Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

How Has the Treatment of Polish Children with Dravet Syndrome Changed? Future Perspectives.

BACKGROUND: This report focuses on the treatment histories of 21 patients diagnosed with Dravet syndrome (DRVT) under the care of the Mother and Child Institute in Warsaw. This paper aims to present typical treatment schemes for patients with drug-resistant epilepsy, as well as to highlight the influence of genetic diagnosis on pharmacotherapeutic management and to present an economic analysis of hospitalization costs. This paper will also summarize the effectiveness of the latest drugs used in DRVT. METHODS: Clinical data were collected retrospectively from available medical records. The effectiveness of anticonvulsant treatment was assessed based on epileptic seizure diaries and observations by caregivers and pediatric neurologists. RESULTS: The study group (n = 21) consisted of patients aged 3-26 years. Orphan drugs dedicated to Dravet syndrome were introduced in all patients due to the genetic diagnosis, which significantly improved the patients' clinical conditions. The breakthrough drugs were stiripentol (in 16/21) and fenfluramine (in 3/21). CONCLUSIONS: In recent years, molecular genetics has rapidly developed in Poland, along with a steady increase in knowledge of Dravet syndrome among the medical profession. Early and precise diagnosis provides the opportunity to target treatment with drugs dedicated to Dravet syndrome with high efficacy.

SCN1A-Characterization of the Gene's Variants in the Polish Cohort of Patients with Dravet Syndrome: One Center Experience.

The aim of this study was to characterize the genotype and phenotype heterogeneity of patients with SCN1A gene mutations in the Polish population, fulfilling the criteria for the diagnosis of Dravet syndrome (DRVT). Particularly important was the analysis of the clinical course, the type of epileptic seizures and the co-occurrence of additional features such as intellectual disability, autism or neurological symptoms such as ataxia or gait disturbances. Based on their results and the available literature, the authors discuss potential predictors for DRVT. Identifying these early symptoms has important clinical significance, affecting the course and disease prognosis. 50 patients of the Pediatric Neurology Clinic of the Institute of Mother and Child in Warsaw clinically diagnosed with DRVT and carriers of SCN1A pathogenic variants were included. Clinical data were retrospectively collected from caregivers and available medical records. Patients in the study group did not differ significantly in parameters such as type of first seizure and typical epileptic seizures from those described in other studies. The age of onset of the first epileptic seizure was 2-9 months. The co-occurrence of intellectual disability was confirmed in 71% of patients and autism in 18%. The study did not show a correlation between genotype and phenotype, considering the severity of the disease course, clinical symptoms, response to treatment, the presence of intellectual disability, autism symptoms or ataxia. From the clinical course, a significant problem was the differentiation between complex febrile convulsions and symptoms of DRVT. The authors suggest that parameters such as the age of the first seizure, less than one year of age, the onset of a seizure up to 72 h after vaccination and the presence of more than two features of complex febrile seizures are more typical of DRVT, which should translate into adequate diagnostic and clinical management. The substantial decrease in the age of genetic verification of the diagnosis, as well as the decline in the use of sodium channel inhibitors, underscores the growing attention of pediatric neurologists in Poland to the diagnosis of DRVT.

Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes.

Mutations of the SCN1A gene, which encodes the voltage-dependent Na+ channel's α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes' variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.

ADCY5-related dyskinesia - case series with literature review.

INTRODUCTION: ADCY5-related dyskinesia is a rare neurological disease caused by mutations in the gene encoding the adenylyl cyclase 5 (ADCY5) isoform, a protein that plays an important role in intracellular transmission. Variants in ADCY5 are associated with a spectrum of neurological disease encompassing dyskinesia, chorea, and dystonia. State of the-art. ADCY5 mutations result in clinically heterogeneous manifestations which comprise a range of core and less to highly variable symptoms. Due to the heterogeneous nature and difficulty in diagnosis of the disorder, available treatments are highly limited. CLINICAL IMPLICATIONS: ADCY5-related dyskinesia was reported in 52 individuals in the literature over a five-year period (January 2017 to January 2022). We have listed all the symptoms and their frequency. The most common symptom reported in these patients was dystonia. Over 50% of patients developed dyskinesia and chorea. We report two cases of familial occurrence of symptomatic ADCY5-related dyskinesia. A 45-year-old patient presented with involuntary movements which had been occurring since childhood. The proband's neurological examination revealed dysarthria, involuntary myoclonic twitches, and choreic movements. The patient's 9-year-old son had developed involuntary movements, mainly chorea and dystonia. FUTURE DIRECTIONS: This paper aims to summarise the recent literature on ADCY5-related neurological disorders and to present a new case of a Polish family with ADCY5 mutation. Genetic diagnostics are important in the context of possible future targeted treatments.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

The Generation of Human iPSC Lines from Three Individuals with Dravet Syndrome and Characterization of Neural Differentiation Markers in iPSC-Derived Ventral Forebrain Organoid Model.

