Publications by authors named "Kern Olofsson"

7 Publications

  • Page 1 of 1

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.
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http://dx.doi.org/10.1093/brain/awab219DOI Listing
June 2021

Cannabidiol treatment of severe refractory epilepsy in children and young adults.

Dan Med J 2021 Apr 28;68(5). Epub 2021 Apr 28.

Introduction: Since 2016, the Paediatric Department of the Filadelfia Epilepsy Hospital, Denmark, has been treating patients with cannabidiol for severe refractory epilepsy. This study describes treatment results, evaluates the effect of clobazam co-medication and compares findings in Dravet and Lennox-Gastaut patients with results in patients with other epilepsies.

Methods: This was a retrospective cohort study including 78 patients treated with off-label cannabidiol in 2016-2019. Diagnoses, previous and concomitant treatment, and presence of motor seizures were assessed. Effect on seizures was evaluated by seizure frequency registration or perceived effect in patients without seizure frequency registration.

Results: In 51 patients with seizure frequency registration, 31.4% had ≥ 50% seizure reduction at three months, 31.1% at six months, 28.1% at 12 months and 20.0% at 24 months. At the same periods, some degree of seizure reduction was: 68.6%, 57.8%, 46.9% and 20.0%, respectively. Seizure reduction was higher with clobazam co-medication. In Dravet and Lennox-Gastaut patients, 70.0% had ≥ 50% seizure reduction at three months compared with 22.0% in patients with other epilepsies, where some degree of seizure reduction at three months were 80.0% and 65.9%, respectively.

Conclusions: Cannabidiol is a treatment option in children and young adults with severe refractory epilepsy other than Dravet and Lennox-Gastaut syndromes, but close evaluation of its effects is important to taper off treatment in case a treatment effect is lacking. Clobazam co-medication increases seizure reduction.

Funding: none.

Trial Registration: not relevant.
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April 2021

Treatment Responsiveness in KCNT1-Related Epilepsy.

Neurotherapeutics 2019 07;16(3):848-857

Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA.

Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
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http://dx.doi.org/10.1007/s13311-019-00739-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694367PMC
July 2019

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies.

Mol Syndromol 2016 Sep 20;7(4):210-219. Epub 2016 Aug 20.

Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including and . Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.
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http://dx.doi.org/10.1159/000448369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073625PMC
September 2016

Noninvasive measurements of regional cerebral perfusion in preterm and term neonates by magnetic resonance arterial spin labeling.

Pediatr Res 2006 Sep 20;60(3):359-63. Epub 2006 Jul 20.

Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.

Magnetic resonance arterial spin labeling (ASL) at 3 Tesla has been investigated as a quantitative technique for measuring regional cerebral perfusion (RCP) in newborn infants. RCP values were measured in 49 healthy neonates: 32 preterm infants born before 34 wk of gestation and 17 term-born neonates. Examinations were performed on unsedated infants at postmenstrual age of 39-40 wk in both groups. Due to motion, reliable data were obtained from 23 preterm and 6 term infants. Perfusion in the basal ganglia (39 and 30 mL/100 g/min for preterm and term neonates, respectively) was significantly higher (p < 0.0001) than in cortical gray matter (19 and 16 mL/100 g/min) and white matter (15 and 10 mL/100 g/min), both in preterm neonates at term-equivalent age and in term neonates. Perfusion was significantly higher (p = 0.01) in the preterm group than in the term infants, indicating that RCP may be influenced by developmental and postnatal ages. This study demonstrates, for the first time, that noninvasive ASL at 3T may be used to measure RCP in healthy unsedated preterm and term neonates. ASL is, therefore, a viable tool that will allow serial studies of RCP in high-risk neonates.
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http://dx.doi.org/10.1203/01.pdr.0000232785.00965.b3DOI Listing
September 2006

Ionized magnesium in Danish children with type 1 diabetes.

Diabetes Care 2004 May;27(5):1216-7

Department of Pediatrics, Glostrup University Hospital, Glostrup, Denmark.

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http://dx.doi.org/10.2337/diacare.27.5.1216DOI Listing
May 2004

[Fever and skin hemorrhages in children--is it meningococcal disease?].

Ugeskr Laeger 2002 May;164(20):2617-23

Amtssygehuset i Gentofte, DK-2900 Hellerup.

Introduction: Our main aims were to establish criteria for early distinction between meningococcal disease and other conditions with similar clinical features, and to identify other causes of haemorrhagic rashes accompanied by fever.

Materials And Methods: This prospective study comprised 264 infants and children hospitalised with fever and skin haemorrhages.

Results: We identified an aetiological agent in 28%: 15% had meningococcal disease, 2% another invasive bacterial infection, 7% enterovirus infection, and 4% adenovirus infection. Five clinical variables discriminated meningococcal disease from other conditions on admission: skin haemorrhages of (1) characteristic appearance; (2) universal distribution and (3) a maximum diameter of > 2 mm; (4) poor general condition; and (5) nuchal rigidity.

Discussion: If any two or more of these clinical variables were present, the probability of identifying a patient with meningococcal disease was 97% and the false-positive rate was only 12%. This diagnostic algorithm did not identify children in whom septicaemia was caused by other bacterial species.
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May 2002
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