Department of Neurology, Washington University in St. Louis, St. Louis, Missouri.
Anna Meyer Children's Hospital, University of Florence, Firenze, Italy.
Am J Med Genet A. 2018 Aug;176(8):1748-1752. doi: 10.1002/ajmg.a.38840. Epub 2018 Jul 28.
Derangements in voltage-gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage-gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile-onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv-specific Pro-Val-Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.
电压门控钾通道功能障碍可导致多种阵发性神经紊乱。编码电压门控钾通道 Kv1.1 的 KCNA1 基因突变可导致发作性共济失调 1 型（EA1）。EA1 患者癫痫发病率增加，但尚未在癫痫性脑病中描述 KCNA1 变异。本研究描述了 4 名具有婴儿期起病的癫痫和认知障碍的患者，他们携带位于 Kv 特异性 Pro-Val-Pro（PVP）基序内的新生 KCNA1 变异，该基序对于通道门控至关重要。前两名患者分别具有 KCNA1 变异（p.Pro405Ser）和（p.Pro405Leu），一对同卵双胞胎具有影响附近残基（p.Pro403Ser）的变异。值得注意的是，先前已经证明 KCNA2 的 PVP 基序中的重复新生变异会破坏通道功能，并导致早发性癫痫性脑病。重要的是，该报告扩展了与 KCNA1 变异相关的表型范围，当涉及 PVP 基序时，还包括癫痫性脑病。
