KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

Kuchenbuch, Mathieu; Barcia, Giulia; Chémaly, Nicole; Carme, Emilie; Roubertie, Agathe; Gibaud, Marc; Bogaert, Patrick Van; Saint‐Martin, Anne de; Hirsch, Édouard; Dubois, Fanny; Sarret, Catherine; Tich, Sylvie Nguyen The; Laroche, Cécile; Portes, Vincent Des; Villemeur, Thierry Billette de; Barthez, Marie-Anne; Auvin, Stéphane; Bahi‐Buisson, Nadia; Desguerre, Isabelle; Kamińska, Anna; Benquet, Pascal; Nabbout, Rima

doi:10.1093/brain/awz240

Cited by 40 publications

(55 citation statements)

References 55 publications

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“…Obviously, other seizure types and developmental trajectories can be seen. Similar to our results, the high prevalence of acquired microcephaly was also noted by Kuchenbuch et al to be as high as 90% after 3 years of follow‐up . Given the cross‐sectional nature of our study, we were not able to delineate different phases experienced by EIMFS patients over time, recently described as the stormy phase, stabilization period, and chronic phase …”

Section: Discussionsupporting

confidence: 74%

“…As previously demonstrated for “de novo” epileptic encephalopathies, 8.3% of parents have mosaicism of their child's pathogenic variant, particularly when there is parental history of seizures . Interestingly, the high prevalence of positive family history of seizures (~30%) in our patients and in another study might indicate the need for future research focused on relatives of patients with KCNT1‐related epilepsy.…”

Section: Discussionsupporting

confidence: 67%

“…Poor response to AEDs is a common characteristic among KCNT1‐related epilepsy patients regardless of the phenotype. Not different from other studies, our patients were exposed to several AEDs over time (mean = 7.4, SD = 3.1), with no seizure freedom achieved. Moreover, more than one‐half (55%, 15/27) reported >50 seizures monthly.…”

Section: Discussioncontrasting

confidence: 55%

“…Given the expression of KCNT1 in muscle tissue, gonads, and the pituitary gland, it has been proposed that KCNT1 mutations can be involved in cardiac anomalies, SUDEP, and precocious puberty . One of our patients (Case 7) was diagnosed with a ventricular septal defect and supraventricular ectopic activity.…”

Section: Discussionmentioning

confidence: 96%

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KCNT1‐related epilepsy: An international multicenter cohort of 27 pediatric cases

et al. 2020

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Objective: Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotypephenotype correlations associated with frequently encountered variants. Methods: A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. Results: Twenty-seven children (15 males, mean age = 40.8 months) were included.Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement.When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. Significance: Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common.Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable. K E Y W O R D Scannabidiol, epilepsy of infancy with migrating focal seizures, KCNT1, ketogenic diet, microcephaly, quinidine

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 67%

Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 96%

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KCNT1‐related epilepsy: An international multicenter cohort of 27 pediatric cases

et al. 2020

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“…Another study investigated the long-term outcome of 17 infants with migrating focal seizures with KCNT1 mutations. They found that an extracerebral involvement, like arteriovenous fistula, dilated cardiomyopathy, may be involved in the high prevalence of SUDEP in these cases 19. To date, several studies had attempted to identify candidate genes from postmortem DNA samples.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Ding

Zhu

et al. 2019

J Neurol Neurosurg Psychiatry

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ObjectiveSudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified.MethodsWe performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP.ResultsAfter the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles.ConclusionsThese three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

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ILAE Genetic Literacy Series: Postmortem Genetic Testing in Sudden Unexpected Death in Epilepsy

Bagnall

Perucca

2023

Epileptic Disorders

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A 24‐year‐old man with non‐lesional bitemporal lobe epilepsy since age 16 years was found dead in bed around midday. He was last seen the previous night when he was witnessed to have a tonic–clonic seizure. Before his death, he was experiencing weekly focal impaired awareness seizures and up to two focal‐to‐bilateral tonic–clonic seizures each year. He had trialed several antiseizure medications and was on levetiracetam 1500 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day at the time of death. Other than epilepsy, his medical history was unremarkable. Of note, he had an older brother with a history of febrile seizures and a paternal first cousin with epilepsy. No cause of death was identified following a comprehensive postmortem investigation. The coroner classified the death as “sudden unexpected death in epilepsy” (SUDEP), and it would qualify as “definite SUDEP” using the current definitions.1 This left the family with many questions unanswered; in particular, they wish to know what caused the death and whether it could happen to other family members. Could postmortem genetic testing identify a cause of death, provide closure to the family, and facilitate cascade genetic testing of first‐degree family members who may be at risk of sudden death? While grieving family members struggle with uncertainty about the cause of death, we as clinicians also face similar uncertainties about genetic contributions to SUDEP, especially when the literature is sparse, and the utility of genetic testing is still being worked out. We aim to shed some light on this topic, highlighting areas where data is emerging but also areas where uncertainty remains, keeping our case in mind as we examine this clinically important area.

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KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

Cited by 40 publications

References 55 publications

KCNT1‐related epilepsy: An international multicenter cohort of 27 pediatric cases

KCNT1‐related epilepsy: An international multicenter cohort of 27 pediatric cases

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

ILAE Genetic Literacy Series: Postmortem Genetic Testing in Sudden Unexpected Death in Epilepsy

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