Search

Célkitűzés – A spinalis izomatrophia (SMA) az alsó motoneuronok pusztulásával járó progresszív, auto­szomális recesszív betegség. Az elmúlt években fordulat következett be az SMA oki kezelésében, két SMN2 splicing módosító és egy génterápiás gyógyszer vált elérhetővé. Kérdésfelvetés – Az új gyógyszerek az SMA gyermekkori lefolyását érdemben módosítják, és egyes gyógyszerek felnőttkori hatásáról is egyre több adat érhető el. Nem áll azonban rendelkezésre olyan szakirodalom, ami a legújabb eredmények alapján segítséget nyújtana a felnőtt SMA-betegek kezeléséhez szükséges döntések meghozatalában. A Magyar Klinikai Neurogenetikai Társaság vezetősége áttekintette az SMA palliatív kezelésének irányelveit, a randomizált, kontrollált gyógyszervizsgálatokat, a felnőtt SMA-betegek retrospektív és prospektív gyógyszeres vizsgálatainak eredményeit. A vizsgálat alanyai – A konszenzusajánlás megalkotása szempontjából azokat a közleményeket értékeltük, amelyek a felnőttkort elérő, főként SMA II- és III-csoportba tartozó betegek gyógyszeres kezelésének eredményeiről szolgáltatnak adatokat. A konszenzusajánlást a felnőtt SMA-betegek kezeléséről kilenc pontban fogalmaztuk meg, ami kitér a gyógyszeres kezelés technikai, szakmai feltételeire, biztonságossági szempontjaira, a betegek kiválasztására, és hosszú távú monitorizálására. Ajánlásunk a legújabb információkra alapozva segíti a felnőtt SMA-betegek palliatív ellátását és gyógyszeres kezelését, a személyre szabott kezelés során figyelembe veendő hatékonysági és biztonságossági szempontokat nyújt. Rávilágít a későbbiekben megválaszo­lan­dó, egyelőre nyitott kérdésekre is. Az ajánlás mindennapi gyakorlatban való használata a kezelés optimalizációját eredményezheti.

Cancer is the leading cause of death and represents a significant economic burden worldwide. The numbers are constantly growing as a result of increasing life expectancy, toxic environmental factors, and adoption of Western lifestyle. Among lifestyle factors, stress and the related signaling pathways have recently been implicated in the development of tumors. Here we present some epidemiological and preclinical data concerning stress-related activation of the ß-adrenoreceptors (ß-ARs), which contributes to the formation, sequential transformation, and migration of different tumor cell types. We focused our survey on research results for breast and lung cancer, melanoma, and gliomas published in the past five years. Based on the converging evidence, we present a conceptual framework of how cancer cells hijack a physiological mechanism involving ß-ARs toward a positive modulation of their own survival. In addition, we also highlight the potential contribution of ß-AR activation to tumorigenesis and metastasis formation. Finally, we outline the antitumor effects of targeting the ß-adrenergic signaling pathways, methods for which primarily include repurposed ß-blocker drugs. However, we also call attention to the emerging (though as yet largely explorative) method of chemogenetics, which has a great potential in suppressing tumor growth either by selectively modulating neuronal cell groups involved in stress responses affecting cancer cells or by directly manipulating specific (e.g., the ß-AR) receptors on a tumor and its microenvironment.

Aberrant activation of the Wnt pathway contributes to differentiation and maintenance of cancer stem cells underlying gliomagenesis. The aim of our research was to determine as to what degrees some Wnt markers are expressed in gliomas of different grades, lineages and molecular subtypes.Nine grade II, 10 grade III and 72 grade IV surgically removed, formalin-fixed paraffin-embedded glioma specimens were included. Mutation status of IDH1 codon 132 was defined by immunohistochemistry and pyrosequencing in all tumors. Grade II and III astrocytic and oligodendroglial tumors were further tested for the expression of p53 and ATRX by immunohistochemistry, and codeletion of 1p19q by fluorescent in situ hybridization. Expression levels of the non-canonical Wnt5a and Fzd2, and the canonical Wnt3a and beta-catenin Wnt pathway markers were determined by immunohistochemistry, and compared between subgroups stratified according to grade, lineage and the presence or absence of IDH1 R132H/C mutations.In the normal brain - grade II-IV glioma comparisons, a gradual increase was observed for the expressions of Wnt5a, Wnt3a, Fzd2 and beta-catenin. In the astroglial and oligodendroglial lineages of grade II and III gliomas, only the Wnt5a expression was significantly higher in the astroglial subgroup. Stratification according to the IDH1 status resulted in a significant increase of the Wnt3 expression in the wild type grade II-IV gliomas.These data extend previous observations and show a correlation of Wnt pathway activity with glioma grade. Further investigations of the Wnt marker expression regulation according to glioma lineage or IDH gene mutational status are in progress by using more exact molecular approaches.A glioma kialakulásában szerepet játszik a Wnt-útvonal aberráns aktiválása az őssejtek dif­fe­ren­ciá­lódásának és fenntartásának szabályozása által. Kutatá­sunk célja volt meghatározni, hogy egyes Wnt-markerek milyen mértékben expresszálódnak a különböző grádiusú, szövettani eredetű és mutációs profilú gliomákban.Kilenc grádius II., 10 grádius III. és 72 grá­dius IV., műtéti úton eltávolított, formalinfixált paraffinba ágyazott gliomát vizsgáltunk. Az IDH1 132 kodon mutációs állapotát immunhisztokémia és piroszekvenálás módszereivel határoztuk meg minden tumorban. A II. és III. grádiusú astroglialis és oligodendroglialis tumorokat tovább vizsgáltuk p53- és ATRX-expresszióra immunhisztokémiával, és 1p19q kodelécióra fluoreszcens in situ hibridizációval. A nem kanonikus Wnt5a és Fzd2, vala­mint a kanonikus Wnt3a és β-katenin Wnt-útvonalmarkerek expressziós szintjét immunhisztokémiai úton határoztuk meg, és az expressziós értékeket összehasonlítottuk a tumorok grádiusa, hisztológiai eredete (asztrocitoid vs. oligodendroglioid) és az IDH1 R132H / C mutációk jelenléte vagy hiánya szerinti alcsoportokban.A normál agyi szövet vs. II–IV. grádiusú gliomák összehasonlítása során egy grádius szerinti fokozatos növekedést figyeltünk meg a Wnt5a, Wnt3a, Fzd2 és a β-katenin expressziójában. A II. és III. grádiusú gliomák astroglialis és oligodendroglialis szövettani ere­detű összehasonlítása során csak a Wnt5a-expresszió volt szignifikánsan magasabb az asztroglia-alcsoportban. Az IDH1 R132H / C mutáns és vad típusú gliomák összehasonlítása során a Wnt3 emelkedését találtuk a vad típusú grade II–IV. gliomák csoportjában.Ezek az adatok kibővítik a korábbi megfigyelések eredményeit, és összefüggést mutatnak a Wnt-útvonal aktivitása, valamint a gliomagrádius között. A Wnt-markerek expressziós szabályozásának további vizsgálata gliomákban már folyamatban van szövettani eredet vagy IDH-génmutációs státusz szerint, nagy felbontású molekuláris vizsgálatok alkalmazásával.

