Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Med Genet. 2014 Mar;51(3):152-8. doi: 10.1136/jmedgenet-2013-102113. Epub 2014 Jan 7.
Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity.
Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time.
In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p.Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p.Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity.
We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.
雷特综合征（RTT）是一种主要影响女孩的神经发育障碍，其特征是在 6-18 个月大时出现运动和沟通能力倒退之前，有一段看似正常的发育时期。超过 95%的 RTT 患者存在甲基化-CpG 结合蛋白 2（MECP2）突变，其蛋白产物调节基因转录。令人惊讶的是，尽管该疾病是由单个基因突变引起的，但受影响个体的疾病严重程度可能存在很大差异。为了探究这种表型变异性的来源，我们提出特定的 MECP2 突变会导致不同程度的疾病严重程度。
利用一个包含 1052 名参与者的数据库，该数据库评估了超过 4940 个独特的就诊记录，这是迄今为止对典型和非典型 RTT 患者进行的最大规模的队列研究，我们研究了 MECP2 突变状态与随时间推移的各种表型测量之间的关系。
与之前的研究大体一致，我们发现某些突变，如 p.Arg133Cys、p.Arg294X、p.Arg306Cys、3°截断和其他点突变，在典型和非典型 RTT 中相对较轻。相比之下，p.Arg106Trp、p.Arg168X、p.Arg255X、p.Arg270X、剪接位点、缺失、插入和缺失则严重得多。我们还表明，对于大多数突变类型，临床严重程度随年龄增长而增加。此外，在 RTT 的临床特征中，步态、手的使用和刻板行为的发病年龄与整体疾病严重程度密切相关。
我们已经证实，MECP2 突变类型是疾病严重程度的有力预测指标。这些数据还表明，无论初始严重程度如何，临床严重程度仍在持续恶化。这些发现将使临床医生和家庭能够更好地预测和准备 RTT 患者的需求。