Dravet syndrome (DRVT) is a rare form of neurodevelopmental disorder with a high risk of sudden unexpected death in epilepsy (SUDEP), caused mainly (>80% cases) by mutations in the SCN1A gene, coding the Nav1.1 protein (alfa-subunit of voltage-sensitive sodium channel). Mutations in SCN1A are linked to heterogenous epileptic phenotypes of various types, severity, and patient prognosis. Here we generated iPSC lines from fibroblasts obtained from three individuals affected with DRVT carrying distinct mutations in the SCN1A gene (nonsense mutation p.Ser1516*, missense mutation p.Arg1596His, and splicing mutation c.2589+2dupT). The iPSC lines, generated with the non-integrative approach, retained the distinct SCN1A gene mutation of the donor fibroblasts and were characterized by confirming the expression of the pluripotency markers, the three-germ layer differentiation potential, the absence of exogenous vector expression, and a normal karyotype. The generated iPSC lines were used to establish ventral forebrain organoids, the most affected type of neurons in the pathology of DRVT. The DRVT organoid model will provide an additional resource for deciphering the pathology behind Nav1.1 haploinsufficiency and drug screening to remediate the functional deficits associated with the disease.

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.

Review of the epidemiology and variability of LRRK2 non-p.Gly2019Ser pathogenic mutations in Parkinson's disease.

Parkinson's disease (PD) is a heterogenous neurodegenerative disorder. Genetic factors play a significant role, especially in early onset and familial cases. Mutations are usually found in the LRRK2 gene, but their importance varies. Some mutations, such as p.Arg1441Cys or other alterations in the 1441 codon, show clear correlation with PD, whereas others are risk factors found also in healthy populations or have neglectable consequences. They also exhibit various prevalence among different populations. The aim of this paper is to sum up the current knowledge regarding the epidemiology and pathogenicity of LRRK2 mutations, other than the well-established p.Gly2019Ser. We performed a review of the literature using PubMed database. 103 publications met our inclusion criteria. p.Arg1441Cys, p.Arg1441Gly, p.Arg1441His, p.Arg1441Ser are the most common pathogenic mutations in European populations, especially Hispanic. p.Asn1437His is pathogenic and occurs mostly in the Scandinavians. p.Asn1437Ser and p.Asn1437Asp have been reported in German and Chinese cohorts respectively. p.Ile2020Thr is a rare pathogenic mutation described only in a Japanese cohort. p.Met1869Thr has only been reported in Caucasians. p.Tyr1699Cys, p.Ile1122Val have only been found in one family each. p.Glu1874Ter has been described in just one patient. We found no references concerning mutation p.Gln416Ter. We also report the first case of a Polish PD family whose members carried p.Asn1437His.

Concise Review: Stem Cell Models of SCN1A-Related Encephalopathies-Current Perspective and Future Therapies.

Mutations in the SCN1A gene can cause a variety of phenotypes, ranging from mild forms, such as febrile seizures and generalized epilepsy with febrile seizures plus, to severe, such as Dravet and non-Dravet developmental epileptic encephalopathies. Until now, more than two thousand pathogenic variants of the SCN1A gene have been identified and different pathogenic mechanisms (loss vs. gain of function) described, but the precise molecular mechanisms responsible for the deficits exhibited by patients are not fully elucidated. Additionally, the phenotypic variability proves the involvement of other genetic factors in its final expression. This is the reason why animal models and cell line models used to explore the molecular pathology of SCN1A-related disorders are only of limited use. The results of studies based on such models cannot be directly translated to affected individuals because they do not address each patient's unique genetic background. The generation of functional neurons and glia for patient-derived iPSCs, together with the generation of isogenic controls using CRISPR/Cas technology, and finally, the 3D brain organoid models, seem to be a good way to solve this problem. Here, we review SCN1A-related encephalopathies, as well as the stem cell models used to explore their molecular basis.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

PLA2G6-associated neurodegeneration in four different populations-case series and literature review.

