Publications by authors named "Karen M Linnet"

4 Publications

  • Page 1 of 1

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Int J Cancer 2020 02 29;146(3):819-828. Epub 2019 Apr 29.

Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark.

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.
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http://dx.doi.org/10.1002/ijc.32341DOI Listing
February 2020

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

Brain 2017 May;140(5):1316-1336

CeGaT - Center for Genomics and Transcriptomics, Tübingen, Germany.

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
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http://dx.doi.org/10.1093/brain/awx054DOI Listing
May 2017

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

The association between preschool behavioural problems and internalizing difficulties at age 10-12 years.

Eur Child Adolesc Psychiatry 2010 Oct 2;19(10):787-95. Epub 2010 Sep 2.

Aarhus University Hospital, Regional Centre for Child and Adolescent Psychiatry, Risskov, Denmark.

The aim was to study the association between preschool behavioural problems and emotional symptoms in 10- to 12-year-old children. The study was based on the Aarhus Birth cohort, Denmark, and included 1,336 children. Based on the parent-administered preschool behaviour questionnaire (PBQ), we identified three not mutually exclusive preschool behavioural categories: anxious-fearful (n = 146), hyperactive-distractible (n = 98), and hostile-aggressive (n = 170). Children without any known symptoms were considered well adjusted (n = 1,000). Borderline emotional (n = 105) and emotional difficulties (n = 136) were measured at age 10-12 years with the parent-administered strength and difficulties questionnaire (SDQ). Multinomial logistic regression analyses were used to adjust for potential confounding factors. We found that anxious-fearful behaviour and hostile-aggressive preschool behaviour were associated with twice the risk of school-age emotional difficulties. Comorbidity or confounding failed to explain these results. Hyperactive-distractible preschool behaviour was not associated with school-age emotional difficulties. Preschool anxious-fearful behaviour was associated with school-age emotional difficulties, suggesting internalizing symptom stability in some children from early childhood. Preschool hostile-aggressive behaviour was also associated with school-age emotional difficulties, which suggests transformation of one behavioural dimension into another through childhood, and the need to focus on both early internalizing difficulties and hostile-aggressive behaviour as risk factors for later internalizing difficulties.
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http://dx.doi.org/10.1007/s00787-010-0128-2DOI Listing
October 2010
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