Elsevier

Brain and Development

Volume 43, Issue 8, September 2021, Pages 851-856
Brain and Development

Original article
Effective treatments for FGF12-related early-onset epileptic encephalopathies patients

https://doi.org/10.1016/j.braindev.2021.04.010Get rights and content

Abstract

Background

FGF12 (FHF1) gene encodes voltage-gated sodium channel (Nav)-binding protein fibroblast growth factor homologous factor 1, which could cause seizures by regulating voltage dependence of Nav fast inactivation and neuron excitability. The most common pathogenic variant FGF12 c.341G > A related early-onset epileptic encephalopathies (EOEE) was characterized by intractable seizures and developmental disabilities.

Results

Using whole exome sequencing, a de novo hotspot variant c.341G > A (NM_021032.4) of FGF12 was identified in three unrelated EOEE probands. All probands were seizure free after a combination treatment of valproic acid (VPA) and topiramate (TPM). The motor and cognitive skills in two probands were improved due to the early and effective treatment. In order to compare the effectiveness of different treatment strategies for the disease, a review of treatments for FGF12-related epilepsy was made.

Conclusion

We reported three FGF12 c.341G > A related EOEE patients responded well to a combination antiepileptic therapy of VPA and TPM. The current study is the first to describe the combination therapy of VPA and TPM in FGF12 c.341G > A related EOEE patients. This study may contribute to future medication consultation for intractable epilepsy with FGF12 hotspot variants.

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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