Garzuly Ferenc címzetes egyetemi tanár hosszú, aktív élet után hunyt el 84 évesen. Közel 60 éven át dolgozott a szombathelyi Markusovszky Egyetemi Oktatókórházban, ahol nevéhez fűződik a neuropatológiai laboratórium öt évtizedes tevékenysége. A neurológiai osztályt 20 éven át vezette, majd nyugdíjazása után a patológiai osztályon dolgozott haláláig. Több, ritka betegségeket tárgyaló könyv szerzője, a Magyar Klinikai Neurogenetikai Tár­saság alapító tagja. A nemzetközi szakmai irodalomban nevét a Fabry-betegség egy speciális mutációval társuló és megadochobasilaris elváltozással járó fenotípusának leírásával tette ismertté, és leírta a familiáris meningo­cerebrovascularis amyloidosis transthyretin mutációval járó magyar típusát.

Glioblastoma (GBM) is a highly heterogeneous and aggressive brain tumor. Comprehensive genomic and transcriptomic analyses revealed that GBM segregates into three subgroups with characteristic signaling pathways. The Wnt pathway recently received increasing attention with the recognition of its importance in tumor development and recurrence through the promotion of glioma stem cells. As an extension of our previous translational studies, here we tested the possible interactions between key subgroup markers (IDH-1 R132H, EGFRvIII and both cytoplasmic and nuclear loss [c-/n-] of NF-1 expression) and the canonical (Wnt3a and beta-catenin) and non-canonical (Wnt5a and Fzd2) Wnt pathway markers by immunohistochemistry. These analyses revealed increased expression levels of both Wnt pathway markers with significant quantitative differences within, but not among subgroups. Wnt5a and Fzd2 levels were higher than the canonical marker levels in all subgroups. The strongest evidence for correlation between expression levels of the EGFRvIII subgroup marker and the Fzd2 Wnt marker was found, but weaker correlations also could be noted for IDH-1 R132H and NF-1 and some Wnt markers. The correlations detected between markers of the canonical and non-canonical pathways raised the possibility of cross-talk between the two pathways. Analyses of tumors with various NF-1 expression patterns (c+/n-; c-/n+ combined with c+/n+, and c-/n-) revealed that aberrant nuclear accumulation of NF-1 is accompanied by nuclear accumulation of beta-catenin, suggesting that they may act synergistically to define the tumor's biology. Altogether, our study presents expression characteristics of Wnt ligands and receptors, and suggests complex molecular interactions in subgroups of GBM.

Glioblastoma is one of the deadliest tumors with barely over one-year median survival despite intensive efforts in defining its molecular characteristics and searching for innovative treatment strategies. While major progress has been made in cataloging cross-sectional genomic, transcriptomic and epigenomic features of the tumor, and inferring its main molecular pathways and niches for potential targeted intervention, we still do not have sufficient knowledge concerning evolutionary patterns and dynamics of molecular changes or the treatment-induced effects affecting glioblastoma biology. In this review, we summarize the results of recent longitudinal genomic, transcriptomic and epigenomic studies that brought us closer to a better understanding of this lethal disease. Evidence suggests that neuronal / glioma stem cells with accumulating mutations initiate glioblastoma development and recurrence, but the hypothetical models describing the courses that lead to established tumors have not been fully proven. Moving from the histopathological phenotype to the results of high resolution OMICS studies, we try to synthesize the currently available information from sequential glioblastoma analyses in order to highlight its multifaceted features and heterogenetity, as well as the expected complexity of potential treatment strategies that might once succeed.

