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Abstract：
Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.
摘要：
发育性和癫痫性脑病35（DEE35）是由ITPA中的双等位基因变异引起的严重神经系统疾病，编码三磷酸肌苷焦磷酸酶，嘌呤代谢中的一种重要酶。我们描述了DEE35的基因型和表型谱，分析了不良临床结局的可能预测因素。我们调查了28名新患者的队列，并回顾了以前描述的病例，提供40个科目的全面表征。进行外显子组测序以鉴定潜在的ITPA致病变体。系统分析脑MRI（磁共振成像）扫描以描绘神经放射学谱。根据Kaplan-Meier方法和对数秩检验的生存曲线用于研究不同亚组患者的预后预测因子。我们确定了18种不同的ITPA致病变异，包括14种新颖的变体，和两个删除。所有受试者都表现出严重的发育迟缓，小头畸形,和难治性癫痫，然后是神经发育退化。脑部MRI翻修显示髓鞘形成延迟和早期髓鞘结构扩散受限的复发模式。先天性小头畸形和心脏受累是具有统计学意义的不良结局的新型临床预测因子。我们改进了分子，临床,和ITPase缺乏症的神经放射学特征，并确定了可能对诊断有潜在重要影响的新临床预测因子，咨询,以及对受影响个人的后续行动。
