BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain ...malformations.
We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development.
We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
Objective
IQSEC2 is an X‐linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic ...variants.
Methods
Forty‐eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians.
Results
Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male‐to‐female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic–clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late‐onset epileptic spasms (three) and Lennox‐Gastaut or Lennox‐Gastaut–like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features.
Significance
The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This commentary is on the original articles by Danielsson et al. on pages 1251–1255 of this issue and Humbertclaude et al. on pages 1256–1263 of this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Introduction Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal ...epileptiform discharges on the electroencephalogram, developmental delay or regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly. Methods We describe two siblings with fatal EOEE, profound global developmental delay and post-natal microcephaly that underwent extensive biochemical and metabolic workup in vain. Neuro-imaging disclosed non-specific progressive cerebral atrophy. Results Whole-exome sequencing (WES) disclosed compound heterozygous mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2 . This gene has been previously described as the cause of pontocerebellar hypoplasia type 6. Conclusion We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post-natal microcephaly, without the distinctive radiological features of pontocerebellar hypoplasia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Abstract Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first ...day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Purpose: The clinical significance of occipital intermittent rhythmic delta activity (OIRDA) on the electroencephalogram has not been fully established. Recent studies suggest that this pattern ...occurs almost exclusively in children and is probably of epileptic origin in most cases. We sought to characterize the electrographic features and clinical correlates of occipital intermittent rhythmic delta activity.
Methods: A review of 697 consecutive pediatric electroencephalograms detected occipital intermittent rhythmic delta activity in 24 studies. Mean patient age was 7.96 years.
Results: Recent convulsions and absence seizures constituted the main indications for the study. Concomitant, independent epileptiform activity was noted in half of the cases. This activity was focal in all but one case. Conversely, in most cases of absence seizures, epileptiform activity intermixed with occipital intermittent rhythmic delta activity. Furthermore, the frequency of the occipital rhythmic discharges in studies of children with absences was generally faster (3–4 Hz) than in localization‐related epilepsy (2–3 Hz). Most patients were awake when occipital intermittent rhythmic delta activity occurred. Chronic encephalopathy was seen in one child only. Analysis of neuroimaging studies in eight cases revealed no structural pathology associated with occipital intermittent rhythmic delta activity.
Conclusions: Occipital intermittent rhythmic delta activity is probably an epileptiform pattern, although it is noted occasionally in encephalopathic children. Its electrographic characteristics appear to differ between localization‐related epilepsy and primary generalized epilepsy, particularly absence seizures.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or ...regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Pediatric video-EEG monitoring is a standard procedure in epilepsy clinics,typically conducted in in-hospital settings.However, hospitalizationis sometimesunnecessary and imposes a burden on children ...and their families. In response to the rise of telehealth, home video-EEG monitoring has emerged, utilizing portable EEG equipment and video-cameras.
The aim of this study was to assess the feasibility of home video-EEGin a pediatric population.
We conducteda prospective pilot study of twentyhome video-EEG tests in children. We evaluated the quality of EEG and video recordings using a 5-point scale.Demographic, clinical and quality data were comparedto a similar group undergoing in-hospital video-EEG monitoring.
Twenty children aged 2.1-17.2 years (mean 9.57±1.01), 12 females (60%), underwent home video-EEG. A higher proportion of children with intellectual disability/autism were observed in the home-EEG group compared to the in-hospital group: 12 patients (60%) vs. 5 (25%) (p<0.05*, Fisher exact test). In the ambulatory group patients with developmental and epileptic encephalopathy were overrepresented (7 i.e., 35% vs. 0), while those withself-limited childhood epilepsy were more prevalent in the in-hospital group (5 i.e., 25% vs 0)(p<0.05*, Chi square). In the ambulatory group the reasons for referral were seizure localization/classification in 11 patients (55%), paroxysmal event classification in 5 (25%) and quantification of sleep epileptic activity in 4(20%),similar to the in-hospital group (40%, 40% and 20% respectively, p>0.05, Chi square). The quality of the EEG recording was higher compared to in-hospital tests: median 5 IQR 3.25-5 vs 4IQR 3-4 ( p<0.05*, Mann-Whitney U test) , while the quality of video recording was lower compared to in-hospital recordings: median 3IQR 2.25-4 vs 5IQR4-5 (p<0.01**, Mann-Whitney U test).
Home video-EEG monitoring is apromising option forlong-termpediatric EEG monitoring, particularlyfor children with special needs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
A complex motor disorder is a combination of various types of abnormal movements that are associated with impaired quality of life (QOL). Current therapeutic options are limited. We studied the ...efficacy, safety, and tolerability of medical cannabis in children with complex motor disorder. This pilot study was approved by the institutional ethics committee. Two products of cannabidiol (CBD) enriched 5% oil formulation of cannabis were compared: one with 0.25% δ-9-tetrahydrocannabinol (THC) 20:1 group, the other with 0.83% THC 6:1 group. Patients aged 1 to 17 years (n = 25) with complex motor disorder were enrolled. The assigned medication was administered for 5 months. Significant improvement in spasticity and dystonia, sleep difficulties, pain severity, and QOL was observed in the total study cohort, regardless of treatment assignment. Adverse effects were rare and included worsening of seizures in 2 patients, behavioral changes in 2 and somnolence in 1.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background:
Congenital mirror movements are involuntary movements of a side of the body imitating intentional movements on the opposite side, appearing in early childhood and persisting beyond 7 ...years of age. Congenital mirror movements are usually idiopathic but have been reported in association with various brain malformations.
Methods:
We describe clinical, genetic, and radiologic features in 9 individuals from 5 families manifesting congenital mirror movements.
Results:
The brain malformations associated with congenital mirror movements were: dysplastic corpus callosum in father and daughter with a heterozygous p.Met1* mutation in DCC; hypoplastic corpus callosum, dysgyria, and malformed vermis in a mother and son with a heterozygous p.Thr312Met mutation in TUBB3; dysplastic corpus callosum, dysgyria, abnormal vermis, and asymmetric ventricles in a father and 2 daughters with a heterozygous p.Arg121Trp mutation in TUBB; hypoplastic corpus callosum, dysgyria, malformed basal ganglia and abnormal vermis in a patient with a heterozygous p.Glu155Asp mutation in TUBA1A; hydrocephalus, hypoplastic corpus callosum, polymicrogyria, and cerebellar cysts in a patient with a homozygous p.Pro312Leu mutation in POMGNT1.
Conclusion:
DCC, TUBB3, TUBB, TUBA1A, POMGNT1 cause abnormal axonal guidance via different mechanisms and result in congenital mirror movements associated with brain malformations.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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