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1.
Am J Med Genet A ; 191(3): 870-877, 2023 03.
Article in English | MEDLINE | ID: mdl-36548033

ABSTRACT

Chromosomal band 17q12 is a gene-rich region flanked by segmental duplications, making the region prone to deletions and duplications via the non-allelic homologous recombination mechanism. While deletions cause a well-described disorder with a specific phenotype called renal cysts and diabetes mellitus, the phenotype caused by reciprocal duplications is less specific, primarily because of variable expressivity, and incomplete penetrance. We present an unusual family with four children carrying the 17q12 microduplication inherited from their clinically healthy mother, who was a carrier of both the duplication and, interestingly, also of an atypical deletion of the 17q12 region. The duplication was inherited from her diabetic father and the deletion from her diabetic mother who also suffered from a renal disorder. Clinical manifestations in the family were variable, but all children showed some degree of a neurodevelopmental disorder, such as epilepsy, intellectual disability, delayed speech development, or attention deficit disorder. The simultaneous occurrence of a deletion and duplication in the same chromosomal region in one family is very rare, and to our knowledge, individuals carrying both a deletion and a duplication of this region have never been described.


Subject(s)
Abnormalities, Multiple , Intellectual Disability , Female , Humans , Chromosome Deletion , Czech Republic , Abnormalities, Multiple/genetics , Phenotype , Intellectual Disability/genetics , Chromosome Duplication/genetics
2.
Brain ; 145(9): 2991-3009, 2022 09 14.
Article in English | MEDLINE | ID: mdl-34431999

ABSTRACT

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.


Subject(s)
Epilepsy, Generalized , Epileptic Syndromes , Intellectual Disability , NAV1.6 Voltage-Gated Sodium Channel , Epilepsy, Generalized/drug therapy , Epilepsy, Generalized/genetics , Epileptic Syndromes/drug therapy , Epileptic Syndromes/genetics , Genetic Association Studies , Humans , Infant , Intellectual Disability/genetics , Mutation , NAV1.6 Voltage-Gated Sodium Channel/genetics , Prognosis , Seizures/drug therapy , Seizures/genetics , Sodium Channel Blockers/therapeutic use
3.
Am J Hum Genet ; 104(6): 1060-1072, 2019 06 06.
Article in English | MEDLINE | ID: mdl-31104773

ABSTRACT

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the µ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the µ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2µ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.


Subject(s)
Adaptor Protein Complex 2/genetics , Adaptor Protein Complex mu Subunits/genetics , Brain Diseases/etiology , Clathrin/metabolism , Endocytosis , Epilepsy/etiology , Mutation, Missense , Neurodevelopmental Disorders/etiology , Adolescent , Animals , Brain Diseases/pathology , Child , Child, Preschool , Clathrin/genetics , Epilepsy/pathology , Female , Humans , Infant , Mice , Mice, Knockout , Neurodevelopmental Disorders/pathology , Exome Sequencing
4.
Neuropediatrics ; 50(1): 57-60, 2019 02.
Article in English | MEDLINE | ID: mdl-30517966

ABSTRACT

INTRODUCTION: Neurodegenerative diseases of childhood present with progressive decline in cognitive, social, and motor function and are frequently associated with seizures in different stages of the disease. Here we report a patient with severe progressive neurodegeneration with drug-resistant epilepsy of unknown etiology from the age of 2 years. METHODS AND RESULTS: Using whole exome sequencing, we found heterozygous missense de novo variant c.628G > A (p.Glu210Lys) in the UBTF gene. This variant was recently described as de novo in 11 patients with similar neurodegeneration characterized by developmental decline initially confined to motor development followed by language regression, appearance of an extrapyramidal movement disorder, and leading to severe intellectual disability. In 3 of the 11 patients described so far, seizures were also present. CONCLUSIONS: Our report expands the complex phenotype of neurodegeneration associated with the c.628G > A variant in the UBTF gene and helps to clarify the relation between this one single recurrent pathogenic variant described in this gene to date and its phenotype. The UBTF gene should be considered a novel candidate gene in neurodegeneration with or without epilepsy.


Subject(s)
Drug Resistant Epilepsy/genetics , Mutation/genetics , Neurodegenerative Diseases/genetics , Phenotype , Pol1 Transcription Initiation Complex Proteins/genetics , Adolescent , Drug Resistant Epilepsy/complications , Drug Resistant Epilepsy/diagnostic imaging , Humans , Male , Neurodegenerative Diseases/complications , Neurodegenerative Diseases/diagnostic imaging
5.
J Med Genet ; 55(2): 104-113, 2018 02.
Article in English | MEDLINE | ID: mdl-29097605

ABSTRACT

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.


