<i>FGF12</i>p.Gly112Ser variant as a cause of phenytoin/phenobarbital responsive epilepsy

Paprocka, Justyna; Jezela‐Stanek, Aleksandra; Koppolu, Agnieszka; Rydzanicz, Małgorzata; Kosińska, Joanna; Stawiński, Piotr; Płoski, Rafał

doi:10.1111/cge.13592

Cited by 7 publications

(11 citation statements)

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“…In both groups, seizures are often drug‐resistant. In some patients, a good response to phenytoin was observed 1,2,4,6,7 . In the present patients, phenytoin was not tried.…”

Section: Discussionmentioning

confidence: 60%

“…In both groups, cerebral MRI scans show mostly normal results or mild nonspecific findings. All but one patient were reported to have variable neurodevelopmental delay 1–7 . Individuals with later seizure onset, either with a duplication or a mutation, show a clear developmental stagnation/regression after seizure onset.…”

Section: Discussionmentioning

confidence: 99%

“…Nineteen intragenic mutations in FGF12 have been reported, including recurrent mutations p.Arg52His and p.Arg114His 1–6 . Only one patient with a small chromosomal duplication involving FGF12 has been reported, who showed similarities with the phenotype in patients with an intragenic mutation, including drug‐resistant epilepsy, severe DD/ID, cerebellar ataxia, and feeding difficulties 7,8 .…”

Section: Introductionmentioning

confidence: 99%

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Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

et al. 2020

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Intragenic mutations in FGF12 are associated with intractable seizures, developmental regression, intellectual disability, ataxia, hypotonia, and feeding difficulties.FGF12 duplications are rarely reported, but it was suggested that those might have a similar gain-of-function effect and lead to a more or less comparable phenotype.A favorable response to the sodium blocker phenytoin was reported in several cases, both in patients with an intragenic mutation and in patients with a duplication of FGF12. We report three individuals from two families with FGF12 duplications. The duplications are flanked and probably mediated by two long interspersed nuclear elements (LINEs). The duplication cases show phenotypic overlap with the cases with intragenic mutations. Though the onset of epilepsy might be later, after the onset of seizures both groups show developmental stagnation and regression in several cases. This illustrates and further confirms that chromosomal FGF12 duplications and intragenic gain-of-function mutations yield overlapping phenotypes. K E Y W O R D S developmental regression, epilepsy, FGF12, intellectual disability, LINE, microduplication 3q28q29 302 | WILLEMSEN Et aL.

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“…In both groups, seizures are often drug‐resistant. In some patients, a good response to phenytoin was observed 1,2,4,6,7 . In the present patients, phenytoin was not tried.…”

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

et al. 2020

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“…We collected the electro-clinical data of 12 previously published patients (#A-K and #Q) [8][9][10][11][12][13][14] and 5 unpublished patients (#L-P). For all patients, both published and unpublished, more information has been collected directly contacting their referring physicians except for patients #C-E and #Q for whom only data coming from publications were available [11,14]. Median age at study was 8,7 ± 8,59 years (range 1 month -33 years); seven patients were female (41%).…”

Section: Resultsmentioning

confidence: 99%

“…Patients #A-K and #Q have been previously reported [8][9][10][11][12][13][14]. Epileptic seizures were classified according to the current International League Against Epilepsy (ILAE) Classification [15,16].…”

