Although genetic revolution of recent years has vastly expanded a list of genes implicated in epilepsies, complex architecture of epilepsy genetics is still largely unknown, consequently, universally ...accepted workflows for epilepsy genetic testing in a clinical practice are missing. We present a comprehensive NGS‐based diagnostic approach addressing both the clinical and genetic heterogeneity of disorders involving epilepsy or seizures. A bioinformatic panel of 862 epilepsy‐ or seizure‐associated genes was applied to Mendeliome (4813 genes) or whole‐exome sequencing data as a first stage, while the second stage included untargeted variant interpretation. Eighty‐six consecutive patients with epilepsy or seizures associated with neurodevelopmental disorders and/or congenital malformations were investigated. Of the 86 probands, 42 harbored pathogenic and likely pathogenic variants, giving a diagnostic yield of 49%. Two patients were diagnosed with pathogenic copy number variations and 2 had causative mitochondrial DNA variants. Eleven patients (13%) were diagnosed with diseases with specific treatments. Besides, genomic approach in diagnostics had multiple additional benefits due to mostly non‐specific, overlapping, not full‐blown phenotypes and abilities to diagnose novel and ultra rare epilepsy‐associated diseases. Likely pathogenic variants were identified in SOX5 gene, not previously associated with epilepsy, and UBA5, a recently associated with epilepsy gene.
The Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations - Questionnaire (ESSENCE-Q) was developed as a brief screener to identify children with developmental concerns who ...might have neurodevelopmental disorders (NDDs). This study aimed to translate the ESSENCE-Q into south Slavic languages, namely, Bosnian, Bulgarian, Croatian, Macedonian, Montenegrin, Serbian, and Slovenian, and to evaluate its psychometric properties for screening purposes in clinical settings.
In the study, the ESSENCE-Q was completed for 251 "typically developing" children and 200 children with 1 or more diagnosed NDDs, all aged 1-6 years. Internal consistency and construct validity were tested first, followed by generating receiver operating characteristic curves and the area under the curve. Optimal cutoff values were then explored.
The Cronbach's α coefficients were 0.91, 0.88, and 0.86 for ESSENCE-Q parent-completed form, and the telephone and direct interview forms administered by trained nurse or specialist, respectively. The 3 versions produced area under the curve values (95% confidence interval): 0.96 (0.93-0.99), 0.91 (0.86-0.95), and 0.91 (0.86-0.97), respectively. An optimal cutoff for ESSENCE-Q parent-completed form was found to be ≥3 points, while for the telephone and direct interviews, it was ≥5 points.
We found adequate measurement properties of the south Slavic languages versions of the ESSENCE-Q as a screener for NDDs in clinical settings. This study provided additional data supporting sound psychometric properties of the ESSENCE-Q.
The aim of this study was to analyze the association of different clinical contributors of hypoxic-ischemic encephalopathy with NOS3 gene polymorphisms. A total of 110 children with hypoxic-ischemic ...encephalopathy and 128 control children were selected for this study. Association of gender, gestational age, birth weight, Apgar score, cranial ultrasonography, and magnetic resonance imaging findings with genotypic data of six haplotype-tagging single nucleotide polymorphisms and the most commonly investigated rs1800779 and rs2070744 polymorphisms was analyzed. The TGT haplotype of rs1800783, rs1800779, and rs2070744 polymorphisms was associated with hypoxic-ischemic encephalopathy. Children with the TGT haplotype were infants below 32 weeks of gestation and they had the most severe brain damage. Increased incidence of the TT genotype of the NOS3 rs1808593 SNP was found in the group of hypoxic-ischemic encephalopathy patients with medium and severe brain damage. The probability of brain damage was twice as high in children with the TT genotype than in children with the TG genotype of the same polymorphism. Furthermore, the T allele of the same polymorphism was twice as frequent in children with lower Apgar scores. This study strongly suggests associations of NOS3 gene polymorphism with intensity of brain damage and severity of the clinical picture in affected children.
Objective Severe myoclonic epilepsy (SMEI; Dravet's syndrome) is a severe form of epilepsy which begins in infancy. The first seizures in Dravet syndrome are often prolonged febrile seizures, the ...course of Dravet syndrome is variable from one child to another. This may delay diagnosis for many months and often years after the onset of seizures. Most children with Dravet syndrome have a mutation in a gene called SCN1A. Methods We present the clinical, laboratory and neuroimaging data of our three SMEI patients, and the importance of genetic diagnosis to treatment decisions. Results First patient has first afebrile atonic episode when she has two months old, then multiple seizure types appeared, sometimes occurring in a daily cluster in spite of various antiepileptic combinations. Extensive neurometabolic and genetic findings including SCN1A gene revealed no abnormalities but due clinical criteria for Dravet syndrome, stiripentol was started with significant improvement in seizures control and development. Second patient presented his first episode of febrile seizures at eight months of age. In following years status epilepticus occurred monthly. At the age of 4 years, a missense mutation was found of the SCN1A gene and treatment with stiripentol was started, seizures stop, and his development is almost normal, but with behavioral disturbances. Third patient has various types of seizures provoked by a febrile state, noise and emotional stimuli. At the age of 12 months DNA diagnostics identified an SCN1A mutation, and then, after various combinations of medications treatment with stiripentol was started. The number of seizures was reduced and developmental delay is minimal. Conclusion The importance is that children with Dravet syndrome can have a genetic diagnosis before the full syndrome has evolved. This will reduce unnecessary diagnostic procedures, enable initiation of appropriate treatment, and thus achieve a better control of seizures and reduce neurological disability.
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