Publications by authors named "Rikke Steensbjerre Møller"

14 Publications

  • Page 1 of 1

Adult phenotype of encephalopathy.

J Med Genet 2021 Apr 2. Epub 2021 Apr 2.

Neurology Department, University Hospital Antwerp, Antwerp, Belgium

Background: Pathogenic variants are a frequent cause of developmental and epileptic encephalopathy.

Methods: We recruited 13 adults (between 18 years and 45 years of age) with encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

Results: While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behaviour and 4 (31%) destructive behaviour with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.

Conclusion: Seizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioural problems are an issue of continuous concern.
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http://dx.doi.org/10.1136/jmedgenet-2020-107449DOI Listing
April 2021

Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Am J Med Genet A 2021 05 31;185(5):1366-1378. Epub 2021 Jan 31.

Division of Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
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http://dx.doi.org/10.1002/ajmg.a.62102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048530PMC
May 2021

Encephalopathy related to status epilepticus during sleep due to a de novo KCNA1 variant in the Kv-specific Pro-Val-Pro motif: phenotypic description and remarkable electroclinical response to ACTH.

Epileptic Disord 2020 Dec;22(6):802-806

Danish Epilepsy Center, Dianalund, Denmark, University of Copenhagen, Copenhagen, Denmark.

Although the classic phenotype of episodic ataxia type 1 (EA1) caused by variants in KCNA1 includes episodic ataxia and myokymia, further genotype-phenotype correlations are difficult to establish due to highly heterogeneous clinical presentations associated with KCNA1 pathogenic variants. De novo variants in the paralogous Pro-Val-Pro motif (PVP) of KCNA2, an essential region for channel gating, have been reported to be associated with severe epilepsy phenotypes, including developmental and epileptic encephalopathies (DEE). Here, we describe the first patient with a DEE who developed an encephalopathy related to status epilepticus during sleep (ESES) and cerebellar signs, harbouring a variant in the Kv-specific PVP motif of the KCNA1 gene. Interestingly, he showed a remarkable long-term electroclinical response to IM ACTH therapy. This report extends the range of phenotypes associated with KCNA1 variants to include that of ESES, and suggests that ACTH therapy is likely to have a positive effect in patients with these variants.
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http://dx.doi.org/10.1684/epd.2020.1222DOI Listing
December 2020

The impact of severe pediatric epilepsy on experienced stress and psychopathology in parents.

Epilepsy Behav 2020 12 22;113:107538. Epub 2020 Nov 22.

Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Filadelfia, Dianalund, Denmark. Electronic address:

Objectives: To assess the prevalence of psychopathology and the level of stress in parents of children with severe epilepsy to gain a better understanding of parental support needs.

Methods: Questionnaires were completed by parents of children with severe epilepsy during the hospitalization of their child at the Danish Epilepsy Center. The questions targeted symptoms of post-traumatic stress disorder (PTSD), complex PTSD (CPTSD), depression, and anxiety, and the level of perceived stress.

Results: A total of 162 caregivers of 140 children with epilepsy participated in the survey. Mothers were more often unemployed than fathers (38% vs. 11%, p < 0.01), and nearly half of the children (47%) attended special needs classes. Psychopathology symptoms were found in 43.5% of parents, fulfilling criteria for one or more diagnoses, and an additional 11% showed symptoms of sub-clinical PTSD. Parent-rated child difficulties were significantly associated with PTSD (M = 5.51, p = 0.001), depression (M = 4.50, p < 0.000), and anxiety (M = 4.61, p = 0.01), and with higher levels of perceived stress (p < 0.001).

Conclusion: Caring for a child with severe epilepsy has a significant psychopathological impact on caregivers. Caregivers' resources and the degree of behavioral difficulties in the child, rather than epilepsy-related factors, are highly correlated with distress and psychopathological symptoms in caregivers.
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http://dx.doi.org/10.1016/j.yebeh.2020.107538DOI Listing
December 2020

Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice.

J Med Genet 2019 10 26;56(10):701-710. Epub 2019 Aug 26.

Department of Pediatrics, University of Montreal, Montreal, Québec, Canada

Background: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.

Methods: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.

Results: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.

Conclusions: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.
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http://dx.doi.org/10.1136/jmedgenet-2018-105879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817694PMC
October 2019

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome.

Mol Syndromol 2016 Sep 17;7(4):234-238. Epub 2016 Aug 17.

Laboratory of Neurogenetics, Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, University of Genoa, 'G. Gaslini' Institute, Genoa, Rome, Italy.

Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.
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http://dx.doi.org/10.1159/000448367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073591PMC
September 2016

The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome.

Epilepsia 2015 Dec 5;56(12):e203-8. Epub 2015 Nov 5.

Danish Epilepsy Center, Dianalund, Denmark.

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.
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http://dx.doi.org/10.1111/epi.13222DOI Listing
December 2015

Dysregulation of FOXG1 by ring chromosome 14.

Mol Cytogenet 2015 9;8:24. Epub 2015 Apr 9.

Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.

