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<p>KCNT1 gene variant-associated epilepsy is a rare genetic disorder with a wide clinical spectrum, ranging from mild symptoms to severe, early onset epileptic encephalopathies. It is commonly characterized by focal seizures, drug resistance, and neurodevelopmental impairments. This review summarizes recent advances in understanding the disorder’s molecular mechanisms, clinical features, experimental models, and emerging therapeutic approaches. KCNT1 mutations disrupt potassium channel function, altering neuronal excitability and impairing network stability. Experimental models—including mice, Drosophila, and patient-derived cells—have provided critical insights into disease mechanisms and potential interventions. In particular, KCNT1 knock-in mouse and cellular models have clarified how specific variants drive disease progression and therapeutic response. Promising strategies under investigation include gene therapy, small-molecule modulators, and ketogenic dietary (KD) interventions, all aimed at restoring neuronal balance. These developments highlight the central role of potassium channel dysfunction in the pathophysiology of KCNT1-related epilepsy. Nevertheless, current models do not fully recapitulate the human condition, underscoring the need for continued research. This review aims to support ongoing efforts to refine precision therapies and improve outcomes for patients affected by this complex disorder.</p>

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KCNT1 gene variant-associated epilepsy: genetic insights, functional mechanisms, and emerging therapies

  • 期刊论文

  • 发表日期：

    2025年6月21日

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  • Ya-ze Duan,
  • Tong-tong Yao,
  • Yi-Ting Shao,
  • Li-ming Liu,
  • Hui Zhou,
  • Yong Cheng

摘要

KCNT1 gene variant-associated epilepsy is a rare genetic disorder with a wide clinical spectrum, ranging from mild symptoms to severe, early onset epileptic encephalopathies. It is commonly characterized by focal seizures, drug resistance, and neurodevelopmental impairments. This review summarizes recent advances in understanding the disorder’s molecular mechanisms, clinical features, experimental models, and emerging therapeutic approaches. KCNT1 mutations disrupt potassium channel function, altering neuronal excitability and impairing network stability. Experimental models—including mice, Drosophila, and patient-derived cells—have provided critical insights into disease mechanisms and potential interventions. In particular, KCNT1 knock-in mouse and cellular models have clarified how specific variants drive disease progression and therapeutic response. Promising strategies under investigation include gene therapy, small-molecule modulators, and ketogenic dietary (KD) interventions, all aimed at restoring neuronal balance. These developments highlight the central role of potassium channel dysfunction in the pathophysiology of KCNT1-related epilepsy. Nevertheless, current models do not fully recapitulate the human condition, underscoring the need for continued research. This review aims to support ongoing efforts to refine precision therapies and improve outcomes for patients affected by this complex disorder.