Genotype-phenotype correlations in Polish patients with SCN8A-related epilepsy: A multicentre observational study.

BACKGROUND: Voltage-gated sodium channels are involved in the initial depolarisation of neurones. As such, they play important roles in neurotransmission. Variants in the genes encoding these channels may lead to altered functionality and neurodevelopmental disorders. Pathogenic variants of SCN8A, which encodes the voltage-gated Na+ channel Nav1.6, have been associated with various encephalopathies characterised by developmental delay and epileptic seizures. Herein, we discuss the genotype-phenotype associations in a group of 17 novel Polish patients with SCN8A mutations, further expanding the molecular and phenotypic spectrum of SCN8A-related diseases. METHODS: The participants were recruited from five clinical centres in Poland. Pathogenic and likely pathogenic SCN8A variants were identified using a next-generation sequencing (NGS) panel and exome sequencing, respectively. Magnetic resonance imaging (MRI) and electroencephalography (EEG) recordings were performed to obtain relevant clinical data on brain malformations and epileptic seizures. RESULTS: Three phenotypes were observed in the study group: developmental and epileptic encephalopathy, early onset epileptic encephalopathy, and neurodevelopmental disorders without epilepsy. Patients in the first two phenotypic subgroups presented with epileptic seizures within the first few months of life. Their semiology evolved with age, comprising mostly tonic, clonic, and tonic-clonic seizures, with eyelid myoclonia, myoclonic seizures, and epileptic spasms. The most prevalent neurological feature was developmental delay. Alterations in muscle tone were more frequent than in previous reports. CONCLUSIONS: Seventeen patients with 11 novel mutations in SCN8A had alterations in muscular tone accompanied by typical features of SCN8A-related encephalopathies (i.e., developmental delay and a wide range of seizures).

Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.

Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in -10-20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

[The evaluation of natural anticoagulants in systemic lupus erythematosus in children]. / Ocena naturalnych inhibitorów ukladu krzepniecia w toczniu rumieniowatym ukladowym u dzieci.

Thromboembolic complications in adults with systemic lupus erythematosus (SLE) are described in literature. We intended to investigate the activity of natural anticoagulants, such as C protein. S protein and antithrombin III (AT III) in children with SLE to obtain data concerning activity of the disease and thrombotic complications. The study population consisted of 36 children with SLE and of 51 healthy children serving as a control group. The results showed a significant decrease of S protein activity, with particularly low levels in the group of patients with the presence of anticardiolipin antibodies (aCL), and decrease of C protein activity in patients with higher activity of the disease. They appear to prove the involvement of these inhibitors in inflammation and, on the other hand, the activation of intravascular coagulation, a risk factor of thrombosis.

[The influence of Sudden Infant Death Syndrome (SIDS) risk factors on health, growth and development in the first year of life. A preliminary report]. / Wplyw zachowan zdrowotnych i praktyk pielegnacyjnych uwazanych za czynniki ryzyka zespolu naglej smierci niemowlat (Sudden Infant Death Syndrome -- SIDS) na rozwój i zachorowalnosc dzieci w pierwszym roku zycia. Obserwacje wstepne.

AIM: To establish the occurrence of SIDS risk factors (including 'removable' ones) and the incidence of the ecg long QT interval (accepted as a risk factor) and their influence upon infants development and morbidity. MATERIAL AND METHODS: A group of 98 infants from normal birth at term to the end of first year of life was observed. The data sources were as follows: 1) a questionnaire filled by mothers before discharge front maternity ward, 2) records of four consecutive medical examinations (including ecg records) performed on 3rd day and 3rd, 6th and 12th month of life. Chi-Square test and Fisher test were used. RESULTS: The most often identified risk factors were: prone sleeping position of infant (60.2%), environmental and maternal tobacco smoking (40.8%) and bed sharing practices (32.6%). A significant but transient signs of delay in psychomotor development (in motor zone) as well as more frequent respiratory tract infections in infants sleeping prone were noted. There were no deaths in the observed group neither cases of long QT interval. CONCLUSIONS: 1) the most frequently occurring SIDS risk factors are: environmental tobacco smoking, infant prone sleeping and bed sharing, 2) these inappropriate nursing practices and improper habits of adult family members known as a 'removable' SIDS risk factors have a bad effect on infant health and development, 3) identification of SIDS risk factors in an infant does not predict crib death.