Subject(s)
DNA-Binding Proteins/genetics , Face/abnormalities , Intellectual Disability/genetics , Mutation , Transcription Factors/genetics , DNA-Binding Proteins/chemistry , Drosophila Proteins/chemistry , Drosophila Proteins/genetics , Eye Abnormalities/genetics , Female , Genetic Association Studies , Humans , Infant, Newborn , Muscle Hypotonia/etiology , Muscle Hypotonia/genetics , Pregnancy , Structural Homology, Protein , Syndrome , Transcription Factors/chemistry
6.
Neuropediatrics ; 49(3): 204-208, 2018 06.
Article in English | MEDLINE | ID: mdl-29444535

ABSTRACT

BACKGROUND: Recently, a study providing insight into GABRB3 mutational spectrum was published (Møller et al 2017). The authors report considerable pleiotropy even for single mutations and were not able to identify any genotype-phenotype correlations. METHODS: The proband (twin B) was referred for massively parallel sequencing of epilepsy-related gene panel because of hypotonia and neonatal seizures. The revealed variant was confirmed with Sanger sequencing in the proband and the twin A, and both parents were tested for the presence of the variant. RESULTS: We report a case of epilepsy of infancy with migrating focal seizures (EIMFS) of neonatal onset in monozygotic twins with a de novo novel GABRB3 variant p.Thr281Ala. The variant has a uniform presentation on an identical genomic background. In addition, early seizure-onset epilepsy associated with GABRB3 mutation has been until now described only for the p.Leu256Gln variant in the GABRB3 (Møller et al 2017, Myers et al 2016) located in the transmembrane domain just as the p.Thr281Ala variant described here. CONCLUSION: De novo GABRB3 mutations may cause neonatal-onset EIMFS with early-onset hypotonia, respiratory distress, and severe developmental delay.


Subject(s)
Diseases in Twins/genetics , Epilepsy/genetics , Mutation , Receptors, GABA-A/genetics , Twins, Monozygotic/genetics , Age of Onset , Diseases in Twins/drug therapy , Diseases in Twins/epidemiology , Epilepsy/drug therapy , Epilepsy/epidemiology , Female , Humans , Infant , Infant, Newborn
7.
BMC Med Genet ; 18(1): 62, 2017 06 02.
Article in English | MEDLINE | ID: mdl-28576131

ABSTRACT

BACKGROUND: Whole exome sequencing is a powerful tool for the analysis of genetically heterogeneous conditions. The prioritization of variants identified often focuses on nonsense, frameshift and canonical splice site mutations, and highly deleterious missense variants, although other defects can also play a role. The definition of the phenotype range and course of rare genetic conditions requires long-term clinical follow-up of patients. CASE PRESENTATION: We report an adult female patient with severe intellectual disability, severe speech delay, epilepsy, autistic features, aggressiveness, sleep problems, broad-based clumsy gait and constipation. Whole exome sequencing identified a de novo mutation in the SYNGAP1 gene. The variant was located in the broader splice donor region of intron 10 and replaced G by A at position +5 of the splice site. The variant was predicted in silico and shown experimentally to abolish the regular splice site and to activate a cryptic donor site within exon 10, causing frameshift and premature termination. The overall clinical picture of the patient corresponded well with the characteristic SYNGAP1-associated phenotype observed in previously reported patients. However, our patient was 31 years old which contrasted with most other published SYNGAP1 cases who were much younger. Our patient had a significant growth delay and microcephaly. Both features normalised later, although the head circumference stayed only slightly above the lower limit of the norm. The patient had a delayed puberty. Her cognitive and language performance remained at the level of a one-year-old child even in adulthood and showed a slow decline. Myopathic facial features and facial dysmorphism became more pronounced with age. Although the gait of the patient was unsteady in childhood, more severe gait problems developed in her teens. While the seizures remained well-controlled, her aggressive behaviour worsened with age and required extensive medication. CONCLUSIONS: The finding in our patient underscores the notion that the interpretation of variants identified using whole exome sequencing should focus not only on variants in the canonical splice dinucleotides GT and AG, but also on broader splice regions. The long-term clinical follow-up of our patient contributes to the knowledge of the developmental trajectory in individuals with SYNGAP1 gene defects.


