Whispering dysphonia in an Australian family (DYT4): A clinical and genetic reappraisal
Whispering dysphonia in an Australian family (DYT4): A clinical and genetic reappraisal
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DOI：
10.1002/mds.23866
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发表时间：
2011-11-01
影响因子：
8.6
通讯作者：
Klein, Christine
中科院分区：
文献类型：
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作者：
Wilcox, Robert A.;Winkler, Susen;Klein, Christine
这个代号DYT4被分配给了一个患有耳语性发音障碍的澳大利亚家庭。在这个家族中，肌张力障碍的已知病因的作用尚未得到全面的调查，也没有与两个兄弟姐妹的威尔逊氏病（WND）的可能关系。对18名家庭成员进行了神经学检查，并获得了DNA样本。用微卫星标记对DYT1、DYT6、DYT7、DYT11、DYT13、DYT15和ATP7B进行连锁分析，并对THAP1 （DYT6）、PRKRA （DYT16）和ATP7B （WND）基因进行测序。对家庭的重新评估确定了9名在世的受影响家庭成员，其中6人是新受影响的家庭成员。表型表达是可变的，范围从孤立的痉挛性发声障碍（通常伴有轻度颅颈肌张力障碍）到严重的全身性肌张力障碍。两个新描述的特征包括一个突出的舌张力障碍和一个独特的嗜好马步态。遗传分析排除了所有检测的基因座。ATP7B区域的单倍型分析结果显示，在2例死亡WND患者的8个被调查的兄弟姐妹中，这两个亲本等位基因有三种不同的组合，表明第四种组合（两个突变等位基因）仅发生在死亡的WND患者中。在这两个等位基因上，我们发现了一个错义（c.2297C>G; p.T766R）和一个剪接位点突变（IVS5+1G>T）。在3名感染和4名未感染的家庭成员中检测到c.2297C>G突变，而在1名感染和未感染的家庭成员中检测到IVS5+1G>T突变。5例DYT4患者没有携带任何突变。DYT4是一种家族性肌张力障碍，与已知的肌张力障碍基因和位点无关。ATP7B突变不与肌张力障碍表型分离，表明该家族存在两种独立的遗传性疾病。(c) 2011年运动障碍协会
The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique hobby horse gait. Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family. (c) 2011 Movement Disorder Society