一名苏丹女孩由新型纯合DnaJ热休克蛋白家族（热休克蛋白40）成员C6移码变异所致的儿童期起病帕金森综合征、肌张力障碍和严重肌肉萎缩，并附带致病性乳腺癌1基因次要发现：一例病例报告

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中文摘要

背景： DNAJC6相关青少年帕金森综合征是一种罕见的常染色体隐性遗传病，由auxilin缺陷所致，auxilin是一种对网格蛋白介导的突触囊泡再循环至关重要的共伴侣蛋白。全球报道的家系不足50个，且当一线检查结果正常时该病容易被漏诊。我们描述一名苏丹青少年，其既往未报道的纯合DNAJC6移码变异是在经历了漫长的诊断过程后才被识别，该过程包括一段其疾病被误归因于功能性神经障碍的时期。临床全外显子组测序还额外返回了一个具有医学可操作性的BRCA1次要发现。
病例介绍： 一名13岁苏丹女孩，为表亲父母的长女，早产出生并在新生儿期因严重呼吸窘迫接受通气治疗。她发育正常直至5岁，此时首次出现孤立性上肢震颤。在接下来的8年中，她的病情进展为严重的青少年帕金森综合征：双侧静止性和动作性震颤、强直、运动迟缓、伴明显口下颌受累的全身性肌张力障碍、吞咽困难、极度恶病质、认知和行为衰退、睡眠和自主神经障碍、发作性动眼危象以及三次独立的癫痫发作。至约11岁时她已依赖轮椅。早期无阳性发现的检查曾导致功能性神经障碍的精神科诊断，而据此处方的多巴胺拮抗剂使她的病情恶化。全外显子组测序后来鉴定出一个新型纯合DNAJC6移码缺失（NM_001256864.2:c.1480del；p.Glu494ArgfsTer12），该变异不存在于人群数据库中，同时还有一个杂合致病性BRCA1缺失被报告为可操作的次要发现。左旋多巴产生了部分运动获益，但并发开期运动障碍、视幻觉和日间过度嗜睡。随后将卡比多巴/左旋多巴上调至约每5小时给药一次，使步态和精细运动功能出现进一步的临床明显改善。
结论： 本病例为DNAJC6目录增添了一个既往未报道的等位基因，并描述了其表型的严重端，其中皮质脊髓体征和危及生命的恶病质伴随更常见的锥体外系特征。它说明了将进行性器质性运动障碍过早标记为功能性疾病所带来的危害，尤其是随后又处方多巴胺拮抗剂时。伴随的致病性BRCA1次要发现显示了临床全外显子组测序可提供的双重诊断产出。对儿童期起病的运动障碍，尤其是存在近亲婚配时，早期遗传学检查应成为常规，而针对可操作次要发现的级联路径应嵌入常规实践。

英文摘要

BACKGROUND: DNAJC6-related juvenile parkinsonism is a rare autosomal recessive disorder of auxilin, a co-chaperone essential for clathrin-mediated synaptic vesicle recycling. Fewer than 50 kindreds have been reported worldwide, and the condition is easily missed when first-line investigations come back normal. We describe a Sudanese adolescent in whom a previously unreported homozygous DNAJC6 frameshift variant was identified only after a prolonged diagnostic journey that included a period during which her illness was mistakenly attributed to a functional neurological disorder. Clinical whole-exome sequencing additionally returned an incidental medically actionable BRCA1 secondary finding.
CASE PRESENTATION: A 13-year-old Sudanese girl, the eldest child of first-cousin parents, was born preterm and ventilated neonatally for severe respiratory distress. Her development was normal until age five, when an isolated upper-limb tremor first appeared. Over the next 8 years her condition progressed into severe juvenile parkinsonism: bilateral rest-and-action tremor, rigidity, bradykinesia, generalized dystonia with prominent oromandibular involvement, dysphagia, profound cachexia, cognitive and behavioral decline, sleep and autonomic disturbance, episodic oculogyric crises and three discrete seizures. By approximately 11 she was wheelchair-dependent. Earlier, unrevealing investigations had led to a psychiatric diagnosis of functional neurological disorder, and the dopamine antagonists prescribed on that basis worsened her condition. Whole-exome sequencing later identified a novel homozygous DNAJC6 frameshift deletion (NM_001256864.2:c.1480del; p.Glu494ArgfsTer12), absent from population databases, alongside a heterozygous pathogenic BRCA1 deletion reported as an actionable secondary finding. Levodopa produced partial motor benefit, complicated by on-state dyskinesias, visual hallucinations and excessive daytime somnolence. Subsequent up-titration of carbidopa/levodopa to approximately 5-hourly dosing produced a further, clinically evident improvement in gait and fine-motor function.
CONCLUSIONS: This case adds a previously unreported allele to the DNAJC6 catalog and characterizes the severe end of its phenotype, where corticospinal signs and life-threatening cachexia accompany the more familiar extrapyramidal features. It illustrates the harm that follows premature labeling of a progressive organic movement disorder as functional, especially when dopamine antagonists are then prescribed. The accompanying pathogenic BRCA1 secondary finding shows the dual diagnostic yield that clinical whole-exome sequencing can deliver. Early genetic investigation in childhood-onset movement disorders, particularly with consanguinity, should be the rule, and cascade pathways for actionable secondary findings embedded in routine practice.