We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
- Klíčová slova
- SCN8A, epilepsy, genetics, personalized medicine,
- MeSH
- blokátory sodíkových kanálů terapeutické užití MeSH
- epilepsie generalizovaná * farmakoterapie genetika MeSH
- epileptické syndromy * farmakoterapie genetika MeSH
- genetické asociační studie MeSH
- kojenec MeSH
- lidé MeSH
- mentální retardace * genetika MeSH
- mutace MeSH
- napěťově řízený sodíkový kanál, typ 6 * genetika MeSH
- prognóza MeSH
- záchvaty farmakoterapie genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- blokátory sodíkových kanálů MeSH
- napěťově řízený sodíkový kanál, typ 6 * MeSH
- SCN8A protein, human MeSH Prohlížeč
BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. DISCUSSION: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.
- MeSH
- činnosti denního života MeSH
- dospělí MeSH
- elektroencefalografie MeSH
- epilepsie * MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- pohybové poruchy * genetika MeSH
- proteiny Munc18 * genetika MeSH
- záchvaty genetika MeSH
- Check Tag
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- proteiny Munc18 * MeSH
- STXBP1 protein, human MeSH Prohlížeč
Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
- Klíčová slova
- Epilepsy, Genetic diagnosis, Infantile spasms, Targeted sequencing, West syndrome,
- MeSH
- draslíkové kanály Shab genetika MeSH
- kineziny genetika MeSH
- kojenec MeSH
- křeče u dětí diagnóza genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- předškolní dítě MeSH
- proteiny přenášející monosacharidy genetika MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go genetika MeSH
- receptory cytoplazmatické a nukleární genetika MeSH
- represorové proteiny genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- draslíkové kanály Shab MeSH
- GNAO1 protein, human MeSH Prohlížeč
- KCNB1 protein, human MeSH Prohlížeč
- KIF1A protein, human MeSH Prohlížeč
- kineziny MeSH
- proteiny přenášející monosacharidy MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go MeSH
- receptory cytoplazmatické a nukleární MeSH
- represorové proteiny MeSH
- TBL1XR1 protein, human MeSH Prohlížeč
- UDP-galactose translocator MeSH Prohlížeč
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.
- MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- dítě MeSH
- dospělí MeSH
- draslíkové kanály genetika MeSH
- elektrická stimulace MeSH
- epilepsie generalizovaná genetika MeSH
- genetické asociační studie MeSH
- hyperpolarizační iontové kanály řízené cyklickými nukleotidy genetika MeSH
- kojenec MeSH
- křeče u dětí genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové potenciály genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- molekulární modely MeSH
- mutace genetika MeSH
- mutageneze cílená metody MeSH
- předškolní dítě MeSH
- senioři MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- draslíkové kanály MeSH
- HCN1 protein, human MeSH Prohlížeč
- hyperpolarizační iontové kanály řízené cyklickými nukleotidy MeSH