Over the second half of the 19th century, numerous theories arose concerning mechanisms involved in understanding of action, imitative learning, language development and theory of mind. These explorations gained new momentum with the discovery of the so called "mirror neurons". Rizzolatti's work inspired large groups of scientists seeking explanation in a new and hitherto unexplored area of how we perceive and understand the actions and intentions of others, how we learn through imitation to help our own survival, and what mechanisms have helped us to develop a unique human trait, language. Numerous studies have addressed these questions over the years, gathering information about mirror neurons themselves, their subtypes, the different brain areas involved in the mirror neuron system, their role in the above mentioned mechanisms, and the varying consequences of their dysfunction in human life. In this short review, we summarize the most important theories and discoveries that argue for the existence of the mirror neuron system, and its essential function in normal human life or some pathological conditions.A 19. század második felében számos teória látott napvilágot a cselekvések megértését, az imitatív tanulási folyamatokat és a nyelv kifejlôdésében szerepet játszó mechanizmusokat illetôen. Ezen kérdésfelvetések új lendületet kaptak az úgynevezett „tükörneuronok” felfedezésével. Rizzolatti munkássága nagy tudóscsoportokat mozgatott meg, akik egy új és addig felfedezetlen területen kereshették a magyarázatot arra, hogyan is észleljük és értjük meg mások cselekedeteit és a mögöttük rejlô szándékot, hogyan tanuljuk meg az életben maradáshoz szükséges mozdulatokat imitáción keresztül, és hogy milyen mechanizmusok segíthettek bennünket a nyelv mint egyedi emberi tulajdonság kialakulásához. Számos tanulmány foglalkozott ezekkel a kérdésekkel az évek során, melyek információt gyûjtöttek magukról a tükörneuronokról, a tükörneuron-rendszer mûködésében részt vevô agyi régiókról és azok szerepeirôl a már említett mechanizmusokban, továbbá diszfunkciójuk következményeirôl az emberi életfolyamatokra vonatkozóan. Ebben a rövid tanulmányban összegyûjtjük a legfontosabb elméleteket és felfedezéseket, amelyek bizonyítják a tökörneuron-rendszer létezését és annak emberi életben és néhány betegségben betöltött szerepét.

Background Wnt signaling plays important roles in tumorigenesis, invasiveness and therapeutic resistance of glioblastoma (GBM). Methods We simultaneously investigated six Wnt pathway markers (Wnt5a, Fzd-2, beta-catenin, Wnt3a, Wnt7b, Fzd-10) at epigenetic and protein levels in 21 sequential formalin-fixed paraffin-embedded GBM pairs and controls. Results Expression levels of Wnt5a, beta-catenin and Wnt3a proteins either moderately or significantly increased, while those of Fzd-2, Wnt7b and Fzd-10 decreased in the primary (GBM-P) and recurrent (GBM-R) tumors compared to the controls. Methylation levels within promoters and genes showed corresponding decreases for Wnt5a, beta-catenin and Wnt3a in tumors vs. controls, while that of Fzd-10 was uniformly high. Comparing the GBM-P and GBM-R pairs, proteins of Fzd-2, beta-catenin and Wnt3a were either moderately or significantly up-, while that of Wnt7b was downregulated in GBM-R, but these patterns were not accompanied by inverse methylation patterns in the corresponding promoters and genes over time. No methylation differences were noted within promoters and genes of the same markers in 112 pairs of primary and recurrent GBMs in a database, suggesting that the observed changes in protein expression levels may not be explained by CpG methylation status alone. The promoter and gene methylation rate was the highest for Fzd-10 in the database cohort too, supporting the noted low Fzd-10 protein expression. Discussion These analyses underscore the relevance of Wnt pathway molecules in the context of their methylation profiles in the development and evolution of GBM, and suggest that Wnt pathway regulation as a potential treatment target merits further studies.

Interest in the hippocampal formation and its role in navigation and memory arose in the second part of the 20th century, at least in part due to the curious case of Henry G. Molaison, who underwent brain surgery for intractable epilepsy. The temporal association observed between the removal of his entorhinal cortex along with a significant part of hippocampus and the developing severe memory deficit inspired scientists to focus on these regions. The subsequent discovery of the so-called place cells in the hippocampus launched the description of many other functional cell types and neuronal networks throughout the Papez-circuit that has a key role in memory processes and spatial information coding (speed, head direction, border, grid, object-vector etc). Each of these cell types has its own unique characteristics, and together they form the so-called "Brain GPS". The aim of this short survey is to highlight for practicing neurologists the types of cells and neuronal networks that represent the anatomical substrates and physiological correlates of pathological entities affecting the limbic system, especially in the temporal lobe. For that purpose, we survey early discoveries along with the most relevant neuroscience observations from the recent literature. By this brief survey, we highlight main cell types in the hippocampal formation, and describe their roles in spatial navigation and memory processes. In recent decades, an array of new and functionally unique neuron types has been recognized in the hippocampal formation, but likely more remain to be discovered. For a better understanding of the heterogeneous presentations of neurological disorders affecting this anatomical region, insights into the constantly evolving neuroscience behind may be helpful. The public health consequences of diseases that affect memory and spatial navigation are high, and grow as the population ages, prompting scientist to focus on further exploring this brain region.A hippocampalis formáció navigációban és memóriában betöltött szerepét a 20. század második felére fokozódó érdek­lô­dés övezte, ami részben Henry G. Molaison esetére vezet­hetô vissza, aki bilaterális medialis temporalis lobectomián esett át epilepsziája kezelése végett. A kezelést követôen egy­ér­tel­mûvé vált, hogy az eltávolított entorhinalis kéreg és a hippocampus jelentôs része elengedhe­tetlen a memória kiala­kí­tásában, ami számos kutatót ösztönzött e régiók további vizsgálatára. A hippocampalis „place” sejtek vagy helysejtek ké­sôbbi felfedezése vezette be számos más funkcionális sejttípus és neuronalis hálózat leírását a Papez-körben, amelyek kulcsszerepet játszanak a memóriafolyamatokban és a tér-idô információk kódolásában (sebesség, fejirány, határok, grid, objektum-vektor stb.) Ezen sejttípusok mind­egyike egyedi tulaj­don­ságokkal rendelkezik, és együttesen alkotják az úgynevezett „agyi GPS-t”. E közlemény célja, hogy bemutassa a limbicus rendszerben, különösképpen a temporalis lebenyben ta­lálható sejttípusokat és neuronalis hálózatokat, melyek gyakran áldozatai különbözô patológiai elváltozásoknak. A korai felfedezések eredményei mellett áttekintjük a legfrissebb megfigyeléseket is, és rávilágítunk arra, hogy a hippocampalis formáció legfôbb sejttípusai milyen szereppel bírnak a térbeli navigációban és a memóriafolyamatokban. Az utóbbi né­hány évtizedben számtalan új, funkcionálisan elkülöníthetô sejttípust írtak le ebben a régióban, de valószínûleg továbbiak még felfedezésre várnak. Az idegrendszeri betegségek jobb megértése érdekében hasznos lehet mélyebb betekintést nyerni a dinamikusan bôvülô idegtudományi irodalomba. A memóriafolyamatokat és a térbeli navigációt érintô betegségek jelentôs közegészségügyi terhet képvi­selnek, és öregedô társadalmunkban a helyzet folyamatosan romlik. Ez különösen ösztönzôen hat ennek az agyterületnek a pontosabb megismerésére és funkcionális feltérképezésére.

