突变，并建议联合BH 4和左旋多巴治疗这种疾病的有用性。
Mutations in the GTP-cyclohydrolase I (GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and autosomal recessive GCH-deficient hyperphenylalaninemia (HPA). Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH-deficient HPA (severe) have not been reported. We conducted genomic DNA sequencing of the GCH gene in two patients (Cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. In the pedigree of Patient 1, there were HPD/DRD patients in three generations preceding the index case. Patients 1 and 2 were compound heterozygotes with maternally and paternally transmitted mutations in the coding region of the GCH gene. In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD. Administration of BH4, in addition to levodopa, further improved the symptomatology of Patient 1. Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder.