Browsing by Subject "EPILEPSY"

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  • Salminen, Jukka K.; Mehtola, Aino; Talala, Kirsi; Taari, Kimmo; Mäkinen, Jussi; Peltola, Jukka; Tammela, Teuvo L. J.; Auvinen, Anssi; Murtola, Teemu J. (2022)
    Background Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. Methods A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. Results The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31-1.23). Conclusions AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.
  • Hokkanen, Laura; Barbosa, Fernando; Ponchel, Amelie; Constantinou, Marios; Kosmidis, Mary H.; Varako, Nataliya; Kasten, Erich; Mondini, Sara; Lettner, Sandra; Baker, Gus; Persson, Bengt A.; Hessen, Erik (2020)
    The prevalence and negative impact of brain disorders are increasing. Clinical Neuropsychology is a specialty dedicated to understanding brain-behavior relationships, applying such knowledge to the assessment of cognitive, affective, and behavioral functioning associated with brain disorders, and designing and implementing effective treatments. The need for services goes beyond neurological diseases and has increased in areas of neurodevelopmental and psychiatric conditions, among others. In Europe, a great deal of variability exists in the education and training of Clinical Neuropsychologists. Training models include master's programs, continuing education courses, doctoral programs, and/or post-doctoral specialization depending on the country, with no common framework of requirements, although patients' needs demand equal competencies across Europe. In the past 5 years, the Standing Committee on Clinical Neuropsychology of the European Federation of Psychologists' Association has conducted a series of surveys and interviews with experts in the field representing 30 European countries. The information, along with information from the existing literature, is used in presenting an overview of current and relevant topics related to policy and guidelines in the training and competencies in Clinical Neuropsychology. An option for the way forward is the EuroPsy Specialist Certificate, which is currently offered in Work and Organizational Psychology, and in psychotherapy. It builds upon the basic certificate and complements national standards without overriding them. General principles can be found that can set the basis for a common, solid, and comprehensive specialty education/training, sharpening the Neuropsychologists' competencies across Europe. The requirements in Clinical Neuropsychology should be comparable to those for the existing specialty areas in the EuroPsy model. Despite the perceived challenges, developing a specialist certificate appears a step forward for the development of Clinical Neuropsychology. Recommendations are proposed toward a shared framework of competencies by the means of a common level of education/training for the professionals in Europe. Benchmarking training standards and competencies across Europe has the potential of providing protection against unqualified and ethically questionable practice, creating transparency, raising the general European standard, and promoting mobility of both Clinical Neuropsychologists and patients in Europe, for the benefit of the professional field and the population.
  • Ylikallio, Emil; Ritari, Niina; Sainio, Markus; Toppila, Jussi; Kivirikko, Sirpa; Tyynismaa, Henna; Auranen, Mari; Isohanni, Pirjo (2020)
  • Stevenson, Nathan J.; Vanhatalo, Sampsa (2018)
    Neonatal seizures are widely considered a neurological emergency with a need for prompt treatment, yet they are known to present a highly elusive target for bedside clinicians. Recent studies have suggested that the design of a neonatal seizure treatment trial will profoundly influence the sample size, which may readily increase to hundreds or even thousands as the achieved effect size diminishes to clinical irrelevance. The self-limiting and rapidly resolving nature of neonatal seizures diminishes the measurable treatment effect every hour after seizure onset and any effect may potentially be confused with spontaneous resolution, precluding the value of many observational studies. The large individual variability in seizure occurrence over time and between etiologies challenges group comparisons, while the absence of clinical signs mandates quantification of seizure occurrence with continuous multi-channel EEG monitoring. A biologically sound approach that views neonatal seizures as a functional cot-side biomarker rather than an object to treat can overcome these challenges. (C) 2018 Elsevier Ltd. All rights reserved.
  • Clayton-Smith, Jill; Bromley, Rebecca; Dean, John; Journel, Hubert; Odent, Sylvie; Wood, Amanda; Williams, Janet; Cuthbert, Verna; Hackett, Latha; Aslam, Neelo; Malm, Heli; James, Gregory; Westbom, Lena; Day, Ruth; Ladusans, Edmund; Jackson, Adam; Bruce, Iain; Walker, Robert; Sidhu, Sangeet; Dyer, Catrina; Ashworth, Jane; Hindley, Daniel; Diaz, Gemma Arca; Rawson, Myfanwy; Turnpenny, Peter (2019)
    Background: A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. Methods: An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. Results: Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. Conclusion: The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.
  • Perez-Palma, Eduardo; Saarentaus, Elmo; Ravoet, Marie; De Ferrari, Giancarlo V.; Nuernberg, Peter; Isidor, Bertrand; Neubauer, Bernd A.; Lal, Dennis (2018)
    Objective After the recent publication of the first patients with disease-associated missense variants in the GRIN2D gene, we evaluate the effect of copy number variants (CNVs) overlapping this gene toward the presentation of neurodevelopmental disorders (NDDs). Methods We exploredClinVar (number ofCNVs = 50,794) andDECIPHER (number ofCNVs = 28,085) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content, and expression, with publicly available reference databases. Results We identified 11 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo, and comparable CNVs are not present in control databases. All patients were reported to have NDDs and dysmorphic features as the most common clinical phenotype (N = 8/11), followed by seizures (N = 6/11) and intellectual disability (N = 5/11). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression, and gene dosage sensitivity analysis, we highlight 4 genes for future evaluation: CARD8, C19orf68, KDELR1, and GRIN2D, which are promising candidates for disease causality. Furthermore, investigation of the literature especially supports GRIN2D as the best candidate gene. Conclusions Our study presents dup19q13.33 as a novel duplication syndrome locus associated with NDDs. CARD8, C19orf68, KDELR1, and GRIN2D are promising candidates for functional follow-up.
  • Sainio, Markus T.; Aaltio, Juho; Hyttinen, Virva; Kortelainen, Mika; Ojanen, Simo; Paetau, Anders; Tienari, Pentti; Ylikallio, Emil; Auranen, Mari; Tyynismaa, Henna (2022)
    Objectives Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult-to-diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland. Methods We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy (n = 57), peripheral neuropathy (n = 16), ataxia (n = 15), spastic paraplegia (n = 4), Parkinsonism (n = 3), and mixed (n = 5). In addition, we gathered the costs of prior diagnostic work-up to retrospectively assess the cost-effectiveness of CES as a first-line diagnostic tool. Results The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5, CHCHD10, CLCN1, DES, DOK7, FKBP14, POLG, PYROXD1, SCN4A, TUBB3, and TTN) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1, AFG3L2, ATL1, CACNA1A, COL6A1, DYSF, IRF2BPL, KCNA1, MT-ATP6, SAMD9L, SGCB, and TPM2). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work-up suggested that early CES would be cost-effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations. Conclusions Based on our results, CES is a cost-effective, powerful first-line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.