Purpose Glioblastoma is the most aggressive form of brain tumors. A better understanding of the molecular mechanisms leading to its evolution is essential for the development of treatments more effective than the available modalities. Here, we aim to identify molecular drivers of glioblastoma development and recurrence by analyzing DNA CpG methylation patterns in sequential samples. Methods DNA was isolated from 22 pairs of primary and recurrent formalin-fixed, paraffin-embedded glioblastoma specimens, and subjected to reduced representation bisulfite sequencing. Bioinformatic analyses were conducted to identify differentially methylated sites and pathways, and biostatistics was used to test correlations among clinical and pathological parameters. Results Differentially methylated pathways likely involved in primary tumor development included those of neuronal differentiation, myelination, metabolic processes, synapse organization and endothelial cell proliferation, while pathways differentially active during glioblastoma recurrence involved those associated with cell processes and differentiation, immune response, Wnt regulation and catecholamine secretion and transport. Conclusion DNA CpG methylation analyses in sequential clinical specimens revealed hypomethylation in certain pathways such as neuronal tissue development and angiogenesis likely involved in early tumor development and growth, while suggested altered regulation in catecholamine secretion and transport, Wnt expression and immune response contributing to glioblastoma recurrence. These pathways merit further investigations and may represent novel therapeutic targets.

Secretory meningioma is a rare form of meningiomas which differentiates from the meningothelial subtype. It is characterized by significant peritumor edema and distinct immunohistochemical and molecular genetic profiles. We present a middle aged female patient with secretory meningioma infiltrating the orbital bone from the primary cranial base location and causing exophthalmos, features rarely described with this tumor. Surgical resection was challenging because of the associated brain swelling and rich vascularization of the tumor. Imaging and immunohistochemical studies revealed characteristic hallmarks of secretory meningioma. While histologically it was a benign tumor, due to the orbital bone and soft tissue infiltration, postoperative management of neurological sequelae was challenging. This case highlights distinctive clinical, imaging and histological features along with individual characteristics of a rare form of meningiomas.

Cerebral cavernous malformations (CCMs) represent a relatively rare and heterogeneous clinical entity with mutations identified in three genes. Both sporadic and familial forms have been reported. We present a young female patient with episodic paresthesia and headaches, but without acute neurological deficits. Her mother had a hemorrhaged cavernoma surgically removed 21 years ago. Cranial magnetic resonance imaging revealed multiple cavernous malformations in the size of a few millimeters and the ophthalmologic exam detected retinal blood vessel tortuosity in the proband. Targeted exome sequencing analysis identified a nonsense mutation in exon 16 of the KRIT1 gene, which resulted in a premature stop codon and a truncated protein underlying the abnormal development of cerebral and retinal blood vessels. This mutation with pathogenic significance has been reported before. Our case points to the importance of a thorough clinical and molecular work up despite the uncertain neurological complaints, since life style recommendations, imaging monitoring and genetic counseling may have major significance in the long term health of the patient.

Glioblastoma (GBM), a highly lethal brain tumor, has been comprehensively characterized at the molecular level with the identification of several potential treatment targets. Data concerning the Wnt pathway are relatively sparse, but apparently very important in defining several aspects of tumor biology. The Wnt ligands are involved in numerous basic biological processes including regulation of embryogenic development, cell fate determination, and organogenesis, but growing amount of data also support the roles of Wnt pathways in the formation of many tumors, including gliomas. Two main Wnt pathways are distinguished: the canonical (β-catenin) and non-canonical (planar cell polarity, Wnt/Ca2+) routes. Wnt signaling regulates glioma stem cells (GSCs), thereby defining invasive potential, recurrence, and treatment resistance of GBM. Some observations suggest that the Wnt pathways are differentially active in molecular subtypes of this tumor, thereby may also guide prognostication and novel therapeutic decisions. In this review, we highlight main elements and biological relevance of the Wnt pathways, primarily focusing on the pathogenesis and subtypes of GBM. Finally, we briefly summarize newer therapeutic strategies targeting networks of the Wnt signaling cascades and their molecular associates that appear to be marked contributors to GBM aggressiveness.

