Brashear Allison, Dobyns William B, de Carvalho Aguiar Patricia, Borg Michel, Frijns C J M, Gollamudi Seema, Green Andrew, Guimaraes João, Haake Bret C, Klein Christine, Linazasoro Gurutz, Münchau Alexander, Raymond Deborah, Riley David, Saunders-Pullman Rachel, Tijssen Marina A J, Webb David, Zaremba Jacek, Bressman Susan B, Ozelius Laurie J
Department of Neurology, Wake Forest University, Winston Salem, NC 27157, USA.
Brain. 2007 Mar;130(Pt 3):828-35. doi: 10.1093/brain/awl340. Epub 2007 Feb 4.
Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.
快速起病性肌张力障碍-帕金森综合征（RDP）（也称为DYT12）的特征是肌张力障碍和帕金森综合征急性起病，由ATP1A3基因突变引起。我们获取了临床数据，并对来自21个家庭的49名被转诊为“可能”患有RDP的受试者的ATP1A3基因进行了测序，并进行了基因型-表型分析。在新转诊进行研究的家庭中，14个家庭中只有3个（21%）显示ATP1A3基因存在突变，但除了我们之前报告的6个突变外，未发现新的突变。将这些家庭与之前报告的家庭相加，我们在10个家庭的36名个体中发现了突变，包括4个新发突变，并排除了11个家庭中13名个体的突变。突变阳性患者的表型包括肌张力障碍急性起病并伴有帕金森综合征特征、头尾梯度以及明显的延髓症状。在一些突变携带者中发现的其他特征包括常见的触发因素报告、起病时极少或无震颤、主要起病前偶尔有轻度肢体肌张力障碍、对多巴胺能药物无反应、晚年症状罕见突然恶化、症状在一个月内稳定以及总体改善极小。在比较ATP1A3突变阳性和阴性患者时，我们发现症状起病时的震颤、头尾梯度倒置以及明显的肢体疼痛可排除RDP诊断。不需要阳性家族史。当出现急性起病、头尾梯度和明显的延髓症状时，建议对ATP1A3基因进行基因检测。
