FHF1 (FGF12) epileptic encephalopathy (2024)

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Supplementary Materials

Voltage-gated sodium channels (Na_vs) are mainstays of neuronal function, and mutations in the genes encoding CNS Na_vs (Na_v1.1 [SCN1A], Na_v1.2 [SCN2A], Na_v1.3 [SCN3A], and Na_v1.6 [SCN8A]) are causes of some of the most common and severe genetic epilepsies and epileptic encephalopathies (EE).¹ Fibroblast-growth-factor hom*ologous factors (FHFs) compose a family of 4 proteins that interact with the C-terminal tails of Na_vs to modulate the channels' fast, and long-term, inactivations.²FHF2 mutation is a rare cause of generalized epilepsy with febrile seizures plus (GEFS+).³ Recently, a de novo FHF1 mutation (p.R52H) was reported in early-onset EE in 2 siblings.⁴ We report 3 patients from unrelated families with the same FHF1 p.R52H mutation. The 5 cases together frame the FHF1 R52H EE from infancy to adulthood. As discussed below, this gain-of-function disease may be amenable to personalized therapy.

Patient 1 (P1, table) is a 3-year-old boy. Convulsive seizures began on day 2 of his life and remain intractable, with frequent status epilepticus (SE) manifesting as generalized or right-sided facial seizures. His EEGs show slow backgrounds and multifocal epileptiform discharges (figure e-1 at Neurology.org/ng). Multiple antiepileptic drug (AED) regimens failed, but he is currently at his best on a combination of the ketogenic diet and medications indicated in the table. He has severe global developmental delay, is nonverbal, has poor visual and social interaction, just started rolling slightly and sitting with support, and is tube-fed. He has generalized hypotonia with head lag and does not track. He suffers from chronic constipation. MRI at onset was normal, and at 2 years revealed widened ventricles and pericerebral CSF spaces (figure e-2A).

Patient 2 (P2) is a 16-year-old girl with intractable seizures since age 6 weeks and frequent SE. Seizures included generalized tonic-clonic (GTC) and partial seizures with left-sided facial twitching and lip-smacking (figure e-3). Phenytoin has been part of her AEDs, and relatively efficacious, since age 6 years. Since age 7, she develops 24 hours of severe ataxia after every GTC, which then gradually improves. Vagal nerve stimulation substantially improved seizure, and ataxia, intensities, and frequencies. MRI at 16 months was unremarkable but at 8 years showed cerebellar atrophy (figure e-2B). She suffers from chronic constipation. She has severe cognitive impairment with single words, has normal motor development, and ambulates. She needs help with all activities of daily living.

Patient 3 (P3) is an 18-year-old girl with intractable epilepsy since day 2 of her life with frequent SE. Seizures include leftward head deviation followed by generalized convulsion. EEGs were slow with multifocal spikes in infancy and Lennox-Gastaut–like in early childhood. She suffers from chronic constipation, hypohydrosis, and reduced lacrimation, suggesting autonomic dysfunction. She has moderate intellectual disability and can read simple books. She ambulates with a spastic circumductive gait and has substantial heel cord tightness. Current therapies (table) include vagal nerve stimulation. MRI at present shows bilateral mesial temporal sclerosis and mild prominence of cerebellar folia, findings not present in MRIs from early childhood (figure e-2C).

All 3 patients had the same de novo FHF1 NM_004113.5:c.155G>A, p.R52H mutation detected by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, and no other relevant de novo change. The table summarizes their clinical features and those of the recently published⁴ original sib-pair. Salient features of the latter pair include neonatal-onset intractable epilepsy, profound intellectual disability, severe feeding difficulties, MRI initially unremarkable and subsequently exhibiting cerebellar atrophy, ataxia, and death in SE.⁴

Based on 5 patients, the core FHF1 R52H disease comprises neonatal-onset persistent intractable epilepsy and moderate-to-severe intellectual disability. Radiologically, neurodegeneration, especially cerebellar, is present, which, beyond a mutational consequence appears to be aggravated by the severity and frequency of SE. It may also be exacerbated by treatment of SE. All 4 patients with cerebellar atrophy, including the original 2, were on phenytoin (table), repeatedly loaded and subsequently chronically maintained because of relative success in SE management and prevention. It may be cautious to use alternative medications, where possible, until this putative phenytoin cerebellar iatrogenicity is clarified.

Siekierska et al.⁴ demonstrated in vitro and in vivo that R52H is a toxic gain-of-function mutation. To date, thousands of patients with EE have undergone exome sequencing. Our rare finding of an FHF1 mutation suggests that FHF1 R52H might be a mutation-specific disease. It is possible that future FHF1 mutations with similar effects will be identified, but these would be expected to act through similar gain-of-function mechanisms. As such, methods to downregulate the R52H and related alleles, e.g., with allele-specific antisense oligonucleotides, could prove therapeutic in this catastrophic encephalopathy.

Supplementary Material

Acknowledgments

Acknowledgment: The study has UK Research Ethics Committee's approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network, the Health Innovation Challenge Fund (grant HICF-1009-003), and the Wellcome Trust Sanger Institute (grant WT098051). BAM holds the University of Toronto Michael Bahen Chair in Epilepsy Research. The authors thank the Next Generation Sequencing/bioinformatics teams at McGill University, the Genome Quebec Innovation Center, the Réseau de Médecine Génétique Appliquée, and Drs. Ledia Brunga (DNA sample management); Dipayan Mitra (MRI); Ms. Gail Charlton (EEG); and Ms. Sylvia Dobrzeniecka (sequencing) for their efforts.

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