一例酪氨酸羟化酶缺乏症导致的小儿帕金森症伴运动延迟的临床及基因变异分析

目的探讨1例酪氨酸羟化酶缺乏症导致的小儿型帕金森伴运动延迟患儿家系的临床特点,并分析其基因变异情况。方法收集2018年6月就诊郑州大学附属儿童医院的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DNA,对患儿多巴反应性肌张力不良相关基因三磷酸鸟苷环水解酶1基因(guanosine triphosphate cyclohydrolaseⅠ,GCH1)、酪氨酸羟化酶基因(tyrosine hydroxylase,TH)、墨蝶蛉还原酶基因(sepiapterin reductase,SPR)全部外显子进行深度测序,对变异位点进行分析并通过Sanger测序验证。结果该患儿7月11天,因"翻身不灵活、不会独坐"就诊。运动功能减退,动作延迟,肌张力稍低,肢体僵硬,头有抖动,轻微斜颈,智力发育稍微落后,自3个月大开始有肢体不自主抖动,持续约十几秒自行缓解,情绪激动时和睡前该动作较多。头颅MRI提示双侧额颞部蛛网膜下腔增宽,颞部增宽明显,被误诊为脑性瘫痪。基因变异分析发现其TH基因c.457C>T(p.R153X)无义变异和c.720C>G(p.I240M)错义变异,分别来源于其父亲和母亲,属于复合杂合变异,符合常染色体隐性遗传,其中c.457C>T(p.R153X)为国内外已报道致病变异,c.720C>G(p.I240M)未见报道。结论报告一例1岁以内发病的因酪氨酸羟化酶缺乏症引起的婴儿型帕金森伴运动迟,TH基因变异是导致酪氨酸羟化酶缺乏症的主要原因之一,本研究结果发现的c.720C>G(p.I240M)变异进一步丰富了TH基因的变异谱。

Clinical and genetic analysis of a case with infantile Parkinsonism with motor delay due to tyrosine hydroxylase deficiency

Objective To explore the clinical characteristics and genetic variants in a child featuring tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay.Methods Clinical feature of the patient was summarized.Genomic DNA was extracted from peripheral blood samples taken from the child and her family members.All exons of GCH1,TH and SPR genes were subjected to targeted capture and next-generation sequencing.Suspected variants were verified by Sanger sequencing.Results The child could not sit alone at 7 month and 11 days.Physical examination suggested motor retardation and hypotonia,limb stiffness,head nodding,slight torticollis,and language and intellectual developmental delays.She developed involuntary shaking of limbs at 3 month old,which lasted approximately 10 seconds and aggregated with excitement and before sleeping.Cranial MRI revealed widening of subarachnoid space on the temporomandibular and particularly temporal sides.Genetic testing revealed that she has carried a nonsense c.457C>T(p.R153X)variant,which was known to be pathogenic,and a novel missense c.720C>G(p.I240M)variant of the TH gene.The two variants were derived from her father and mother,respectively.Conclusion The child was diagnosed as tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay due to compound heterozygous variants of the TH gene.Above finding has enriched the spectrum of TH gene variants.