Oncogenesis is related to a sequential accumulation of somatic mutations. Comprehensive characterizations of the genomic landscapes have been completed recently for several tumors, glioblastoma being among the first ones. Our own translational research studies have been focused on defining molecular subtypes of glioblastoma in the clinical setting because of an expected prognostic and therapeutic utility of the information. Somatic mutations in genes of the isocitrate dehydrogenase (IDH) enzyme family appear to be among the best-defined biomarkers that also influence tumor behavior and confer clinical utility.We have reviewed the literature including our own results to summarize basic science and clinical correlates of IDH mutations.The surveyed data reveal genomic, transcriptomic, epigenomic and biochemical consequences of IDH mutations in the context of glioblastoma biology and phenotype. In addition, a few studies highlight the therapeutic potential of targeting IDH, although thus far all tests have only been conducted in the preclinical setting.Somatic mutations in isoforms of IDH genes represent important biomarkers that correlate with biochemical, biological and phenotypic features of glioblastoma, and may also facilitate the development of new therapeutic strategies complementing the currently available approved protocols.Az onkogenezis sorozatos szomatikus mutációk felhalmozódásához köthető. Számos daganat esetében megtörtént a genomikai háttér átfogó elemzése, és a glioblastoma az elsők között volt. Saját transzlációs kutatásunk célja a glioblastoma altípusainak klinikai környezetben történő meghatározása volt, ennek prognosztikus értéke és terápiás haszna miatt. Az izocitrát-dehidrogenáz (IDH) család génjeinek szomatikus mutációi a legjobban jellemzett biomarkerek közé tartoznak, melyek a tumor viselkedését is meghatározzák, egyben ismeretük klinikailag is hasznosnak bizonyul.Áttekintettük a szakirodalmat, beleértve saját eredményeinket is, hogy az IDH-mutáció alaptudományos és klinikai összefüggéseit összegezzük.Az áttekintett adatok alapján rávilágítunk az IDH-mutációk genomikai, transzkriptomikai, epigenomikai és biokémiai következményeire a glioblastoma biológiájának és fenotípusának vonatkozásában. Klinikai vizsgálatok eredményeinek bemutatásával utalunk az IDH-t célba vevő terápiás megközelítések lehetőségeire, bár e vizsgálatok jelenleg még preklinikai stádiumban vannak.Az IDH-izoformák génjeiben történő szomatikus mutációk értékes biomarkerek, amelyek korrelálnak a glioblastoma fenotípusával, biokémiai és biológiai tulajdonságaival, továbbá ismeretük új irányú, a jelenlegi protokollt kiegészítő terápiás stratégiák fejlesztéséhez vezethet.

Until recently, the diagnosis of spinal muscular atrophy (SMA) has been associated with severe life-long motor disability in adults and with early death in infants. The new experimental therapeutic approaches of the last few years have become more and more promising, while nusinersen was approved for the treatment of SMA in December 2016 in the USA, and in May 2017 in Hungary. Our paper presents mechanisms and clinical benefits of this new medication, and highlights some of the other therapeutic strategies still in experimental stages.

Comprehensive molecular characterization of and novel therapeutic approaches to glioblastoma have been explored as a result of advancements in biotechnologies. In this study, we aimed to bring basic research discoveries closer to clinical practice and ultimately incorporate molecular classification into the routine histopathological evaluation of grade IV gliomas. Integrated results of genome-wide sequencing, transcriptomic and epigenomic analyses by The Cancer Genome Atlas Network defined the classic, proneural, neural and mesenchymal subtypes of this tumor. In a retrospective cohort, we analyzed selected subgroup-defining molecular markers in formalin-fixed paraffin-embedded surgical specimens by immunohistochemistry. Quantitative and qualitative scores of marker expression were tested in hierarchical cluster analyses to evaluate segregations of the molecular subgroups, which then were correlated with clinical parameters including patients' age, gender and overall survival. Our study has confirmed the separation of molecular glioblastoma subgroups with clear trends regarding clinical correlations. Future analyses in a larger, prospective cohort using similar methods are expected to facilitate the development of a molecular diagnostic panel that may complement routine histological work up and support prognostication as well as treatment decisions in glioblastoma.

// Balazs Murnyak 1 , Mahan C. Kouhsari 1 , Rotem Hershkovitch 1 , Bernadette Kalman 2, 3 , Gyorgy Marko-Varga 4 , Almos Klekner 5 and Tibor Hortobagyi 1, 6 1 Division of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary 2 Institute of Diagnostics, Faculty of the Health Sciences, University of Pecs, Pecs, Hungary 3 Molecular Pathology Unit, Markusovszky Teaching Hospital, Szombathely, Hungary 4 Division of Clinical Protein Science & Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden 5 Department of Neurosurgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary 6 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK Correspondence to: Tibor Hortobagyi, email: hortobagyi@med.unideb.hu , tibor.hortobagyi@kcl.ac.uk Keywords: glioma, glioblastoma, p53, PARP1 Received: December 27, 2016 Accepted: April 24, 2017 Published: May 19, 2017 ABSTRACT Overexpression of PARP1 exists in various cancers, including glioblastoma (GBM). Although PARP1 inhibition is a promising therapeutic target, no comprehensive study has addressed PARP1’s expression characteristics and prognostic role regarding molecular heterogeneity in astrocytomas including GBM. Our aim was to evaluate PARP1’s associations with survival, WHO grade, lineage specific markers, and GBM transcriptomic subtypes. We collected genomic and clinical data from the latest glioma datasets of The Cancer Genome Atlas and performed PARP1, ATRX, IDH1, and p53 immunohistochemistry on GBM tissue samples. We demonstrated that PARP1 gain and increased mRNA expression are characteristics of high-grade astrocytomas, particularly of Proneural and Classical GBM subtypes. Additionally, higher PARP1 levels exhibited an inverse correlation with patient survival (p

