Ring Chromosome 20: A Pediatric Potassium Channelopathy Responsive to Treatment with Ezogabine

doi:10.1016/j.pediatrneurol.2013.06.005

Pediatric Neurology

Volume 49, Issue 5, November 2013, Pages 368-369

https://doi.org/10.1016/j.pediatrneurol.2013.06.005 Get rights and content

Abstract

Background

Ring chromosome 20 is a genetic disorder characterized by intractable epilepsy, behavioral problems, and cognitive deficit. The potassium channel–coding gene KCNQ2 is localized at the locus q13.3 on the chromosome 20, the most common site where the ring occurs. Ezogabine is the first potassium channel opener marketed in the United States.

Patients

We describe an 8-year-old girl with mosaic ring chromosome 20 and refractory epilepsy who had a remarkable improvement in seizure control with ezogabine.

Conclusions

This is the first report using the new antiepileptic drug ezogabine to treat pediatric epilepsy. We hypothesize that ring chromosome 20 patients have epilepsy related to abnormalities in the potassium channels, making it susceptible for treatment with potassium channel openers.

Introduction

Ring chromosome 20 syndrome is a relatively rare genetic syndrome that can present with developmental delay or cognitive deficit and intractable epilepsy between the ages of 9 months and 17 years.¹ Some authors have suggested that this condition is a potassium channelopathy.² The potassium channel gene KCNQ2 is localized on the long arm of chromosome 20 at q13.3. The most common fusion site in ring chromosome 20 is between the telomeres of the short arm (p13) and the long arm (q13.3).² Other epilepsies, including benign neonatal familial convulsions, are also due to abnormalities on this gene.³ Ezogabine is the first potassium channel opener marketed in the United States; it was approved in June 2011 by the US Food and Drug Administration for adjunctive therapy of partial seizures in adults. We report an 8-year-old girl with mosaic ring chromosome 20 (p13q13.3) and refractory epilepsy who, after being treated with 15 antiepileptic drugs and the ketogenic diet without success, had a remarkable improvement in seizure control with ezogabine.

Section snippets

Case report

A previously healthy 6-year-old girl at first evaluation was referred for evaluation of new onset of complex partial seizures.

The patient was born full term via vaginal delivery with no complications and her early development was normal. She walked at 1 year of age and had normal speech development. She had no other relevant medical history, and her family history was noncontributory.

At the time of her initial evaluation, she was doing well in first grade at school.

The examination showed a

Discussion

Ring chromosome 20 is a rare disease, with an unknown prevalence, but at least 100 cases have been reported in the medical literature since 1972.1, 4 Rings result from intrachromosomal fusions. The most common fusion sites reported on ring chromosome 20 are between regions p13 and q13.3. The q13.3 locus contains at least two channel genes that have been related to human epilepsy.2, 5 CHRNA4 (nicotinic acetylcholine receptor) has been related to with autosomal dominant nocturnal frontal lobe

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Ring chromosome 20 syndrome: electroclinical description of six patients and review of the literature
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P.J. Serrano-Castro et al.
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E.C. Cooper
Potassium channels: how genetic studies of epileptic syndromes open paths to new therapeutic targets and drugs
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Cited by (15)

