Clinical Spectrum of Kufor-Rakeb Syndrome in the Chilean Kindred with ATP13A2 Mutations
Clinical Spectrum of Kufor-Rakeb Syndrome in the Chilean Kindred with ATP13A2 Mutations
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DOI：
10.1002/mds.22996
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发表时间：
2010-09-15
影响因子：
8.6
通讯作者：
Ramirez, Alfredo
中科院分区：
文献类型：
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作者：
Behrens, Maria I.;Brueggemann, Norbert;Ramirez, Alfredo
我们报告了库福-拉克布综合征(KRS)的原始智利家庭的临床特征，导致在PARK9基因座发现ATP13A2基因。KRS是一种少见的少年性常染色体隐性遗传病，其特征是进行性帕金森氏症、锥体体征和认知能力下降，此外还有垂直凝视麻痹和面-咽-指最小肌阵挛。在10年期间进行神经学和神经心理学检查、录像、神经成像和测量ATP13A2启动子区域的DNA甲基化。父母无血缘关系的17个孩子中，最小的5个携带复合杂合子ATP13A2突变，发育正常，直到10-12岁，这时学校表现恶化，出现迟钝、僵硬和频繁摔倒。检查发现运动迟缓，轻微的姿势/动作震颤，齿轮僵硬，痉挛，向上凝视麻痹，平稳追赶并伴有跳动，以及痴呆。其他体征包括面部-穹隆-手指微小阵挛、姿势反射消失、视觉/听觉幻觉和失眠。在这个家庭中，左旋多巴的反应不能完全判断。T2*磁共振成像序列显示双侧尾状核(头部和体部)和豆状核明显弥漫性低信号。疾病进展缓慢，包括癫痫、恶病质和构音障碍。4名受影响成员在28.5+/-5.5(平均+/-SD)年后死亡。两个杂合子携带者，母亲和最大的兄弟姐妹，表现出干性口周肌肉收缩和手部运动笨拙。ATP13A2启动子区DNA甲基化与疾病进展无明显相关性。明显的尾状核和豆状核T2*-低信号提示KRS可能属于与脑铁蓄积相关的神经退行性疾病家族。(C)2010年流动无序社会
We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages similar to 10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 +/- 5.5 (mean +/- SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation. (C) 2010 Movement Disorder Society