BACKGROUND: PLA2G6-Associated Neurodegeneration, PLAN, is subdivided into: Infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and adult-onset dystonia parkinsonism [1]. It is elicited by a biallelic pathogenic variant in phospholipase A2 group VI (PLA2G6) gene. In this study we describe new cases and provide a comprehensive review of previously published cases. METHODS: Eleven patients, from four different institutions and four different countries. All underwent a comprehensive chart review. RESULTS: Ages at onset ranged from 1 to 36 years, with a median of 16 and a mean of 16.18 ± 11.91 years. Phenotypic characteristics were heterogenous and resembled that of patients with infantile neuroaxonal dystrophy (n = 2), atypical neuroaxonal dystrophy (n = 1), adult-onset dystonia parkinsonism (n = 1), complex hereditary spastic paraparesis (n = 3), and early onset Parkinson's disease (n = 2). Parental genetic studies were performed for all patients and confirmed with sanger sequencing in five. Visual evoked potential illustrated optic atrophy in P4. Mineralization was evident in brain magnetic resonance imaging of P1, P2, P4, P5, P7, and P11. Single photon emission computed tomography was conducted for three patients, revealed decreased perfusion in the occipital lobes for P10. DaTscan was performed for P11 and showed decreased uptake in the deep gray matter, bilateral caudate nuclei, and bilateral putamen. Positive response to Apomorphine was noted for P10 and to Baclofen in P2, and P3. CONCLUSIONS: PLAN encompasses a wide clinical spectrum. Age and symptom at onset are crucial when classifying patients. Reporting new variants is critical to draw more attention to this condition and identify biomarkers to arrive at potential therapeutics.

Pediatric CIDP: Diagnosis and Management. A Single-Center Experience.

Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare acquired polyneuropathy that especially among youngest children should be differentiated with hereditary neuropathies. Even though upon diagnosis treatment options are similar in children and adults, diagnostic challenges are faced in the pediatric population. Methods: We conducted a retrospective analysis of clinical symptoms, nerve conduction study results, modes of treatment, and final outcome in 37 children aged 3.5-17 years with a final diagnosis of CIDP (18 girls, 19 boys). We established three groups of patients based on age at onset of CIDP: 0-4, 4-13, and 13-18 years. Follow-up ranged from 10 to 222 months. Results: In our analysis, 19/37 patients (51.4%) had an atypical presentation: distal variant of CIDP in 12/37 patients (32.4%) and pure motor variant of CIDP in 5/37 patients (13.5%), and one patient had a pure sensory variant (1/37, 2.7%). Furthermore, 3/37 patients (8.1%) had additional concurring symptoms, including involuntary movements of face muscles (1/37, 2.7%) or hand tremor (2/37, 5.4%). During the follow-up, 23/37 patients (62.2%) received intravenous immunoglobulin (IVIg); 22/37 patients (59.5%) received steroids, 6/37 patients (16.2%) received IVIg and steroids, and 12/37 patients (32.4%) received immunosuppressive drugs, mostly azathioprine, but also methotrexate and rituximab. One patient was treated with plasmapheresis. Complete remission was achieved in 19/37 patients (51.4%) with CIDP in its typical form. Remission with residual symptoms or minimal deficit was observed in 4/37 patients (10.8%), whereas 14/37 patients (37.8%) remain on treatment with gradual improvement. Conclusion: Childhood CIDP may occur in its typical form, but even ~50% of children can present as an atypical variant including distal, pure motor, or pure sensory. Most children have a good prognosis; however, many of them may require long-term treatment. This highlights the importance of an early diagnosis and treatment for childhood CIDP.

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

Genetics of Parkinson's disease in the Polish population.

