Location: A surrogate for personalized treatment of sodium channelopathies

Holland, Katherine D.; Bouley, Thomas M.; Horn, Paul S.

doi:10.1002/ana.25268

Cited by 11 publications

(20 citation statements)

References 33 publications

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“…Sodium channel blockers are unlikely to be effective in patients with LoF variants in this region. Contrary to previous work, we observe that variants in the S4 region are not associated with one predominant effect, but a range of LoF, mixed, and GoF effects, suggesting that function is determined by the individual variant change, rather than a particular S4 region effect …”

Section: Discussioncontrasting

confidence: 99%

“…LoF Brugada syndrome variants are mainly observed in the S5‐6 pore loop, whereas no pore loop variants are seen in GoF LQT3 carriers . We observe the same effect in SCN2A/8A , where variants in the S5‐6 pore loop region appear to be mainly LoF, implying that variants in this region often lead to LoF across different SCNs . Sodium channel blockers are unlikely to be effective in patients with LoF variants in this region.…”

Section: Discussionmentioning

confidence: 56%

“…43 We observe the same effect in SCN2A/8A, where variants in the S5-6 pore loop region appear to be mainly LoF, implying that variants in this region often lead to LoF across different SCNs. 44 Sodium channel blockers are unlikely to be effective in patients with LoF variants in this region. Contrary to previous work, we observe that variants in the S4 region are not associated with one predominant effect, but a range of LoF, mixed, and GoF effects, suggesting that function is determined by the individual variant change, rather than a particular S4 region effect.…”

Section: Variant Effects Across Different Channel Subtypesmentioning

confidence: 99%

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Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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Objective Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. Methods We analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. Results Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. Significance Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 56%

Section: Variant Effects Across Different Channel Subtypesmentioning

confidence: 99%

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Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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“…Conversely, all the patients who carried a mutation in TMO, IG, and C regions were from group 1 (Figure B,C). The distribution of epilepsy‐associated missense variants in the different regions over the protein for our patients was similar to what was already described …”

Section: Resultssupporting

confidence: 87%

“…The relative frequency of variants was calculated using the method reported by Holland et al . Thus, the pore region was defined as segments S5, S5‐S5, S6; the voltage sensor region (VSR) as S4, and its associated linkers (S3‐S4 and S4‐S5).…”

Section: Methodsmentioning

confidence: 99%

Clinical study of 19 patients with SCN8A‐related epilepsy: Two modes of onset regarding EEG and seizures

Denis

Villeneuve

Cacciagli³

et al. 2019

Epilepsia

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Summary Objective To describe the mode of onset of SCN8A‐related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. Methods We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy‐associated missense variant localization over the protein. Results We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic–clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep‐related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. Significance SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.

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SCN1A variants from bench to bedside—improved clinical prediction from functional characterization

et al. 2019

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Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed.We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype.Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch-clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole-cell current, whereas those without any wholecell current were often associated with DS (p = .024).These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS. K E Y W O R D SDravet syndrome, electrophysiology, familial hemiplegic migraine, functional testing, GEFS+, patch-clamp, SCN1A *Andreas Brunklaus and Stephanie Schorge contributed equally to this study.

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Location: A surrogate for personalized treatment of sodium channelopathies

Cited by 11 publications

References 33 publications

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Clinical study of 19 patients with SCN8A‐related epilepsy: Two modes of onset regarding EEG and seizures

SCN1A variants from bench to bedside—improved clinical prediction from functional characterization

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