Section: Introductionmentioning

confidence: 99%

Defining the phenotype of FHF1 developmental and epileptic encephalopathy

et al. 2020

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Objective: Fibroblast-growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 gene encodes a cytosolic protein that interacts with neuronal sodium channel. Aim of this study is to report the largest series of patients with pathogenic FHF1 genetic variants in order to define electro-clinical phenotype, genotype-phenotype correlation, and information about management and prognosis. Methods: Through an international collaboration, we retrospectively collected detailed clinical, genetic, neurophysiologic and neuroimaging data of 17 patients with FHF1-related epilepsy. Results: Fourteen patients carried heterozygous missense variant c.341G>A (p.Arg114His) in FHF1 gene, two patients heterozygous missense variant c.334G>A (p.Gly112Ser) and one patient carried a chromosomal microduplication involving FHF1 gene. The majority of variants were de novo, although in 29% of cases somatic or germline parent mosaicism occurred. Patients with c.341G>A variant presented with a phenotype consisting of early onset DEE. Drug resistant epilepsy, intellectual disability, psychiatric features and status epilepticus were also common features. Tonic seizures were the most frequent seizure type. Patients who carried c.334G>A variant and FHF1 gene duplication showed a delayed epilepsy onset compared with patients carring the hotspot variant (c.341G>A). Brain MRI was normal at onset while a mild cerebral and/or cerebellar atrophy appeared during follow-up in 8 out of 17 patients (47%). Conclusion: FHF1-related DEE is characterized by an almost homogeneous clinical phenotype characterized by early-onset and drug-resistant epilepsy, intellectual disability, and psychiatric features in patients with c.334G>A variant. Few cases with a milder phenotype can occur, although a genotype-phenotype correlation had been identified. Because of the possibility of germline or somatic mosaicism, it is appropriate to offer prenatal diagnosis to couples with a child with FHF1related DEE. Recently, de novo mutations in fibroblast-growth-factor homologous factor 1 (FHF1) gene, encoding a voltage-gate sodium channel subunit (Nav1.6) binding protein, have been reported in patients with severe epilepsies [8-14], although a definite clinical phenotype has not clearly emerged. FHF1 gene is located on the long arm of chromosome 3 (3q28-q29) and c.334G>A (p.Gly112Ser) FHF1 missense variant has been demonstrated to lead to a gain-of-function of voltage-gate sodium channel (Nav1.6), predicting an increasing of neuronal excitability [12]. Aim of this study is to report the largest series of patients with pathogenic FHF1 mutations in order to delineate the electro-clinical features of FHF1-related DEE, identify genotype-phenotype correlation, improve management and define prognosis. Methods This is an international retrospective multicenter study. We collected 17 patients with FHF1-related epilepsy, followed-up in 14 epilepsy centers across the world (

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Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Fry

Marra

Derrick

et al. 2021

The American Journal of Human Genetics

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Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na v ) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi-and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na v 1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na v channel function.Voltage-activated sodium channels (Na v ) play an essential role in the generation and spread of action potentials in excitable tissues. 1,2 Variants in Na v channels and their regulatory partners are a major cause of infantile-onset developmental and epileptic encephalopathies (DEEs). 3,4 DEEs are typically associated with developmental delay or regression, treatment-resistant seizures, and electroencephalographic abnormalities. 5,6 The developmental consequences of DEEs are due to frequent epileptiform activity in combination with the direct effects of the genetic variant. 7,8 Fibroblast growth factor homologous factors (FHFs) are intracellular proteins that bind to the C-terminal domain of Na v channels to modulate their function and location. [9][10][11][12] FHFs were initially identified due to their homology with fibroblast growth factors (FGFs). 13 However, FHFs are not secreted by cells and have only limited ability to activate FGF receptors. 9,14,15 There are four FHF genes in mammals (often referred to by their FGF names): FHF1 (FGF12 [MIM: 601513]), FHF2 (FGF13 [MIM: 300070]), FHF3 (FGF11 [MIM: 601514]), and FHF4 (FGF14 [MIM: 601515]). 9 The FHF genes have multiple transcription initiation sites. The alternative first exons produces multiple isoforms with variable N-terminal domains. 16 The isoforms differ in their localization and ability to regulate Na v channels. 9 FHF2, located at Xq26.3-q27.1, is highly expressed in the developing and adult brain. 9,13 FHF2 is also expressed in endocrine tissues, ovaries, skeletal muscle, and the myocardium of the developing heart. [17][18][19] FHF2 has been implicated...

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FGF12p.Gly112Ser variant as a cause of phenytoin/phenobarbital responsive epilepsy

Abstract: A patient harboring a novel p.Gly112Ser variant in FGF12 gene had a positive response to phenytoin/phenobarbital treatment. All the 11 previously reported FGF12‐associated epilepsy cases had a single neighboring p.(Arg114His) variant and presented similar phenotype.

Cited by 7 publications

References 4 publications

Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

Defining the phenotype of FHF1 developmental and epileptic encephalopathy

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

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