Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications
Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications
复制标题
DOI：
10.1001/jamaneurol.2013.3646
复制
发表时间：
2013-11-01
期刊：
影响因子：
29
通讯作者：
Bassett, Anne S.
中科院分区：
文献类型：
--
作者：
Butcher, Nancy J.;Kiehl, Tim-Rasmus;Bassett, Anne S.
帕金森综合征与半合子22q11.2缺失和相关的多系统综合征22q11.2缺失综合征（22q11.2DS）共同发生的临床病例报告表明，22q11.2缺失可能导致早发性帕金森病（PD）的风险增加。PD及其神经病理表现的频率在这种常见的遗传condition. ObjectiveTo评估22q11.2缺失和PD之间可能的关联。设计、设置和参与者一项观察性研究，在世界上最大的具有良好特征的成年人队列中，分子诊断为22q11.2DS，（n = 159 [6例尸检组织];年龄范围，18.1-68.6岁）在加拿大安大略多伦多进行。结果22q11.2DS患者的PD发生率明显高于正常人，而22q11.2DS患者的PD发生率明显高于正常人，PD的发生率明显高于正常人，PD的发生率明显高于正常人，PD的发生率明显高于正常人，PD的发生率明显高于正常人估计值（标准化发病率比= 69.7; 95%CI，19.0-178.5）。所有病例均表现为早期发作和典型的PD症状模式、治疗反应和病程。所有患者的PD家族史和已知的致病性PD相关突变均为阴性。在22q11.2DS患者中常用抗精神病药物治疗相关精神症状，可将PD诊断延迟长达10年。尸检脑组织显示所有3例尸检22 q11.2DS-PD病例中脑多巴胺能神经元均出现典型缺失。典型的α-突触核蛋白阳性路易体存在于预期的分布在2例，但不存在于another.CONCLUSIONS和RELEVANCE这些研究结果表明，22q11.2缺失代表了一种新的遗传风险因素，早发性帕金森病与可变的神经病理学表现让人想起LRRK 2相关的PD神经病理学。具有早发性PD和22q11.2DS典型特征的个体应考虑进行基因检测，已知22q11.2缺失的个体应监测帕金森病症状的发展。包括DGCR 8在内的相关基因的分子研究可能有助于阐明22q11.2DS和特发性PD的潜在病理生理学。
IMPORTANCE Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition.OBJECTIVE To evaluate a possible association between 22q11.2 deletions and PD.DESIGN, SETTING, AND PARTICIPANTS An observational study of the occurrence of PD in the world's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.MAIN OUTCOMES AND MEASURES A clinical diagnosis of PD made by a neurologist and neuropathological features of PD.RESULTS Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical a-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.CONCLUSIONS AND RELEVANCE These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.