  • Kotisaari, Kaisa; Virtanen, Pekka; Forss, Nina; Strbian, Daniel; Scheperjans, Filip (2017)
    Purpose: To determine the frequency of emergent imaging findings on head computed tomography (CT) in an adult population of first seizure (FS) patients presenting to an emergency department (ED); and to search for associations between clinical features and emergent imaging findings among these patients. Methods: For this retrospective registry-based study, adult FS patients presenting to Helsinki University Hospital ED in 2006 were identified based on ICD-10 diagnosis. Clinical parameters were extracted from patient records. A neuroradiologist blinded to clinical information reviewed the CT scans for emergent imaging findings prompting changes in acute treatment, predefined as intracranial haemorrhage, acute ischemia, central nervous system infection, mass effect, midline shift, obstructive hydrocephalus and/or brain oedema. Results: 449 FS patients were identified, of which 416 (93%) had undergone emergency CT imaging. Of these, 49 (12%) had emergent imaging findings on non -contrast CT. Logistic regression suggested that headache (odds ratio (OR) 3.62, 95% confidence interval (CI) 1.30-10.12), focal motor sign in the ED (OR 3.23, 95% CI 1.58-6.62), history of malignancy (OR 3.05, 95% CI 1.17-7.92), and altered mental state in the ED (OR 2.27, 95% CI 1.15-4.49) were associated with emergent imaging findings on NCCT. Presence of at least one of these factors had 84% sensitivity for emergent imaging findings. Conclusion: In FS patients, clinical information can be used to guide imaging decisions in the ED. However, if emergency imaging is not performed, urgent outpatient imaging and pre-imaging follow up should be secured. (C) 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
  • Videman, Mari; Stjerna, Susanna; Roivainen, Reina; Nybo, Taina; Vanhatalo, Sampsa; Gaily, Eija; Leppanen, Jukka M. (2016)
    Introduction: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developitiental aberrations associated with prenatal AED exposure-could be-detected already in infancy and whether effects on visual attention can be observed at this early age. Material and methods: We compared a prospective cohort of infants with in utero exposure to AED (n = 56) with infants without drug exposures (n = 62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. Results: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. Discussion: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure. (C) 2016 Elsevier Inc. All rights reserved.
  • Ojanen, Petri; Zabihi, Morteza; Knight, Andrew; Roivainen, Reina; Lamusuo, Salla; Peltola, Jukka (2022)
    The aim of the study: This pilot study assessed the ability of a video/audio-based seizure monitoring system to evaluate (I) baseline frequency and severity of nocturnal seizures with motor features in patients with drugresistant epilepsy (DRE) and (II) the individual effect of brivaracetam (BRV) treatment on number, duration and movement intensity of these seizure types. Algorithmic feature analysis was developed for assessment of qualitative changes in movement intensity measurements within seizure types before and after BRV intervention. Materials and methods: Night-time motor seizures of recruited patients were recorded in two separate four-week monitoring periods. The first period defined a prescreening phase (n = 13 patients) to establish a baseline, and the second period defined the intervention phase (n = 9 patients), with BRV initiated during the second week of the second monitoring period. All recorded nights were analyzed by an expert video reviewer, and all unequivocal seizures were classified by an epileptologist. Seizure frequencies using both seizure diaries and video monitoring were compared. The effect of BRV on both seizure duration and movement intensity was assessed by numerical comparison of visual features calculated from motion characteristics of the video, as well as spectral features from the recorded audio. The statistical significance of changes in seizure duration and intensity before and after the intervention were investigated by Wilcoxon rank-sum test and visual inspection of Kernel density estimation. Results: 8 patients marked seizures in their seizure diaries during the prescreening phase. During the three-week follow-up, three patients achieved > 50% seizure decrease, four patients did not respond to treatment, and two patients experienced worsening of seizures. Five patients were able to document 40-70% of their seizures compared to the video/audio monitoring system. According to the signal feature analysis the intervention decreased movement intensity with clear clinical significance in three patients, whereas statistically significant differences in features appeared in 8 out of 9 patients. Conclusions: The novel video/audio monitoring system improved the evaluation of treatment effect compared to the seizure diaries and succeeded in providing a comparative intra-patient assessment of the movement intensity and duration of the recorded seizures.