New anti-epileptic drugs in Paediatrics
2019, Anales de Pediatria
Se estima que unos 70 millones de personas padecen epilepsia a nivel mundial de los cuales más de la mitad son niños, en los que la prevalencia estimada se sitúa en torno al 0,5-0,8%. Aunque existen diversas terapias, el tratamiento de la epilepsia se basa mayoritariamente en fármacos, que en función de su año de comercialización se clasifican como de primera, segunda o tercera generación. En el presente artículo se revisan las principales características de los fármacos antiepilépticos de última generación (lacosamida, acetato de eslicarbazepina, brivaracetam, perampanel, retigabina, everolimus y cannabidiol) que, con excepción de la retigabina (ya no está comercializada), se consideran seguros y efectivos en población pediátrica. El everolimus y el cannabidiol tienen indicaciones muy concretas (esclerosis tuberosa, síndrome de Dravet y síndrome de Lennox Gastaut) mientras que el resto están indicados en el manejo de crisis de origen focal en niños a partir de 4 años. Estas nuevas moléculas han sido desarrolladas para aportar un perfil farmacocinético y de tolerancia superior a los fármacos previamente disponibles y es previsible que a medida que aumente su uso, se vaya perfilando y ampliando su verdadero potencial. Además, por primera vez en epileptología pediátrica, se ha utilizado la extrapolación de datos de efectividad en adultos (junto con estudios de seguridad y farmacocinética específicos en población pediátrica), para acelerar la aprobación de uso en población infantil.
It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population.
Specificity of electroclinical features in the diagnosis of ring chromosome 20
2018, Epilepsy and Behavior
Citation Excerpt :
One patient also improved with vagus nerve stimulation, in line with previous reports [6,31]. Two patients were treated with a ketogenic diet, resulting in no significant improvement, similar to one case described in the literature [37]. One patient was treated with retigabine/ezogabine without any improvement, in contrast to a previous report [37].
Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20.
In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases.
We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%.
Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad.
In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted.
Epilepsy in ring chromosome 20 syndrome
2016, Epilepsy Research
Citation Excerpt :
Eyelid myoclonia recorded in adult patients in this series can also be related to the frontal circuitry, as recently demonstrated by fMRI studies in patients with eyelid myoclonia with absences, in whom systems encompassing frontal lobe networks and bilateral thalami were involved (Vaudano et al., 2014b). Interestingly, with respect to epilepsy genes, also the voltage-gated potassium channel KCNQ2 maps on 20q13.33, and Ezogabine, a potassium channel opener, was reported to be effective in treating seizures in a girl with r(20) syndrome (Walleigh et al., 2013). However, the phenotype caused by mutations or deletions in KCNQ2 (a spectrum ranging from benign familial neonatal seizures to early infantile epileptic encephalopathy) is different from the one seen in r(20) syndrome.
Ring chromosome 20 syndrome is characterized by severe, drug resistant childhood onset epilepsy, often accompanied by cognitive impairment. We characterized the electro-clinical phenotype and the long-term course of epilepsy in a large series.
We reviewed the electro-clinical phenotype of 25 patients (aged 8–59 years), and assessed the relationship between epilepsy severity and clinical and/or genetic variables. We also searched for reports of patients diagnosed with r(20) syndrome in the literature, included those whose clinical information was sufficiently accurate, and compared their clinical features with the ones of our patients.
Epilepsy exhibited an age dependent course. When seizure onset occurred in childhood (21 patients), terrifying hallucinations associated with focal motor seizures, often sleep-related (8 patients), or dyscognitive seizures (13 patients), were prominent features, often evolving into epileptic encephalopathy associated with non-convulsive status epilepticus (11 patients). In the long-term, progressive stabilization of drug resistant epilepsy associated with non-convulsive status epilepticus, focal seizures with motor and autonomic features, and eyelid myoclonia were noticed. Epilepsy onset in adolescence (3 patients) was accompanied by a milder developmental course, dyscognitive seizures and non-convulsive status epilepticus, and no cognitive decline. Only three older patients became seizure free (>5 years) We found statistically significant correlations between age at epilepsy onset and cognitive level. Although in the study cohort the relationship between r(20) ratio, age at epilepsy onset and cognitive level was non-statistically significant, it reached significance evaluating the larger cohort of patients previously published.
In ring(20) syndrome, epilepsy has an age dependent course and a worse outcome when age at seizure onset is earlier. The r(20) ratio and severity of cognitive impairment appear to be directly related to each other and inversely correlated with the age at epilepsy onset.
Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies
2016, Seminars in Pediatric Neurology
Citation Excerpt :
A single case report describes the successful use of ezogabine (A positive allosteric modulator of the KCNQ2 channel, which opens the channel, resulting in decreased neuronal excitability.) in the treatment of refractory seizures in a child with ring 20 chromosome.25 The voltage-gated potassium channel gene, KCNQ2, is located on chromosome 20.
The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future.
Third generation antiepileptic drugs: mechanism of action, pharmacokinetics, interaction and use in childhood
2023, Epilepsy and Paroxysmal Conditions
Autism Spectrum Disorder and a De Novo Kcnq2 Gene Mutation: A Case Report
2022, Pediatric Reports

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Clinical ObservationsRing Chromosome 20: A Pediatric Potassium Channelopathy Responsive to Treatment with Ezogabine

Abstract

Background

Patients

Conclusions

Introduction

Section snippets

Case report

Discussion

Eur J Med Genet.

Epilepsy Behav

Rev Neurol

Potassium channels: how genetic studies of epileptic syndromes open paths to new therapeutic targets and drugs

Epilepsia

Clinical Observations
Ring Chromosome 20: A Pediatric Potassium Channelopathy Responsive to Treatment with Ezogabine