In this study we performed molecular characterization of a patient with an extra ring chromosome derived from chromosome 14, with severe intellectual disability, epilepsy, cerebral paresis, tetraplegia, osteoporosis and severe thoraco-lumbal scoliosis. Array CGH analysis did not show any genomic imbalance but conventional karyotyping and FISH analysis revealed the presence of an interstitial 14q12q24.3 deletion and an extra ring chromosome derived from the deleted material. The deletion and ring chromosome breakpoints were identified at base-pair level by mate-pair and Sanger sequencing. Both breakpoints disrupted putative long non-coding RNA genes (TCONS00022561;RP11-148E17.1) of unknown function. However, the proximal breakpoint was 225 kb downstream of the forkhead box G1 gene (FOXG1), within the known regulatory landscape of FOXG1. The patient represents the first case of a r(14) arising from an interstitial excision where the phenotype is compatible with dysregulation of FOXG1. In turn, the phenotypic overlap between the present case, the FOXG1 syndrome and the r(14) syndrome supports that dysregulation of FOXG1 may contribute to the classical r(14)-syndrome, likely mediated by dynamic mosaicism.
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http://dx.doi.org/10.1186/s13039-015-0129-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404611PMC
April 2015

[Early-onset epileptic encephalopathy caused by CDKL5 mutation].

Ugeskr Laeger 2014 Dec;176(25A)

Epilepsihotellet, Dianalund, Kolonivej 1, 4293 Dianalund.

Two girls suffering from early-onset epileptic encephalopathy are described. Both girls had changes involving the gene CDKL5. They both had seizures in the first weeks of life and normal EEG interictally. Both developed infantile spasms and severe developmental defect. The epilepsy was difficult to treat.
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December 2014

[Glucose transporter-1 deficiency syndrome can cause various clinical symptoms].

Ugeskr Laeger 2013 Dec;175(50A):V04130248

Forskning og Udvikling, Epilepsihospitalet. Artillerivej 100b, 5. tv., 2300 København S.

Glucose transporter-1 deficiency syndrome (GLUT1-DS) is caused by a decreased function of the glucose transporter GLUT1 protein, which is located in the blood brain barrier. This leads to inadequate glucose levels for brain metabolism and can cause various clinical symptoms including medically intractable epilepsy, developmental delay and complex movement disorders. Ketonic diet is the golden standard for treatment of GLUT1-DS. GLUT1-DS should be suspected in patients with early-onset intractable epilepsy with developmental delay or activity-induced movement disorders with or without epilepsy.
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December 2013

The role of SLC2A1 in early onset and childhood absence epilepsies.

Epilepsy Res 2013 Jul 8;105(1-2):229-33. Epub 2013 Jan 8.

Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.

Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE.
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http://dx.doi.org/10.1016/j.eplepsyres.2012.11.004DOI Listing
July 2013

[Genetic causes of infantile spasms--a systematic review].

Ugeskr Laeger 2012 Apr;174(17):1152-5

HC Andersen Børnehospital, Odense Universitetshospital, Sdr. Boulevard 29, 5000 Odense, Denmark.

Infantile spasms are a symptom of a severe epileptic encephalopathy. It is important to determine the aetiology for a child's disease. When a standard programme for evaluating the aetiology of the infantile spasms is unsuccessful genetic causes should be considered. We suggest array CGH as the first-line analysis and present an overview of relevant present possibilities for genetic testing.
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April 2012

[Mowat-Wilson syndrome: a report of three Danish cases].

Ugeskr Laeger 2011 Sep;173(36):2199-200

Pædiatrisk Afdeling, Regionshospitalet Herning, 7400 Herning, Denmark.

Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies. Some cases also present epilepsy, growth retardation and microcephaly. The syndrome is caused by mutations or deletions of the ZEB2 gene at chromosome 2q22-q23. MWS was first described in 1998 and until now approximately 180 cases have been reported worldwide. We report the first three molecularly confirmed Danish cases with MWS.
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September 2011

Characterization of a t(5;8)(q31;q21) translocation in a patient with mental retardation and congenital heart disease: implications for involvement of RUNX1T1 in human brain and heart development.

Eur J Hum Genet 2009 Aug 28;17(8):1010-8. Epub 2009 Jan 28.

Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Denmark.

The chromosome break points of the t(8;21)(q21.3;q22.12) translocation associated with acute myeloid leukemia disrupt the RUNX1 gene (also known as AML1) and the RUNX1T1 gene (also known as CBFA2T3, MTG8 and ETO) and generate a RUNX1-RUNX1T1 fusion protein. Molecular characterization of the translocation break points in a t(5;8)(q32;q21.3) patient with mild-to-moderate mental retardation and congenital heart disease revealed that one of the break points was within the RUNX1T1 gene. Analysis of RUNX1T1 expression in human embryonic and fetal tissues suggests a role of RUNX1T1 in brain and heart development and support the notion that disruption of the RUNX1T1 gene is associated with the patient's phenotype.
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http://dx.doi.org/10.1038/ejhg.2008.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986559PMC
August 2009