Subject(s)
Intellectual Disability/genetics , ras GTPase-Activating Proteins/genetics , Adult , Base Sequence , Exome , Female , Follow-Up Studies , Genetic Variation , Genomics , Humans , Intellectual Disability/diagnosis , Karyotyping , Microarray Analysis , Microcephaly/diagnosis , Microcephaly/genetics , Mutation , Phenotype , Sequence Analysis, DNA
9.
Eur J Paediatr Neurol ; 48: 17-29, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38008000

ABSTRACT

OBJECTIVE: Developmental and epileptic encephalopathies (DEEs) are a group of severe, early-onset epilepsies characterised by refractory seizures, developmental delay, or regression and generally poor prognosis. DEE are now known to have an identifiable molecular genetic basis and are usually examined using a gene panel. However, for many patients, the genetic cause has still not been identified. The aims of this study were to identify causal variants for DEE in patients for whom the previous examination with a gene panel did not determine their genetic diagnosis. It also aims for a detailed description and broadening of the phenotypic spectrum of several rare DEEs. METHODS: In the last five years (2015-2020), 141 patients from all over the Czech Republic were referred to our department for genetic testing in association with their diagnosis of epilepsy. All patients underwent custom-designed gene panel testing prior to enrolment into the study, and their results were inconclusive. We opted for whole exome sequencing (WES) to identify the cause of their disorder. If a causal or potentially causal variant was identified, we performed a detailed clinical evaluation and phenotype-genotype correlation study to better describe the specific rare subtypes. RESULTS: Explanatory causative variants were detected in 20 patients (14%), likely pathogenic variants that explain the epilepsy in 5 patients (3.5%) and likely pathogenic variants that do not fully explain the epilepsy in 11 patients (7.5%), and variants in candidate genes in 4 patients (3%). Variants were mostly de novo 29/40 (72.5%). SIGNIFICANCE: WES enables us to identify the cause of the disease in additional patients, even after gene panel testing. It is very important to perform a WES in DEE patients as soon as possible, since it will spare the patients and their families many years of a diagnostic odyssey. In particular, patients with rare epilepsies might significantly benefit from this approach, and we propose using WES as a new standard in the diagnosis of DEE instead of targeted gene panel testing.


Subject(s)
Epilepsy, Generalized , Epilepsy , Humans , Exome Sequencing , Epilepsy/diagnosis , Epilepsy/genetics , Epilepsy, Generalized/genetics , Genetic Testing , Genetic Association Studies , Phenotype
10.
Ital J Pediatr ; 49(1): 11, 2023 Jan 19.
Article in English | MEDLINE | ID: mdl-36658659

ABSTRACT

BACKGROUND: Schimke immunoosseous dysplasia (SIOD) is an ultra-rare inherited disease affecting many organ systems. Spondyloepiphyseal dysplasia, T-cell immunodeficiency and steroid resistant nephrotic syndrome are the main symptoms of this disease. CASE PRESENTATION: We aimed to characterize the clinical, pathological and genetic features of SIOD patients received at tertiary Pediatric Nephrology Center, University Hospital Motol, Prague, Czech Republic during the period 2001-2021. The mean age at diagnosis was 21 months (range 18-48 months). All patients presented with growth failure, nephropathy and immunodeficiency. Infections and neurologic complications were present in most of the affected children during the course of the disease. CONCLUSIONS: Although SIOD is a disease characterized by specific features, the individual phenotype may differ. Neurologic signs can severely affect the quality of life; the view on the management of SIOD is not uniform. Currently, new therapeutic methods are required.


Subject(s)
Immunologic Deficiency Syndromes , Nephrotic Syndrome , Osteochondrodysplasias , Humans , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/genetics , Nephrotic Syndrome/complications , Osteochondrodysplasias/diagnosis , Osteochondrodysplasias/genetics , Osteochondrodysplasias/therapy , Tertiary Care Centers , Czech Republic , Quality of Life , Rare Diseases , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/complications
11.
Brain Commun ; 5(6): fcad283, 2023.
Article in English | MEDLINE | ID: mdl-38425576

ABSTRACT

Voltage-gated sodium channel ß1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding ß1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C>T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b-/- mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C>T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in Scn1b-/- mice. ß1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, ß1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of ß1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b-/- mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C>T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared with Scn1b-/- mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.

12.
Res Sq ; 2023 Sep 29.
Article in English | MEDLINE | ID: mdl-37841849

ABSTRACT

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

13.
Neurology ; 100(6): e603-e615, 2023 02 07.
Article in English | MEDLINE | ID: mdl-36307226

ABSTRACT

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.