  • Macharey, Georg; Väisänen-Tommiska, Mervi; Gissler, Mika; Ulander, Veli-Matti; Rahkonen, Leena; Nuutila, Mika; Heinonen, Seppo (2018)
    Purpose: To evaluate whether a trial of planned vaginal breech labor affects neurologic development in children. Methods: This is a nationwide, Finnish, population-based record linkage study. An odds ratio with 95% confidence intervals was used to estimate the relative risk that a child delivered by planned vaginal breech labor would be diagnosed with adverse neurodevelopmental outcome (cerebral palsy, epilepsy, intellectual disability, sensor neural developmental outcome, hyperactivity, speech and language problems) at the age of 4 years. The reference group were children born by planned cesarean section. Results: During a study period of 7 years, 8374 infants were delivered in breech position. Among them, 3907 (46.7%) had an attempted labor and 4467 (53.3%) infants were delivered by planned cesarean section. There were no differences in the neurodevelopmental outcome. In the planned vaginal labor group, 133 (3.4%) children had an abnormal neurodevelopmental outcome at the age of 4 years compared to 142 (3.2%) in the planned cesarean section group. Conclusion: The absolute risk of abnormal neurological outcome in breech deliveries at term was low, regardless of planned mode of birth. Planned vaginal breech labor did not increase the risk for abnormal neurological outcome compared to planned cesarean section.
  • Leu, Costin; Bautista, Jocelyn F.; Sudarsanam, Monica; Niestroj, Lisa-Marie; Stefanski, Arthur; Ferguson, Lisa; Daly, Mark J.; Jehi, Lara; Najm, Imad M.; Busch, Robyn M.; Lal, Dennis (2020)
    Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3x2 chi (2)), P=0.30; PNES vs. epilepsy (2x2 chi (2)), P=0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.
  • Jokiranta-Olkoniemi, Elina; Gyllenberg, David; Sucksdorff, Dan; Suominen, Auli; Kronström, Kim; Chudal, Roshan; Sourander, Andre (2021)
    To examine the risk for premature mortality and intentional self-harm in autism spectrum disorders (ASD). Based on a national birth cohort. Children born in 1987-2005, diagnosed with ASD by 2007 (n = 4695) were matched with four non-ASD subjects (n = 18,450) and followed until 2015 for mortality and intentional self-harm. The risk among ASD subjects was elevated only for natural cause of death. The risk for intentional self-harm was increased in the unadjusted analyses, but decreased to non-significant after adjusting for comorbid psychiatric disorders. ASD subjects are at increased risk for premature mortality due to natural causes of death. While ASD subjects die of suicide and present with more self-harm, the association is explained by comorbid psychiatric disorders.
  • Määttänen, Laura; Ripatti, Liisa; Rautava, Päivi; Koivisto, Mari; Haataja, Leena (2020)
    Aim To study whether cerebral palsy (CP) increases the risk of hospital-treated injuries in children up to 13 years of age. Methods A Finnish population-based cohort (n=328 903) of children born during 2001 to 2006 was followed up for hospital-treated injuries until the end of 2014 via linkage of nation-wide registers. The rate of first injury was compared in children with and without CP. The effect of CP type, gender, severe comorbidities (intellectual disability, epilepsy, hearing or visual impairment), and the type of injury was evaluated. Results Children with CP had an increased risk of injury compared with children without CP (unadjusted HR: 1.2, 95% CI: 1.0 - 1.4, p=0.40). Girls with CP (n=191) had a higher risk of injury compared with girls without CP (29% vs 22%, HR: 1.4, 95% CI: 1.1 to 1.8, p = 0.01). Any comorbidity increased the risk of injury (HR: 1.5, 95% CI: 1.1 to 2.2, p = 0.015) among children with CP. Children with CP had a higher risk of traumatic brain injury (HR: 1.7, 95% CI 1.2 to 2.4, p = 0.002) than children without CP. Conclusion Girls with CP had the highest risk of hospital-treated injury. Children with CP are particularly prone to traumatic brain injuries.
  • Ottka, Claudia; Weber, Corinna; Mueller, Elisabeth; Lohi, Hannes (2021)
    Introduction Phenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized. Objectives To identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels. Methods Leftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 mu g/mL to 50.8 mu g/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific H-1 NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression. Results Increasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value <.0033, and area under the curve (AUC) > .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed. Conclusion The identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.
