From focal epilepsy to Dravet syndrome – Heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the Nav1.1 subunit

Objective The aim of this study was to analyze the intra-/interfamilial phenotypic heterogeneity due to variants at the highly evolutionary conservative p.Arg1596 residue in the Nav1.1 subunit. Materials/participants Among patients referred for analysis of the SCN1A gene one recurrent, heritable mutation was found in families enrolled into the study. Probands from those families even clinically diagnosed with atypical Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+), and focal epilepsy, had heterozygous p.Arg1596 His/Cys missense substitutions, c.4787G>T and c.4786C>T in the SCN1A gene. Method Full clinical evaluation, including cognitive development, neurological examination, EEGs, MRI was performed in probands and affected family members in developmental age. The whole SCN1A gene sequencing was performed for all probands. The exon 25, where the identified missense substitutions are localized, was directly analyzed for the other family members. Results Mutation of the SCN1A p.1596Arg was identified in three families, in one case substitution p.Arg1596Cys and in two cases p.Arg1596His. Both mutations were previously described as pathogenic and causative for DS, GEFS+ and focal epilepsy. Spectrum of phenotypes among presented families with p.Arg1596 mutations shows heterogeneity ranged from asymptomatic cases, through FS and FS+ to GEFS+/Panayiotopoulos syndrome and epilepsies with and without febrile seizures, and epileptic encephalopathy such as DS. Phenotypes differ among patients displaying both focal and generalized epilepsies. Some patients demonstrated additionally Asperger syndrome and ataxia. Conclusion Clinical picture heterogeneity of the patients carrying mutation of the same residue indicates the involvement of the other factors influencing the SCN1A gene mutations’ penetrance

Częstość występowania mutacji w genach PARK2, PINK1, PARK7 w grupie polskich pacjentów z chorobą Parkinsona o wczesnym początku

Background and purpose Parkinson disease (PD) is a complex disease, comprising genetic and environmental factors. Despite the vast majority of sporadic cases, three genes, i.e. PARK2, PINK1 and PARK7 (DJ-1), have been identified as responsible for the autosomal recessive form of early-onset Parkinson disease (EO-PD). Identified changes of these genes are homozygous or compound heterozygous mutations. The frequency of PARK2, PINK1 and PARK7 mutations is still under debate, as is the significance and pathogenicity of the single heterozygous mutations/variants, which are also detected among PD patients. The aim of the study was to analyze the incidence of autosomal recessive genes PARK2, PINK1, PARK7 mutations in Polish EO-PD patients. Material and methods The analysis of the PARK2, PINK1 and PARK7 genes was performed in a group of 150 Polish EO-PD patients (age of onset < 45 years). Mutation analysis was based on sequencing and gene dosage abnormality identification. Results Mutations were identified only in the PARK2 and PINK1 genes with the frequency of 4.7% and 2.7% of subjects, respectively. In PARK2, point mutations and exons' rearrangements, and in PINK1 only missense mutations were detected. In both genes mutations were found as compound heterozygous/homozygous and single heterozygous. EO-PD patients’ genotype-phenotype correlation revealed similarities of clinical features in mutation carriers and non-carriers. Conclusions The frequency of the PARK2, PINK1, PARK7 mutations among Polish EO-PD patients seems to be low. The role of single heterozygous mutations remains a matter of debate and needs further investigations.Wstęp i cel pracy Pomimo że wśród osób z chorobą Parkinsona (ChP) dominują przypadki sporadyczne, trzy geny: PARK2, PINK1 i PARK7, zostały scharakteryzowane jako odpowiedzialne za występowanie autosomalnie recesywnej postaci ChP o wczesnym początku. Mutacje w tych genach mogą mieć charakter zmian homozygotycznych lub heterozygotycznych złożonych, dotyczących obu alleli. U części pacjentów identyfikuje się tylko mutacje jednoalleliczne, a ich udział w patogenezie ChP pozostaje wciąż sprawą kontrowersyjną. Celem badania jest analiza częstości występowania i rodzaju mutacji w genach PARK2, PINK1 i PARK7 w polskiej populacji chorych na ChP o wczesnym początku. Material i metody Analizę występowania mutacji w genach PARK2, PINK1 i PARK7 przeprowadzono w grupie 150 polskich pacjentów z ChP o wczesnym początku (wiek w chwili wystąpienia objawów choroby < 45 lat). Badanie obejmowało analizę sekwencji kodujących wszystkich genów oraz identyfikację rearanżacji (delecje/duplikacje) w ich obrębie. W analizach mutacji wykorzystano bezpośrednie sekwencjonowanie genów oraz metodę MLPA (multiplex ligation-dependent probe amplification). Wyniki Mutacje zidentyfikowano tylko w genach PARK2 i PINK1 z częstością odpowiednio 4,7% i 2,7%. W genie PARK2 znaleziono mutacje punktowe oraz rearanżacje, natomiast w PINK1 tylko mutacje punktowe typu zmiany sensu. Zidentyfikowane mutacje występują zarówno jako heterozygotyczne złożone/homozygotyczne, jak i jednoalleliczne. Korelacja fenotypowo-genotypowa wśród pacjentów z ChP o wczesnym początku jest podobna zarówno dla nosicieli, jak i dla osób bez mutacji. Wnioski Częstość występowania mutacji w genach PARK2, PINK1 i PARK7 wśród polskich pacjentów z wczesną postacią ChP wydaje się mała. Rola pojedynczych heterozygotycznych mutacji w patogenezie ChP o wczesnym początku pozostaje sprawą dyskusyjną i w celu jej wyjaśnienia potrzebne są dalsze badania

Genetic Risk Factors for Neurological Disorders in Children with Adverse Events Following Immunization: A Descriptive Study of a Polish Case Series

Studies conducted on large populations show a lack of connection between vaccination and serious neurological symptoms. However, there are isolated cases that indicate such a relationship. These reports on adverse effects following immunization (AEFI) reduce social confidence in vaccination; however, their background may be rare genetic defects. The aim of the presented study was to examine if neurological AEFI in children may be associated with variants in genes related to neurodevelopment. To identify such possible associations, a descriptive study of the Polish case series was conducted. We performed next-generation sequencing in patients who, up to 4 weeks of injection of any vaccine, manifested neurological AEFI. We included 23 previously normally developing children with first seizures that occurred after vaccination. We identified pathogenic/likely pathogenic variants in genes engaged in neurodevelopment in nine patients and variants of uncertain significance in another nine patients. The mutated genes belonged to the group of genes related to epilepsy syndromes/epileptic encephalopathy. We showed that AEFI might have a genetic background. We hypothesized that in some AEFI patients, the vaccine might only trigger neurological symptoms that would have been manifested anyway as a result of a pathogenic variant in a gene engaged in neurodevelopment