Subject(s)
Epilepsy, Generalized , Epilepsy , Ether-A-Go-Go Potassium Channels , Child , Humans , Infant, Newborn , Epilepsy/genetics , Epilepsy, Generalized/genetics , Mutation , Phenotype , Seizures/genetics , Ether-A-Go-Go Potassium Channels/genetics
14.
Eur J Med Genet ; 64(9): 104263, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34174466

ABSTRACT

INTRODUCTION: Biallelic variants in the SLC1A4 gene have been so far identified as a very rare cause of neurodevelopmental disorders with or without epilepsy and almost exclusively described in the Ashkenazi-Jewish population. PATIENTS AND METHODS: Here we present Czech patient with microcephaly, severe global developmental delay and intractable seizures whose condition remained undiagnosed despite access to clinical experience and standard diagnostic methods including examination with an epilepsy targeted NGS gene panel. RESULTS: Whole exome sequencing revealed a novel variant NM_003038.4:c.1370G > A p.(Arg457Gln) of the SLC1A4 gene in a homozygous state in the patient, and afterwards Sanger sequencing in both parents confirmed the biallelic origin of the variant. A variant in the same codon, but with a different amino acid exchange, was described previously in a patient that had a very similar phenotype, however, without epilepsy. CONCLUSION: Our data suggest that the SLC1A4 gene should be considered in the diagnosis of patients with severe, early onset neurodevelopmental impairment with epilepsy and encourage the analysis of SLC1A4 gene variants via targeted NGS gene panel or whole exome sequencing.


Subject(s)
Amino Acid Transport System ASC/genetics , Microcephaly/genetics , Neurodevelopmental Disorders/genetics , Seizures/genetics , Child , Homozygote , Humans , Male , Microcephaly/pathology , Mutation , Neurodevelopmental Disorders/pathology , Seizures/pathology
15.
Eur J Paediatr Neurol ; 28: 81-88, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32811771

ABSTRACT

BACKGROUND: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism. MATERIAL AND METHODS: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients. RESULTS: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal. CONCLUSION: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.


Subject(s)
Carrier Proteins/genetics , Iron Metabolism Disorders/genetics , Iron Metabolism Disorders/metabolism , Iron/blood , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Biomarkers/blood , Child , Epilepsy/blood , Epilepsy/genetics , Epilepsy/metabolism , Female , Humans , Intellectual Disability/blood , Intellectual Disability/genetics , Intellectual Disability/metabolism , Iron Metabolism Disorders/blood , Male , Movement Disorders/blood , Movement Disorders/genetics , Movement Disorders/metabolism , Neurodegenerative Diseases/blood , Phenotype
16.
Epilepsy Res ; 156: 106181, 2019 10.
Article in English | MEDLINE | ID: mdl-31394400

ABSTRACT

Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.


Subject(s)
Kinesins/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Shab Potassium Channels/genetics , Spasms, Infantile/genetics , Child, Preschool , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Humans , Infant , Monosaccharide Transport Proteins/genetics , Mutation/genetics , Repressor Proteins/genetics , Spasms, Infantile/diagnosis
17.
Neuro Endocrinol Lett ; 29(4): 512-7, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18766147

ABSTRACT

OBJECTIVES: Autism is a severe neurodevelopmental disorder with a high rate of epilepsy and subclinical epileptiform activity. High physical connectivity on a microcolumnar level leading to epileptiform activity and low functional informational connectivity are assumed in autism. The aim of this study was to investigate nonlinear EEG brain dynamics in terms of synchronization in a group of children with autism spectrum disorders compared to a control group. We expected a lower degree of synchronization in autistic subjects. METHODS: The autistic group consisted of 27 patients with autism spectrum disorders diagnosed according to ICD-10. The mean age of the sample was 7.1 (SD 3.6) years, 14 of them were mentally retarded. Normal EEG was found in 9 patients, epileptiform EEG in 18 autistic patients. Four patients had a history of epileptic seizures, fully compensated in long term. The control group consisted of 20 children (mean age of 8.4, SD 2.3 years) with normal intelligence, without an epileptic history, investigated within the frame of the research program for cochlear implantation. They had normal neurological examination and suffered from perceptive deafness. Normal EEG was found in 17 of the control subjects, epileptiform EEG was in 3 control subjects. We analyzed night sleep EEG recordings from 10 channels (F3, F4, F7, F8, C3, C4, T3, T4, P3 and P4) with the inclusion of sleep stages NREM 2, 3 and 4 in the subsequent analyses. Coarse-grained entropy information rates between neighbouring electrodes were computed, expressing the synchronization between 11 selected electrode couples. RESULTS: Synchronization was significantly lower in the autistic group in all three examined NREM stages even when age and intelligence were taken into account as covariates. CONCLUSIONS: The results of the study confirmed the validity of the underconnectivity model in autism.


