Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations

Hortigüela, Montesclaros; Fernández–Marmiesse, Ana; Cantarín, Verónica; Gouveia, Sofía; Garcı́a-Peñas, Juan José; Fons, Carmen; Armstrong, Judith; Barrios, Desirée; Díaz‐Flores, Felicitas; Tirado, Pilar; Couce, María L.; Gutiérrez-Solana, Luis González

doi:10.1038/jhg.2016.104

Cited by 19 publications

(24 citation statements)

References 30 publications

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“…The fact that the current density of the heteromeric mutant E130K/Kv7.3 is about 60% of control means that the dominant‐negative impact of this mutation is partial. In contrast to the more severe phenotype observed for the G281R mutant, this patient had moderate motor and cognitive impairment …”

Section: Discussioncontrasting

confidence: 68%

“…Although BFNS usually bears an excellent long‐term prognosis, seizure recurrences later in life have also been described . More recently, it was found that de novo mutations in KCNQ2 are responsible for 5%‐23% of early infantile epileptic encephalopathies (EIEEs) . KCNQ2 encephalopathy often presents in the first week of life with a distinct electroclinical pattern characterized by intractable and prominent tonic seizures, with or without autonomic features, and burst‐suppression or multifocal epileptiform abnormalities with attenuation on electroencephalography (EEG).…”

Section: Introductionmentioning

confidence: 99%

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Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy

et al. 2018

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Objective: To gain insight into the mechanisms underlying KCNQ2 encephalopathy by examining the electrophysiologic properties of mutant Kv7.2 channels in different multimeric configurations. Methods: We analyzed the genotype-phenotype relationship in 4 patients with KCNQ2 encephalopathy and performed electrophysiologic analysis of M-currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels.Results: Negligible or no current was recorded in cells expressing homomeric E130K, W270R, or G281R de novo mutants, and it was reduced by more than 90% for the L243F maternally inherited mutant. The E130K and G281R mutants presented a marked dominant-negative behavior, whereas the current density was partially reduced (L243F) or not affected (W270R) when coexpressed with wildtype Kv7.2 subunits. In contrast, the extent of Kv7.3 "rescue," which yields negligible currents on its own, followed the sequence E130K > L243F > W270R, whereas no rescue was observed with the G281R mutant. No significant effects on current density were observed when subunits were expressed in a 0.5:0.5:1.0 (Kv7.2:mutant:Kv7.3) DNA ratio to mimic the genetic balance. There was an increase in sensitivity to phosphatidylinositol 4,5-bisphosphate (PIP 2 ) depletion for W270R/Kv7.3, but no substantial differences were observed when the mutated subunits were coexpressed with Kv7.2 or both Kv7.2 and Kv7.3. Significance: There was a marked disparity of the impact of these mutations on Kv7.2 function, which varied on association with Kv7.2 or Kv7.3 subunits. Current density of homomeric channels was the most reliable property relating Kv7.2 function to encephalopathy, but other factors are required to explain the milder phenotype for some individuals carrying the maternally inherited L243F mutation.We hypothesize that the role of homomeric Kv7.2 channels for fine-tuning neuronal connections during development is critical for the severity of the KCNQ2 encephalopathy. K E Y W O R D Searly infantile epileptic encephalopathies, epilepsy, KCNQ2, M-current, PIP 2

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Section: Discussioncontrasting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy

et al. 2018

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“…Patients 7 and 9 had de novo missense mutations which have been previously associated with KCNQ2 encephalopathy [16,17,18]. Patient 8 had a de novo missense mutation previously reported in both a patient with BFNS and a patient with KCNQ2 encephalopathy [8,19]. Frameshift mutations and whole-gene deletions are well-known to be associated with BFNS.…”

Section: Resultsmentioning

confidence: 99%

A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with <b><i>KCNQ2</i></b> Mutations

Vilan¹,

Ribeiro

Striano

et al. 2017

Neonatology

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Background: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigmof the workup and management of neonatal seizures. Objective: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy. Subjects and Methods: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported. Results: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases. Conclusion: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.

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“…Both benign epilepsy and epileptic encephalopathy have been reported to be associated with KCNQ2 mutations [28]. Families with KCNQ2 mutations and variable phenotypes have been described previously [29,30].…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

et al. 2017

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Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75.9%). A total of 42 families had PRRT2 mutations, 9 had KCNQ2 mutations, 8 had SCN2A mutations, and 1 had a GABRA6 mutation. In total three of four BFNE families were detected with KCNQ2 mutations. Mutations were detected in all BFNIE families, including 3 KCNQ2 mutations, 3 SCN2A mutations, and 1 PRRT2 mutation. Gene mutations were identified in 50 out of 68 BFIE families (73.5%), including 41 PRRT2 mutations (41 out of 68, 60.3%), 5 SCN2A mutations, 3 KCNQ2 mutations, and 1 GABRA6 mutation. Our results confirmed that mutations in KCNQ2, SCN2A, and PRRT2 are major genetic causes of benign familial epilepsy in the first year of life in the Chinese population. KCNQ2 is the major gene related to BFNE. PRRT2 is the main gene responsible for BFIE.

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Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations

Cited by 19 publications

References 30 publications

Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy

Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy

A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with <b><i>KCNQ2</i></b> Mutations

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

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