Key clinical features to identify girls with CDKL5 mutations
Key clinical features to identify girls with CDKL5 mutations
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DOI：
10.1093/brain/awn197
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发表时间：
2008-10-01
期刊：
影响因子：
14.5
通讯作者：
Bienvenu, Thierry
中科院分区：
文献类型：
--
作者：
Bahi-Buisson, Nadia;Nectoux, Juliette;Bienvenu, Thierry
人类X-连锁细胞周期蛋白依赖性激酶样蛋白5(CDKL5)基因的突变已被证明会导致婴儿痉挛和Rett综合征(RTT)样表型。到目前为止，报告的不到25种不同的突变。到目前为止，关于CDKL5相关性脑病的关键临床诊断标准和自然病史的数据仍然很少。我们用变性高效液相色谱和直接测序的方法对183例早期癫痫发作的女性脑病患者进行了CDKL5全编码区的突变筛查，在20名无关女孩中发现了18种不同的突变，其中包括7种新的突变。在8名具有RTT样特征的脑病患者、5名婴儿痉挛患者和7名脑病合并难治性癫痫的患者中发现了这些突变。发作间期脑电正常和严重低眼压的早期癫痫是识别可能存在CDKL5突变的患者的关键临床特征。我们的研究还表明，这些患者明显表现出一些RTT特征，如头部生长减速、刻板印象和手部失用，这些RTT特征在老年和非卧床患者中变得更加明显。然而，一些RTT征象明显缺乏，如所谓的RTT病程(几乎正常发展，随后在儿童早期丧失获得性精细手指技能和特征性的密集眼球交流的退化期)和RTT脑电的特征演变。有趣的是，除了CDKL5基因突变导致的总体典型症状(发病年龄和疾病演变)外，还观察到了与CDKL5相关的非典型形式的疾病。我们的数据表明，表型异质性与突变的性质或位置或X染色体失活的模式无关，但最可能与CDKL5突变的功能转录和/或翻译后果有关。综上所述，我们的报告表明，CDKL5突变的寻找适用于早发的严重顽固性癫痫障碍或伴有严重低眼压的婴儿痉挛的女孩，以及具有RTT样表型和早发性癫痫发作的女孩，尽管在我们的队列中，CDKL5突变约占受这些疾病影响的女孩的10%。
Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome (RTT)-like phenotype. To date, less than 25 different mutations have been reported. So far, there are still little data on the key clinical diagnosis criteria and on the natural history of CDKL5-associated encephalopathy. We screened the entire coding region of CDKL5 for mutations in 183 females with encephalopathy with early seizures by denaturing high liquid performance chromatography and direct sequencing, and we identified in 20 unrelated girls, 18 different mutations including 7 novel mutations. These mutations were identified in eight patients with encephalopathy with RTT-like features, five with infantile spasms and seven with encephalopathy with refractory epilepsy. Early epilepsy with normal interictal EEG and severe hypotonia are the key clinical features in identifying patients likely to have CDKL5 mutations. Our study also indicates that these patients clearly exhibit some RTT features such as deceleration of head growth, stereotypies and hand apraxia and that these RTT features become more evident in older and ambulatory patients. However, some RTT signs are clearly absent such as the so called RTT disease profile (period of nearly normal development followed by regression with loss of acquired fine finger skill in early childhood and characteristic intensive eye communication) and the characteristic evolution of the RTT electroencephalogram. Interestingly, in addition to the overall stereotypical symptomatology (age of onset and evolution of the disease) resulting from CDKL5 mutations, atypical forms of CDKL5-related conditions have also been observed. Our data suggest that phenotypic heterogeneity does not correlate with the nature or the position of the mutations or with the pattern of X-chromosome inactivation, but most probably with the functional transcriptional and/or translational consequences of CDKL5 mutations. In conclusion, our report show that search for mutations in CDKL5 is indicated in girls with early onset of a severe intractable seizure disorder or infantile spasms with severe hypotonia, and in girls with RTT-like phenotype and early onset seizures, though, in our cohort, mutations in CDKL5 account for about 10% of the girls affected by these disorders.