FGF12-Related Early-Onset Epileptic Encephalopathies: Therapeutic Response to Sodium Channel Blockers.
PMID 42057324 | DOI 10.1002/ajmg.a.70182 · American journal of medical genetics. Part A · 2026
Developmental and epileptic encephalopathies (DEEs) comprise a clinically and genetically heterogeneous group of severe neurodevelopmental disorders, frequently caused by pathogenic variants in genes encoding neuronal ion channels or synaptic proteins. The fibroblast growth-factor 12 (FGF12) encodes a binding protein for voltage-gated sodium channels. Variants in FGF12 have recently been associated with autosomal dominant DEEs characterized by early-onset epilepsy and neurodevelopmental impairment. We report three patients with a duplication involving exons 1-4 of FGF12 on chromosome 3q28-q29 and systematically review 24 previously published cases of FGF12-related DEE. Clinical features, electroencephalographic findings, neuroimaging data, and responses to anti-seizure medications (ASMs) were analyzed across a total cohort of 27 patients. Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T). Nine patients had copy number duplications involving FGF12. Seizure onset ranged from 1 day to 4 years of age, with 54.1% presenting in the neonatal period. Tonic seizures were the most common seizure type, and 79.1% of patients exhibited moderate to severe intellectual disability. Brain MRI showed mild cerebral and/or cerebellar atrophy in 41.6% of cases. Across reported cases, variable responsiveness to ASMs was observed, with sodium channel blockers including carbamazepine and phenytoin frequently associated with seizure reduction. This study expands the clinical and genetic spectrum of FGF12-related DEE and highlights considerable phenotypic variability across variant types. While treatment responses were heterogeneous, sodium channel blockers were commonly associated with clinical improvement. These findings support cautious consideration of sodium channel targeting therapies in FGF12-DEE and underscore the need for systematic studies to better define genotype treatment relationships.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | FGF12 | “The fibroblast growth-factor 12 (FGF12) encodes a binding protein for voltage-gated sodium channels.” | 0.98 | hgnc_dict_v1 |
| phenotype | epilepsy | “Variants in FGF12 have recently been associated with autosomal dominant DEEs characterized by early-onset epilepsy and neurodevelopmental impairment.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | intellectual disability | “Tonic seizures were the most common seizure type, and 79.1% of patients exhibited moderate to severe intellectual disability.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | neurodevelopmental disorder | “Developmental and epileptic encephalopathies (DEEs) comprise a clinically and genetically heterogeneous group of severe neurodevelopmental disorders, frequently caused by pathogenic variants in genes encoding neuronal ion channels or synaptic proteins.” | 0.93 | phenotype_alias_lexicon_v2 |
| population | Population | “We report three patients with a duplication involving exons 1-4 of FGF12 on chromosome 3q28-q29 and systematically review 24 previously published cases of FGF12-related DEE.” | 0.80 | saudi_context_rules_v1 |
| variant | p.Arg114His | “Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T).” | 0.95 | hgvs_regex_v1 |
| variant | p.Gly112Ser | “Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T).” | 0.95 | hgvs_regex_v1 |
| variant | p.Glu87Lys | “Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T).” | 0.95 | hgvs_regex_v1 |
| variant | g.192335434C>T | “Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T).” | 0.95 | hgvs_regex_v1 |