酪氨酸羟化酶缺乏症导致的多巴反应性肌张力不全一例临床特点及基因检测

摘要

目的 分析酪氨酸羟化酶缺乏症导致的多巴反应性肌张力障碍患儿临床特征及基因突变,探讨其分子遗传学机制.方法 归纳1例酪氨酸羟化酶缺乏症患儿的临床特点,提取患儿及其家系成员外周血全基因组DNA,用PCR方法扩增三磷酸鸟苷环水解酶1基因、酪氨酸羟化酶基因(TH)、墨蝶呤还原酶基因全部外显子及与其相连的内含子区,扩增产物行双向测序,查找突变位点.结果 患儿男,3岁10个月,因“全身肌力低下3年余”就诊.无明显智力受损,四肢肌力Ⅴ级,四肢僵硬,肌张力增高,双侧膝腱反射亢进,病理征(-).头颅MRI、肌电图、肌酸激酶、血浆铜蓝蛋白等辅助检查均无明显异常,试用小剂量多巴丝肼治疗后症状明显好转.基因分析提示:患儿携带TH基因c.605G＞ A(p.R202H)纯合突变,父母均携带此杂合突变,符合常染色体隐性遗传,为国内外已报道致病突变.结论 报道1例酪氨酸羟化酶缺乏症,1岁以内发病,不明原因的运动功能受损,肌张力障碍为其突出表现.对多巴反应特效.TH基因c.605G＞ A(p.R202H)可能为国内外TH轻中度缺陷型常见突变类型.%Objective To analyze the clinical characteristics of the patient with tyrosine hydroxylase deficiency,and investigate it's molecular mechanism.Method The clinical characteristics of a patient with tyrosine hydroxylase deficiency were summarized and analyzed,his and his family's peripheral blood specimens were collected after informed consent was signed.All exons and the intron-exon boundaries of gnanosine triphosphate hydroxylase Ⅰ gene,tyrosine hydroxylase gene and sepiapterin reductase gene were examined by DNA-PCR,bi-directional sequencing.Result The patient was a 3-year-old boy,presented with unexplained dystonia for 3 years,without significant impairment of intelligence.Physical examination showed limb muscle strength grade Ⅴ,rigidity of extremities,hypertonicity,brisk deep tendon reflexes in limbs,without obvious abnormalities in auxiliary examination,such as brain MRI,hepatic biochemical panel,creatine kinase,and ceruloplasmin.He dramatically responded to small doses of levodopa in the follow-up for half a year.A homozygous missense change in exon 5 of TH gene,c.605G ＞ A (p.R202H),which was a known pathogenic mutation,was found in the patient.His parents were heterozygous for the R202H mutation.Conclusion The age of onset in tyrosine hydroxylase deficiency patients is usually within the first year of life.Unexplained dystonia and hypokinesia were the main clinical features of tyrosine hydroxylase deficiency.The dopa-responsive effects for some patients are so obvious that we should strengthen awareness of the disease.TH gene c.605G ＞ A (p.R202H) may be a common type of causative mutations for the mild form at home and abroad.