INTRODUCTION: Genetic forms of Parkinson's disease (PD) often cluster in different ethnic groups and may present with recognisable unique clinical manifestations. Our aim was to summarise the current state of knowledge regarding the genetic causes of PD and describe the first Polish patient with SNCA duplication. METHODOLOGY: We searched the electronic database, PubMed, for studies between January 1995 and June 2020 that evaluated genetics in Polish patients with PD, using the search terms 'Parkinson's disease, 'Polish', 'genetics', 'mutations', and 'variants'. RESULTS: In total, 73 publications were included in the review; 11 genes responsible for monogenic forms and 19 risk factor genes have been analysed in the Polish population. Pathogenic variants were reported in four monogenic genes (LRRK2, PRKN, PINK1, and SNCA). Eight genes were associated with PD risk in the Polish population (GBA, TFAM, NFE2L2, MMP12, HLA-DRA, COMT, MAOB, and DBH). Multiplex ligation-dependent probe amplification and Sanger sequencing in PRKN, PINK1, DJ1, LRRK2, and SNCA revealed SNCA duplication in a 43-year-old Polish patient with PD examined by movement disorder specialists. CONCLUSION: Only a limited number of positive results have been reported in genes previously associated with PD in the Polish population. In the era of personalised medicine, it is important to report on genetic findings in specific populations.

Frequency of spinocerebellar ataxia mutations in patients with multiple system atrophy.

PURPOSE: Investigate single nucleotide variants and short tandem repeats in 39 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy. METHODS: Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia-related genes. Novel variants were validated in two independent disease cohorts: 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients, and CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls. RESULTS: No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR = 4.11, P = 0.21). There was a significant association between the occurrence of a repeat length of longer alleles (> 38 repeats) and an increased risk of multiple system atrophy (OR = 1.64, P = 0.03). CONCLUSION: Occurrence of TBP CAG/CAA repeat length of longer alleles (> 38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.

Corrigendum: Pediatric CIDP: Diagnosis and Management. A Single-Center Experience.

[This corrects the article DOI: 10.3389/fneur.2021.667378.].

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.

Variety of symptoms of GLUT1 deficiency syndrome in three-generation family.

OBJECTIVE: Glucose transporter type 1 deficiency (G1D) syndrome is generally a genetic disorder because of a mutation of the SLC2A1 gene. The clinical picture of G1D is heterogeneous. The aim of this paper was to present the case of G1D, recognized in a three-generation family, caused by missense mutation p.Arg92Trp in SLC2A1 gene, and showing high clinical heterogeneity and evolution of symptoms over time. METHODS: Three-generation family members, showing symptoms suggesting G1D, have been characterized in terms of the clinical picture, electroencephalogram (EEG) recordings, brain neuroimaging, and the psychological assessment data. All subjects were offered genetic testing of the SLC2A1 gene. RESULTS: We sequenced the SLC2A1 gene in the proband of the family and identified the c.274C > T variant (p.Arg92Trp). The presence of the same mutation was confirmed in all affected family members; however, significant variations in the clinical picture among them were observed. In addition to the typical symptoms for G1D (e.g., epilepsy, intellectual disability), patients presented movement disorders, stiffness, and dysarthria, as well as psychiatric symptoms. After using the ketogenic diet, epileptic seizures disappeared, but the rest of the symptoms were resistant to treatment. CONCLUSIONS: Despite the same underlying mutation, clinical symptoms may vary among members of one family. Different clinical symptoms are observed depending on the patient's age. Not all symptoms occur in all patients within one family despite the same genetic background. However, the importance of early therapy for the clinical course of the disease requires further study.

The matter of significance - Has the p.(Glu121Lys) variant of TOR1A gene a pathogenic role in dystonia or Parkinson disease?

Next Generation Sequencing (NGS), has now become a very powerful tool for decoding variants of genes involved in pathogenesis of number of human disorders. One of the challenges of this method is to decipher the real pathogenic variants from a number of identified, not related to the disorder in analyzed case. Another issue is recognition of new phenotypes previously unrecognized but related to new variants combinations' in known genes. The other aspect is the HGMD or ClinVar mutation databases usage in data interpretation. The aim of this paper is to discuss pathogenicity of p.(Glu121Lys) missense mutation in the TOR1A gene previously described as dystonia causing variant. The patient diagnosed with typical Parkinson disease and positive family history was included into analysis. Also the internal whole exome sequencing (WES) database containing 600 subjects who has performed WES due to different causes was searched. All subjects had WES performed on SureSelect Human All Exon v.6 enrichment, Illumina NovaSeq 6000 platform, (annotations according to internal Institute Mother and Child's pipeline). The TOR1A p.(Glu121Lys) heterozygous mutation was revealed in 1 patient diagnosed with PD and 2 healthy subjects who has no dystonia symptoms. To conclude the TOR1A p.Glu121Lys variant should not be recognized as clearly pathogenic now.