Autoimmune diseases represent a heterogeneous group of common disorders defined by complex trait genetics and environmental effects. The genetic variants usually align in immune and metabolic pathways that affect cell survival or apoptosis and modulate leukocyte function. Nevertheless, the exact triggers of disease development remain poorly understood and the current therapeutic interventions only modify the disease course. Both the prevention and the cure of autoimmune disorders are beyond our present medical capabilities. In contrast, a growing number of single gene autoimmune disorders have also been identified and characterized in the last few decades. Mutations and other gene alterations exert significant effects in these conditions, and often affect genes involved in central or peripheral immunologic tolerance induction. Even though a single genetic abnormality may be the disease trigger, it usually upsets a number of interactions among immune cells, and the biological developments of these monogenic disorders are also complex. Nevertheless, identification of the triggering molecular abnormalities greatly contributes to our understanding of the pathogenesis of autoimmunity and facilitates the development of newer and more effective treatment strategies.

Summary Background Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator deferiprone can reduce brain iron and slow disease progression. Methods We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA. Patients aged 4 years or older with a genetically confirmed diagnosis of PKAN, a total score of at least 3 points on the Barry-Albright Dystonia (BAD) scale, and no evidence of iron deficiency, neutropenia, or abnormal hepatic or renal function, were randomly allocated (2:1) to receive an oral solution of either deferiprone (30 mg/kg per day divided into two equal doses) or placebo for 18 months. Randomisation was done with a centralised computer random number generator and with stratification based on age group at onset of symptoms. Patients were allocated to groups by a randomisation team not masked for study intervention that was independent of the study. Patients, caregivers, and investigators were masked to treatment allocation. Co-primary endpoints were the change from baseline to month 18 in the total score on the BAD scale (which measures severity of dystonia in eight body regions) and the score at month 18 on the Patient Global Impression of Improvement (PGI-I) scale, which is a patient-reported interpretation of symptom improvement. Efficacy analyses were done on all patients who received at least one dose of the study drug and who provided a baseline and at least one post-baseline efficacy assessment. Safety analyses were done for all patients who received at least one dose of the study drug. Patients who completed the randomised trial were eligible to enrol in a single-arm, open-label extension study of another 18 months, in which all participants received deferiprone with the same regimen as the main study. The trial was registered on ClinicalTrials.gov , number NCT01741532 , and EudraCT, number 2012-000845-11. Findings Following a screening of 100 prospective patients, 88 were randomly assigned to the deferiprone group (n=58) or placebo group (n=30) between Dec 13, 2012, and April 21, 2015. Of these, 76 patients completed the study (49 in the deferiprone group and 27 in the placebo group). After 18 months, the BAD score worsened by a mean of 2·48 points (SE 0·63) in patients in the deferiprone group versus 3·99 points (0·82) for patients in the control group (difference −1·51 points, 95% CI −3·19 to 0·16, p=0·076). No subjective change was detected as assessed by the PGI-I scale: mean scores at month 18 were 4·6 points (SE 0·3) for patients in the deferiprone group versus 4·7 points (0·4) for those in the placebo group (p=0·728). In the extension study, patients continuing deferiprone retained a similar rate of disease progression as assessed by the BAD scale (1·9 points [0·5] in the first 18 months vs 1·4 points [0·4] in the second 18 months, p=0·268), whereas progression in patients switching from placebo to deferiprone seemed to slow (4·4 points [1·1] vs 1·4 points [0·9], p=0·021). Patients did not detect a change in their condition after the additional 18 months of treatment as assessed by the PGI-I scale, with mean scores of 4·1 points [0·2] in the deferiprone–deferiprone group and of 4·7 points [0·3] in the placebo–deferiprone group. Deferiprone was well tolerated and adverse events were similar between the treatment groups, except for anaemia, which was seen in 12 (21%) of 58 patients in the deferiprone group, but was not seen in any patients in the placebo group. No patient discontinued therapy because of anaemia, and three discontinued because of moderate neutropenia. There was one death in each group of the extension study and both were secondary to aspiration. Neither of these events was considered related to deferiprone use. Interpretation Deferiprone was well tolerated, achieved target engagement (lowering of iron in the basal ganglia), and seemed to somewhat slow disease progression at 18 months, although not significantly, as assessed by the BAD scale. These findings were corroborated by the results of an additional 18 months of treatment in the extension study. The subjective PGI-I scale was largely unchanged during both study periods, indicating that might not be an adequate tool for assessment of disease progression in patients with PKAN. Our trial provides the first indication of a decrease in disease progression in patients with neurodegeneration with brain iron accumulation. The extensive information collected and long follow-up of patients in the trial will improve the definition of appropriate endpoints, increase the understanding of the natural history, and thus help to shape the design of future trials in this ultra-orphan disease. Funding European Commission, US Food and Drug Administration, and ApoPharma Inc.

Until recently, the diagnosis of spinal muscular atrophy (SMA) has been associated with severe life-long motor disability in adults and with early death in infants. The new experimental therapeutic approaches of the last few years have become more and more promising, while nusinersen was approved for the treatment of SMA in December 2016 in the USA, and in May 2017 in Hungary. Our paper presents mechanisms and clinical benefits of this new medication, and highlights some of the other therapeutic strategies still in experimental stages.A spinalis izomatrophia (SMA) diagnózisa néhány éve még többségében élethosszig tartó mozgáskorlátozottságot, cse­csemők esetén pedig a biztos korai halált jelentette. Az el­múlt évek széles körű terápiás próbálkozásai egyre ígéretesebbnek tűntek, míg 2016 decemberében az USA-ban, majd 2017 májusában Magyarországon is megkapta a forgalmazási engedélyt az első, SMA terápiájára kifejlesztett hatóanyag, a nusinersen. Cikkünk az új terápiás lehetőség lényegét, eddigi eredményeit és az egyelőre kísérleti stádiumban lévő további lehetőségeket tárgyalja.

