Original articleEffective treatments for FGF12-related early-onset epileptic encephalopathies patients
Introduction
FGF12 (FHF1) gene encodes voltage-gated sodium channel (Nav)-binding protein fibroblast growth factor homologous factor 1 and played a role in early-onset epileptic encephalopathies (EOEE). FGF12 variants acted as a gain-of-function manner in EOEE pathogenesis by elevating voltage dependence of Nav fast inactivation and increasing neuron excitability [1]. There were only 3 variants reported causing FGF12-related epilepsy since 2016 [1], [2], [3]. The most common pathogenic variant FGF12 c.341G > A (NM_021032.4) related EOEE was characterized by intractable seizures and severe brain dysfunctions [1], [3], [4], [5], [6], [7], [8].
Most FGF12-related epilepsy patients failed to response to anti-epileptic treatments which could lead to neurological impairments, developmental dysfunction and even brain atrophy. As a consequence, patients usually have poor life quality and bad prognosis [1]. Although traditional anti-epileptic drug (AED) phenytoin (PHT) and phenobarbital (PB) have been proved effective in some cases, they exerts multiple side effects on patients [9]. In our study, we applied a combination treatment of topiramate (TPM) and valproic acid (VPA) for FGF12 c.341G > A related EOEE patients with improved clinical outcomes.
Section snippets
Case study
A de novo heterozygous missense hotspot variant c.341G > A was identified in FGF12 gene in all three unrelated probands using whole exome sequencing (WES) and validated by Sanger sequencing (Fig. 1a-c). The patients were diagnosed according to the International League Against Epilepsy diagnostic criteria [10]. The clinical features were presented as following. All parents of participants signed informed consent forms, and the study was approved by the ethics committee of the Maternal and Child
Treatments on FGF12-related epilepsy
In our study, the seizures of all three patients were controlled in a month after the adoption of a combination of anti-epileptic drugs (VPA: 30 mg/kg/d; TPM: 10 mg/kg/d). At the time when seizures were relieved, the patients 1 and 3 began to develop intellectual and motor abilities. The patient 3 showed better cognitive and motor ability improvements than patient 1 for the earlier application of the drugs. In patient 2, although the seizures were free after the combination use of VPA and TPM,
Discussion
The pathogenic variant FGF12 c.341G > A is the first and the most common pathogenic variant reported in FGF12-related EOEE[1]. The variant functioned as a gain-of-function variant and could elevate neuronal excitability by altering sodium channel fast inactivation. FGF12 c.341G > A-related EOEE patients manifested with severe clinical features including early-onset intractable seizures, developmental delay, intellectual disabilities, cerebellar atrophy etc[7].
The treatment of FGF12-related
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81801136), Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1010, 2019SK1012, 2019SK1014), the National Key R&D Program of China (No. 2019YFC1005100), the China Postdoctoral Science Foundation (2019 M662804) and the Natural Science Foundation of Hunan Province (2020JJ4854) and the Changsha Municipal Natural Science Foundation (kq2007048).
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