Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.
目的： 探讨酪氨酸羟化酶（TH）基因变异致多巴反应性肌张力障碍（DRD）患儿的临床和遗传学特征。 方法： 回顾分析2017年1月至2022年8月郑州大学第三附属医院儿童康复科收治的9例TH基因变异致DRD患儿的一般情况、临床表现、实验室检查、基因检测结果及随访资料。 结果： 9例TH基因变异致DRD患儿中男3例、女6例，确诊年龄为12.0（8.0，15.0）月龄。8例重型患儿首发症状为运动发育落后或发育倒退，临床表现包括运动发育落后8例，躯干肌张力低下8例，四肢肌张力低下7例，运动减少6例，面部表情少4例，震颤3例，四肢肌张力障碍3例，晨轻暮重2例，上睑下垂2例，四肢肌张力增高1例，多涎1例。1例极重型患儿首发症状为运动发育落后，临床表现包括明显运动发育落后、躯干肌张力低下、频繁动眼危象、肌张力障碍持续状态、运动减少、面部表情少、睡眠明显减少。9例患儿基因检测共发现11个TH基因变异，包括5个错义变异、3个剪切位点变异、2个无义变异、1个插入变异，其中2个变异［c.941C>A（p.T314K）、c.316_317insCGT（p.F106delinsSF）］为尚未见报道的新变异。9例患儿随访40（29，43）个月，无失访。8例重型患儿中1例应用左旋多巴片，7例应用多巴丝肼片治疗，症状均有明显改善；后期随着患儿体重增加，未增加药物剂量，疗效仍稳定，未见明显不良反应。应用多巴丝肼片治疗的1例重型患儿治疗早期出现异动症，加用盐酸苯海索片后症状消失。末次随访时，7例重型患儿运动发育恢复正常，1例重型患儿因治疗时间仅2个月仍存在运动发育落后；1例极重型患儿对多巴丝肼片极度敏感、用药后有明显烦躁的不良反应，治疗无明显效果。 结论： TH基因变异致DRD以重型多见，临床表现多样，易误诊，重型患儿对左旋多巴片或多巴丝肼片反应良好，但需较长时间才能确定治疗效果，长期用药虽然患儿体重增加，但无需增加剂量仍疗效稳定，无明显不良反应。.