Glioblastoma is the most aggressive form of gliomas and is associated with short survival. Recent advancements in molecular genetics resulted in the identification of glioma genomic, epigenomic and transcriptomic hallmarks, and multidimensional data allowed clustering of glioblastomas into molecular subtypes. Parallel with these developments, much scientific attention has been attracted by the exploration of two functional processes linked to mitochondrial regulation. One of these processes involves genomic and mitochondrial gene mutations, mitochondrial protein expression modifications and altered metabolic regulation that define glioblastoma. The second mitochondrially-centered process involves complex molecular interactions and pathways that influence the extrinsic or the intrinsic mechanisms of apoptosis regulation and may underlie the uncontrolled spreading, recurrence and drug resistance of glioblastoma. While the available data are not yet comprehensive, these two complex processes represent important aspects of tumor cell biology, which may provide complementary opportunities for therapeutic manipulations of this highly resistant tumor type.

Environmental factors greatly contribute to the development of complex trait disorders. With the rapid developments in the fields of biotechnology and informatics, the investigations of molecular interactions between host and environmental factors became very detailed and comprehensive. The effects of ultraviolet irradiation, vitamin D synthesis, and receptor binding, and then the involvements of the ligand-receptor complexes in the regulation of cell function received much attention in the last few years and paralleled the accumulation of information concerning genetic determinants of disease susceptibility, transcriptional regulation, cell cycle, mitochondrial biochemistry, and many other elements of cell biology. The importance of vitamin D in contributing to immune regulation, autoimmunity, and susceptibility to multiple sclerosis (MS) is now also recognized, and there are ongoing treatment trials with vitamin D to define whether it is capable of modifying susceptibility to or the course of the disease. This survey aims to capture that part of vitamin D research that helps to better understand the interactions of this molecule and its receptor with the human genome, and the downstream effects of these interactions relevant to immune homeostasis and MS. This relatively narrow scope reveals a very complex molecular network underlying inflammatory demyelination and allows us to hope that a better understanding of the roles of vitamin D and other environmental factors will once make the risk of MS modifiable or, to some degrees, the disease preventable.

Introduction: Parathyroid hormone levels provide important information in chronic renal failure. Aim: To compare parathyroid hormone levels measured by two assays in correlation with vitamin D supply. Method: Parathyroid hormone and 25-hydroxi-vitamin-D were determined in 104 patients (31 patients with chronic renal failure without renal replacement therapy, 36 patients treated with peritoneal dialysis and 37 patients treated with hemodialysis). Results: Good correlation was found between results of the two parathyroid hormone methods, but the intact parathyroid hormone levels were higher than the biointact values. 87% and 13% of the patients had vitamin-D deficiency and insufficiency, respectively. The frequency of serious vitamin-D deficiency was higher in the peritoneal dialysis than in the hemodialysis group. Intact parathyroid hormone levels were different in dialysed patients having vitamin-D-deficiency and insufficiency, and the difference was higher for the biointact than intact values. Negative correlation was detected between biointact parathyroid hormone and 25-hydroxivitamin-D in the hemodialysis group. Conclusions: Biointact parathyroid hormone levels better reflect the vitamin D supply and bone metabolism than intact levels, especially in hemodialysed patients. Orv. Hetil., 2013, 154(51), 2025–2036.

Cuprizone is a copper-chelating mitochondrial toxin that causes oligodendrocyte apoptosis and demyelination preferentially in the corpus callosum (CC) and the superior cerebellar peduncles, but not in the spinal cord (SC) of C57BL/6 mice. Here we aimed to determine the activities of copper-containing enzymes in correlation with the distribution of demyelination during exposure to cuprizone. The study revealed mitochondrial complex IV and superoxide dismutase activity alterations in both the pathology-affected CC and the non-affected SC. This observation raises the possibility that regionally different subcellular molecular interactions lead to the selective oligodendrocyte loss induced by the nonselective mitochondrial toxin, cuprizone.

Neurology has been continuously transforming by the refinement of molecular diagnostics and the development of disease-modifying treatments. The discovery of new antibody markers has elucidated the pathogenesis, provided the means of diagnostics, and offered cure or treatment for several immune-mediated neurological and neuropsychiatric disorders. The identification of pathogenic and marker autoantibodies has also facilitated defining the associated phenotypic spectra and the overlap among the phenotypes linked to individual immune markers.This survey presents the list of currently known autoimmune encephalitis entities along with the associated marker autoantibodies, highlights the phenotypic and immune pathogenic relationships, calls attention to the recently described rare syndromes, discusses the biological significance of the autoantibodies and targeted molecules, points out the potential postinfectious origin of immune pathogenesis in several of the disorders, and directs the readers to the latest diagnostic guidelines as well as to the generally used treatment approaches.Owing to the successful and usually combined use of various methods to detect serum and cerebrospinal fluid autoantibodies on rodent brain sections, in primary neuronal cell culture, in immune precipitation, and cell-based assays, or in other antigen-specific immune assays (Western blot, enzyme-linked immunosorbent assay, and radioimmune assay), the subgroup of antibody marker-negative autoimmune encephalopathy syndromes is contracting, whereas the numbers of entities within the overall group are expanding. Recognition of the correct diagnosis is becoming increasingly rewarding not only for neurologists, but also for pediatric neurologists and psychiatrists.