Subject(s)
Autistic Disorder/physiopathology , Electroencephalography , Sleep/physiology , Child , Child, Preschool , Humans , Intellectual Disability/physiopathology , Polysomnography
18.
Orphanet J Rare Dis ; 13(1): 71, 2018 05 02.
Article in English | MEDLINE | ID: mdl-29720203

ABSTRACT

BACKGROUND: Epilepsy is a heterogeneous disease with a broad phenotypic spectrum and diverse genotypes. A significant proportion of epilepsies has a genetic aetiology. In our study, a custom designed gene panel with 112 genes known to be associated with epilepsies was used. In total, one hundred and fifty-one patients were tested (86 males / 65 females). RESULTS: In our cohort, the highest probability for the identification of the cause of the disease was for patients with a seizure onset within the first four weeks of life (61.9% clarification rate) - about two times more than other groups. The level of statistical significance was determined using a chi-square analysis. From 112 genes included in the panel, suspicious and rare variants were found in 53 genes (47.3%). Among the 151 probands included in the study we identified pathogenic variants in 39 patients (25.8%), likely pathogenic variants in three patients (2%), variants of uncertain significance in 40 patients (26.5%) and likely benign variants in 69 patients (45.7%). CONCLUSION: Our report shows the utility of diagnostic genetic testing of severe childhood epilepsies in a large cohort of patients with a diagnostic rate of 25.8%. A gene panel can be considered as a method of choice for the detection of pathogenic variants within patients with unknown origin of early onset severe epilepsy.


Subject(s)
Epilepsy/genetics , Seizures/genetics , Chi-Square Distribution , Child , Child, Preschool , Female , Genetic Predisposition to Disease/genetics , Humans , Infant , Male , Mutation , Spasms, Infantile/genetics
19.
Epileptic Disord ; 9 Suppl 1: S28-35, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18319198

ABSTRACT

We present results of analysis of overnight sleep video-EEG in 8 patients with developmental dysphasia and rolandic discharges. We evaluated the incidence of epileptiform discharges (expressed as paroxysmal activity density) at one or more electrodes in different sleep stages in three different periods of the night (after falling asleep, around midnight and before awakening). The difference of paroxysmal activity density was never higher than 21%, indicating that quantifying the discharges in the whole night recording is not necessary. We also showed that two independent foci may differ in the frequency of discharges. We propose a scheme for evaluation of EEG reflecting both frequency and distribution of discharges.


Subject(s)
Circadian Rhythm , Electroencephalography , Epilepsy/complications , Language Development Disorders/complications , Videotape Recording , Child , Child, Preschool , Epilepsy/diagnosis , Epilepsy/physiopathology , Functional Laterality/physiology , Humans , Language Development Disorders/diagnosis , Male , Severity of Illness Index
20.
Genet Test Mol Biomarkers ; 21(10): 613-618, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28872899

ABSTRACT

BACKGROUND: Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact. METHODS: Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed. Sanger sequencing was used to confirm the novel variants. For confirmation of the functional consequence of an intronic CDKL5 variant in patient 2, an RNA study was done. RESULTS: DNA sequencing revealed de novo variants in CDKL5, a c.2578C>T (p. Gln860*) present in a hemizygous state in a 3-year-old boy, and a potential splice site variant c.463+5G>A in heterozygous state in a 5-year-old girl. Multiple in silico splicing algorithms predicted a highly reduced splice site score for c.463+5G>A. A subsequent mRNA study confirmed an aberrant shorter transcript lacking exon 7. CONCLUSIONS: Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing.


Subject(s)
Protein Serine-Threonine Kinases/genetics , Rett Syndrome/genetics , Spasms, Infantile/genetics , Child, Preschool , Epilepsy/genetics , Epileptic Syndromes , Exons , Female , Genetic Variation/genetics , High-Throughput Nucleotide Sequencing , Humans , Male , Mutation , Protein Serine-Threonine Kinases/metabolism
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