Department of Cell Biology, and Genetics, Institute of Molecular Medicine, and Oncology, Chongqing Medical University, Chongqing 400016, China.
Int J Mol Sci. 2024 Oct 12;25(20):10983. doi: 10.3390/ijms252010983.
Deleterious variations in are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as encephalopathy (-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. A girl was first diagnosed with unexplained disorders of movement and cognition, which later developed into -E with unexpected leukoaraiosis and late onset of seizures. Genetic screening and molecular tests alongside neurological examinations were employed to investigate the genetic etiology and establish the diagnosis. A heterozygous mutation of c.37+2dupT at the splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) did not result in any truncated proteins but immediately triggered mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of . The patient showed atypical phenotypes characterized by hypomyelinating leukodystrophy, and late onset of epileptic seizures, which had never previously been delineated in -E. These findings strongly indicated that the haploinsufficiency of could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies.
在 中发生的有害变异导致了早发性婴儿癫痫性脑病 4 型（EIEE4，OMIM #612164），因为它在中枢神经系统中的功能障碍。与 STXBP1 异常相关的神经发育迟缓的临床谱被统称为 脑病（-E），其显著特征是早期发作无结构脑异常的癫痫发作。一名女孩最初被诊断为运动和认知障碍，但后来发展为-E，并伴有意外的脑白质疏松和癫痫发作迟发。遗传筛查和分子测试以及神经学检查用于研究遗传病因并建立诊断。在受影响的女孩中发现了一个杂合突变 c.37+2dupT 位于 剪接位点，这是致病原因。该新生突变（DNM）不会导致任何截短蛋白，但会立即通过无义介导的 mRNA 降解（NMD）触发 mRNA 降解，从而导致 的杂合性不足。该患者表现出非典型表型，特征为脱髓鞘性白质营养不良和癫痫发作迟发，这在-E 中以前从未描述过。这些发现强烈表明，由于脑病亚组中的遗传异质性， 的杂合性不足也可能表现出不同的临床表型。
