Boeri Silvia, Piai Maria, Russo Silvia, Alari Valentina, Cogliati Francesca, Simonetta Davide, Benke Timothy A, Nobili Lino, Prato Giulia
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
Unit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Epicare Network for Rare Disease, Genoa, Italy.
Orphanet J Rare Dis. 2025 Sep 2;20(1):473. doi: 10.1186/s13023-025-03935-6.
Rett Syndrome (RTT) is a rare, and severe neurodevelopmental disorder that primarily affects females and is primarily (> 96%) due to pathogenic loss-of-function genetic variants of methyl-CpG-binding protein 2 (MECP2). Despite the rarity of the syndrome, sporadic twin cases have been reported. The descriptions have often focused on the phenotype, emphasizing differences or similarities. We report the case of monozygotic (MZ) twins with RTT carrying the same MECP2 mutation and perform a systematic review of the cases of MZ twins.
We searched PubMed and Embase for articles reporting MZ twins with RTT who met Neul criteria and carried mutations in the MECP2 gene. We focused on phenotypic discordance and X chromosome inactivation (XCI).
Our search yielded 115 results, 18 of which were included in our systematic review. We identified 17 pairs of twins, with 11 showing a discordant phenotype. Data on XCI were reported for only six pairs. We describe MZ twins with typical RTT syndrome who shared the same p.Thr158Met pathogenic variant on the MECP2 gene but exhibited different severity of clinical phenotype, especially regarding epilepsy. The XCI pattern and expression of the wild-type allele in blood were similar in both twins, suggesting that XCI differences assessed in blood may not account for the phenotypic variability. Mononucleate cells were isolated from both twins to generate induced pluripotent stem cells (iPSCs). The patient with more mutated clones presented a more severe phenotype.
Cases of MZ twins with RTT are few, and the phenotypic difference described in our case and presented in the literature does not seem to be explained by different XCI patterns. Therefore, more detailed genetic investigations are necessary.
雷特综合征（RTT）是一种罕见且严重的神经发育障碍，主要影响女性，主要（>96%）由甲基CpG结合蛋白2（MECP2）的致病性功能丧失基因变异引起。尽管该综合征罕见，但已有散发性双胞胎病例的报道。这些描述通常集中在表型上，强调差异或相似之处。我们报告了一对患有RTT的同卵双胞胎（MZ）病例，他们携带相同的MECP2突变，并对MZ双胞胎病例进行了系统综述。
我们在PubMed和Embase上搜索报告符合Neul标准且携带MECP2基因突变的RTT MZ双胞胎的文章。我们重点关注表型不一致和X染色体失活（XCI）。
我们的搜索产生了115条结果，其中18条纳入了我们的系统综述。我们确定了17对双胞胎，其中11对表现出不一致的表型。仅报告了6对双胞胎的XCI数据。我们描述了一对患有典型RTT综合征的MZ双胞胎，他们在MECP2基因上共享相同的p.Thr158Met致病性变异，但表现出不同严重程度的临床表型，尤其是在癫痫方面。双胞胎血液中野生型等位基因的XCI模式和表达相似，这表明血液中评估的XCI差异可能无法解释表型变异性。从双胞胎中分离出单核细胞以生成诱导多能干细胞（iPSC）。具有更多突变克隆的患者表现出更严重的表型。
RTT的MZ双胞胎病例很少，我们病例中描述的以及文献中呈现的表型差异似乎无法用不同的XCI模式来解释。因此，需要更详细的基因研究。
