Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome.
Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome.
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DOI：
10.1136/jmedgenet-2013-102113
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发表时间：
2014-03
影响因子：
4
通讯作者：
Olsen ML
中科院分区：
文献类型：
--
作者：
Cuddapah VA;Pillai RB;Shekar KV;Lane JB;Motil KJ;Skinner SA;Tarquinio DC;Glaze DG;McGwin G;Kaufmann WE;Percy AK;Neul JL;Olsen ML
雷特综合症 (RTT) 是一种主要影响女孩的神经发育障碍，其特征是在 6-18 个月大之前发育明显正常，此时运动和沟通能力会退化。超过 95% 的 RTT 患者的甲基 CpG 结合蛋白 2 (MECP2) 存在突变，该蛋白产物可调节基因转录。令人惊讶的是，尽管这种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差异很大。为了探索这种表型变异的根源，我们提出特定的 MECP2 突变会导致不同程度的疾病严重程度。我们使用由 1052 名参与者组成的数据库评估了超过 4940 次独特就诊，这是迄今为止研究的最大的典型和非典型 RTT 患者队列，我们研究了 MECP2 突变状态与生长、运动协调、沟通能力、呼吸功能、自主神经症状、脊柱侧凸和癫痫发作测量之间的关系。与之前的研究基本一致，我们发现特定突变，例如 p.Arg133Cys、p.Arg294X、p.Arg306Cys、3' 截断和其他点突变，在典型和非典型 RTT 中相对不太严重。相比之下，p.Arg106Trp、p.Arg168X、p.Arg255X、p.Arg270X、剪接位点、大缺失、插入和缺失明显更严重。我们还证明，对于大多数突变类型，临床严重程度随着年龄的增长而增加。此外，在 RTT 的临床特征中，行走、手部使用和刻板印象发病年龄与总体疾病严重程度密切相关。因此，我们已经证实 MECP2 突变类型是疾病严重程度的有力预测因子。然而，无论最初的严重程度如何，随着年龄的增长，临床严重程度都会逐渐恶化。这些发现将使临床医生和家庭能够更好地预测和准备满足 RTT 患者的需求。
Rett Syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterized by a period of apparently normal development until 6–18 months of age, when motor and communication abilities regress. More than 95% of people 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 measures of growth, motor coordination, communicative abilities, respiratory function, autonomic symptoms, scoliosis, and seizures 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, Large 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. Thus, we have confirmed that MECP2 mutation type is a strong predictor of disease severity. However, clinical severity continues to become progressively worse with advancing age regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.
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