Abstract：
BACKGROUND: Research has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring.
METHODS: The clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature.
RESULTS: The infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient\'s seizures decreased remarkably after administering ketogenic diet (KD).
CONCLUSIONS: CHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.
METHODS: The clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature.
RESULTS: The infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient\'s seizures decreased remarkably after administering ketogenic diet (KD).
CONCLUSIONS: CHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.
摘要：
背景：研究表明ATN1基因与核受体信号有关。它在进化上保守的富含组氨酸的基序中的突变可能导致CHEDDA，先天性肌张力减退的简称，癫痫,发育迟缓和数字异常，最近发现的一种神经发育综合征，可能演变成发育性和癫痫性脑病（DEE）。到目前为止,报告的病例不到20例，其临床特点和治疗方法值得深入探讨。
方法：分析1例CHEDDA和进一步DEE患儿的临床特征和遗传资料，携带通过三重全外显子组测序鉴定的从头ATN1变体。在文献中回顾了患有这种神经发育综合征和癫痫发作的患者。
结果：在ATN1中具有从头错义突变的婴儿（c.3155A>C;p.His1052Pro）几乎具有CHEDDA的所有特征，并表现为耐药性癫痫性痉挛，与先前报道的具有相同基因变体的病例不同，该基因变体表现出更温和的癫痫发作易于控制。我们进一步回顾了文献中的11例CHEDDA癫痫发作患者，并比较了CHEDDA患者中大脑结构异常与难治性癫痫发生率之间的相关性。幸运的是,给予生酮饮食（KD）后，该患者的癫痫发作显着减少。
结论：CHEDDA患者具有显著的表型差异，尤其是在癫痫的严重程度和耐药性方面，即使它们携带相同的突变热点。对于ATN1相关的难治性癫痫，应建议使用生酮饮食和其他治疗方法，例如托吡酯，因为它们对阳离子-氯化物协同转运蛋白表达和细胞超极化的调节。
方法：分析1例CHEDDA和进一步DEE患儿的临床特征和遗传资料，携带通过三重全外显子组测序鉴定的从头ATN1变体。在文献中回顾了患有这种神经发育综合征和癫痫发作的患者。
结果：在ATN1中具有从头错义突变的婴儿（c.3155A>C;p.His1052Pro）几乎具有CHEDDA的所有特征，并表现为耐药性癫痫性痉挛，与先前报道的具有相同基因变体的病例不同，该基因变体表现出更温和的癫痫发作易于控制。我们进一步回顾了文献中的11例CHEDDA癫痫发作患者，并比较了CHEDDA患者中大脑结构异常与难治性癫痫发生率之间的相关性。幸运的是,给予生酮饮食（KD）后，该患者的癫痫发作显着减少。
结论：CHEDDA患者具有显著的表型差异，尤其是在癫痫的严重程度和耐药性方面，即使它们携带相同的突变热点。对于ATN1相关的难治性癫痫，应建议使用生酮饮食和其他治疗方法，例如托吡酯，因为它们对阳离子-氯化物协同转运蛋白表达和细胞超极化的调节。
