Penkl Anja, Reunert Janine, Debus Otfried M, Homann Anna, Och Ulrike, Rust Stephan, Marquardt Thorsten
Department of Pediatrics, University Hospital of Münster, Münster, Germany.
Department of Pediatrics, Clemenshospital Münster, Münster, Germany.
Am J Med Genet A. 2022 Mar;188(3):941-947. doi: 10.1002/ajmg.a.62581. Epub 2021 Dec 7.
SCN2A (sodium channel 2A) encodes the Nav1.2 channel protein in excitatory neurons in the brain. Nav1.2 is a critical voltage-gated sodium channel of the central nervous system. Mutations in SCN2A are responsible for a broad phenotypic spectrum ranging from autism and developmental delay to severe encephalopathy with neonatal or early infantile onset. SCN2A can be spliced into two different isoforms, a neonatal (6N) and an adult (6A) form. After birth, there is an equal or higher amount of the 6N isoform, protecting the brain from the increased neuronal excitability of the infantile brain. During postnatal development, 6N is gradually replaced by 6A. In an infant carrying the novel SCN2A mutation c.643G > A (p.Ala215Thr) only in the neonatal transcript, seizures started immediately after birth. The clinical presentation evolved from a burst-suppression pattern with 30-50 tonic seizures per day to hypsarrhythmia. The first exome analysis, focusing only on common transcripts, missed the diagnosis and delayed early therapy. A reevaluation including all transcripts revealed the SCN2A variant.
SCN2A（钠通道2A）在大脑兴奋性神经元中编码Nav1.2通道蛋白。Nav1.2是中枢神经系统中一种关键的电压门控钠通道。SCN2A突变可导致广泛的表型谱，从自闭症和发育迟缓到新生儿期或婴儿早期发病的严重脑病。SCN2A可剪接成两种不同的异构体，即新生儿型（6N）和成人型（6A）。出生后，6N异构体的含量相等或更高，可保护大脑免受婴儿期大脑神经元兴奋性增加的影响。在出生后的发育过程中，6N逐渐被6A取代。在一名仅在新生儿转录本中携带新型SCN2A突变c.643G＞A（p.Ala215Thr）的婴儿中，出生后立即开始出现癫痫发作。临床表现从每天30 - 50次强直发作的爆发抑制模式演变为高峰节律紊乱。首次外显子组分析仅关注常见转录本，漏诊并延误了早期治疗。包括所有转录本的重新评估揭示了SCN2A变异。