  • Sato, Sebastian Sulis; Artoni, Pietro; Landi, Silvia; Cozzolino, Olga; Parra, Riccardo; Pracucci, Enrico; Trovato, Francesco; Szczurkowska, Joanna; Luin, Stefano; Arosio, Daniele; Beltram, Fabio; Cancedda, Laura; Kaila, Kai; Ratto, Gian Michele (2017)
    Intracellular chloride ([Cl-](i)) andpH(pH(i)) are fundamental regulators of neuronal excitability. They exert wide-ranging effects on synaptic signaling and plasticity and on development and disorders of the brain. The ideal technique to elucidate the underlying ionic mechanisms is quantitative and combined two-photon imaging of [Cl-](i) and pH(i), but this has never been performed at the cellular level in vivo. Here, by using a genetically encoded fluorescent sensor that includes a spectroscopic reference (an element insensitive to Cl-and pH), we show that ratiometric imaging is strongly affected by the optical properties of the brain. We have designed a method that fully corrects for this source of error. Parallel measurements of [Cl-](i) and pH(i) at the single-cell level in the mouse cortex showed the in vivo presence of the widely discussed developmental fall in [Cl-](i) and the role of the K-Cl cotransporter KCC2 in this process. Then, we introduce a dynamic two-photon excitation protocol to simultaneously determine the changes of pHi and [Cl-](i) in response to hypercapnia and seizure activity.
  • Smith, Richard S.; Kenny, Connor J.; Ganesh, Vijay; Jang, Ahram; Borges-Monroy, Rebeca; Partlow, Jennifer N.; Hill, R. Sean; Shin, Taehwan; Chen, Allen Y.; Doan, Ryan N.; Anttonen, Anna-Kaisa; Ignatius, Jaakko; Medne, Livija; Bönnemann, Carsten G.; Hecht, Jonathan L.; Salonen, Oili; Barkovich, A. James; Poduri, Annapurna; Wilke, Martina; de Wit, Marie Claire Y.; Mancini, Grazia M. S.; Sztriha, Laszlo; Im, Kiho; Amrom, Dina; Andermann, Eva; Paetau, Ritva; Lehesjoki, Anna-Elina; Walsh, Christopher A.; Lehtinen, Maria K. (2018)
    Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel Na(V)1.3. Pathogenic Na(V)1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (Na(V)1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.
  • Hikmat, Omar; Naess, Karin; Engvall, Martin; Klingenberg, Claus; Rasmussen, Magnhild; Tallaksen, Chantal M. E.; Samsonsen, Christian; Brodtkorb, Eylert; Ostergaard, Elsebet; de Coo, Rene; Pias-Peleteiro, Leticia; Isohanni, Pirjo; Uusimaa, Johanna; Darin, Niklas; Rahman, Shamima; Bindoff, Laurence A. (2020)
    Objective To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.
  • Peteri, Ulla-Kaisa; Pitkonen, Juho; de Toma, Ilario; Nieminen, Otso; Utami, Kagistia Hana; Strandin, Tomas M.; Corcoran, Padraic; Roybon, Laurent; Vaheri, Antti; Ethell, Iryna; Casarotto, Plinio; Pouladi, Mahmoud A.; Castren, Maija L. (2021)
    Astrocyte function intertwines with the extracellular matrix, whose glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities are found in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We generated human induced pluripotent stem cell-derived FXS and control astrocytes and we found that several pathways associated with urokinase plasminogen activator (uPA) that modulates degradation of extracellular matrix were activated in FXS astrocytes compared with controls. Expression of uPA was increased in FXS astrocytes and levels of uPA were also increased in conditioned medium collected from FXS astrocyte cultures. Levels of uPA correlated inversely with intracellular Ca2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB, indicating effects of uPA on neuronal plasticity. FXS-specific changes of gene expression during neuronal differentiation preceding astrogenesis likely contributed to altered properties of FXS astrocytes. Our results identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.