The rare, genetically determined group of diseases characterized by pathological accumulation of iron in the central nervous system and progressive, typically movement disorder's symptoms are called NBIA (neurodegeneration with brain iron accumulation). By the rapid development of molecular genetics, it has become apparent that different mutations in numerous genes can lead to pathological cerebral iron accumulation. Simultaneously, it has also been recognized that the age of onset, the symptoms and the prognosis of NBIA disorders are much more diverse than it was previously perceived. To our knowledge, a review article on the most recent clinical data of NBIA has not been published in Hungarian. In the first part of this publication, we survey the general clinical characteristics and the diagnostic algorithm of NBIA diseases and address some considerations for differential diagnostics. In the second part of this review, the particular NBIA disorders are presented in details. The purpose of this article is to provide a clinical overview that may be useful for neurologists, pediatricians and any other medical practitioners interested in this field.

The relation between vitamin-D (VD) status and healing after hip fracture had not been sufficiently addressed. Currently serum total 25-hydroxy-VD (t-25OHD) is the most widely used indicator of VD status. It is unclear whether free or bioavailable VD are better markers of 25OHD availability for tissues. Validity of overall cut-off values of t-25OHD is limited. Objectives: (1) Assess serum levels of circulating forms of 25OHD in patients with hip fracture (PwHF: N = 199) compared to active controls without history of fracture (N = 102), (2) determine relationship between 25OHD fractions and functional performance after surgery (FPAS) and survival. The t-25OHD, VD binding protein and albumin levels were measured. Comorbidities, lifestyle, FPAS and survival were recorded at seven months. VD deficiency occurred more frequently in PwHF than in controls (72% vs. 38%). Patients with better FPAS showed higher 25OHD in all fractions than with poor FPAS. Controlled by lifestyle, 25OHD levels were independent predictive factors (p &lt, 0.001). Good FPAS values forecasted longer survival (OR: 6.5CI:3.2&ndash, 13.3, p &lt, 0.0001). All 25OHD forms showed a tendency to predict survival. Mortality rate decreased to 8% in individuals with t-25OHD levels of &gt, 22.6&ndash, 39.5 nmol/L and increased to 14% with &gt, 40 nmol/L. These observations highlight the importance of serum 25OHD assessment and moderate VD substitution for healing and survival.

Objective To test if mitochondrial (mt)DNA deletions accumulate in brains of patients with multiple sclerosis (MS). Background Previous studies demonstrated an accumulation of oxidative damage to mtDNA and decreased activity of mitochondrial enzymes in lesions of MS, where activated immune cells produce increased amounts of reactive oxygen species and nitric oxide. The unknown link between oxidative damage and decreased activity of mitochondrial enzymes may be the accumulation of deletions in mtDNA molecules. mtDNA deletions in the brain have been associated with neurodegeneration and aging. Methods mtDNA deletions were quantified by using real-time PCR in laser-dissected, COX-positive and COX-negative single neuronal and glial cells from frozen postmortem brain tissue specimens including normal appearing gray (NAGM) and white matter (NAWM) regions and chronic active plaques of MS patients, and gray matter (GM) and white matter (WM) regions of age-matched controls. Three patients with advance Alzheimer’s and Parkinson’s diseases were included as positive controls. The proportion of deleted mtDNA molecules was correlated with pathology and age. Results We detected no pathology-related accumulation of mtDNA deletions when comparisons were made among NAGM, NAWM, and plaque of MS brains, or between NAGM–GM and NAWM–WM of patients and age-matched controls. However, an accumulation of mtDNA deletions was noted in non-neurological controls beyond 60 years of age and in patients with Alzheimer’s and Parkinson’s diseases. As expected, the rate of mtDNA deletions was higher in COX− than in COX+ cells. Conclusion While aging and neurodegeneration in PD and AD are associated with accumulation of COX− cells and mtDNA deletions, the pathology of MS is not.

Pathogenic variants of the gap junction beta 1 (GJB1) gene are responsible for the Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). In this study, we report the mutation frequency of GJB1 in 210 Hungarian CMT patients and the phenotype comparison between male and female CMTX1 patients. Altogether, 13 missense substitutions were found in the GJB1 gene. Among them, 10 have been previously described as pathogenic variants (p.Arg15Trp, p.Val63Ile, p.Leu89Val, p.Ala96Gly, p.Arg107Trp, p.Arg142Gln, p.Arg164Trp, p.Arg164Gln, p.Pro172Ala and p.Asn205Ser), while 3 were novel, likely pathogenic alterations (p.Val13Glu, p.Glu186Gly, p.Met194Ile). These variants were not present in controls and were predicted as disease causing by in silico analysis. The frequency of the variants was 6.7% in our cohort which refers to a common cause of hereditary neuropathy among Hungarian patients. In addition to the classical phenotype, CNS involvement was proved in 26.1% of the CMTX1 patients. GJB1 pathogenic alterations were found mainly in males but we also detected them in female probands. The statistical analysis of CMTX1 patients revealed a significant difference between the two genders regarding the age of onset, Charcot-Marie-Tooth neuropathy and examination scores.

Identification of etiological connections among virtually distinct diseases in a patient may be sometimes challenging. We report a unique case with two B cell malignancies and an inflammatory leukoencephalopathy. Three days prior to admission, the elderly male patient developed fatigue, headaches, recurrent vomiting, memory disturbances, depression and somnolence. Clinical, laboratory and imaging evaluations as well as post mortem histological studies were performed. Simultaneous presence of primary central nervous system B cell lymphoma, temporal lobe inflammatory leukoencephalopathy and multiple (smoldering) myeloma, was revealed by the detailed work up in the treatment-naïve patient. Based on recent data from genomic studies, we propose that a sequential evolution of molecular pathology lead to the co-occurrence of multiple myeloma and primary central nervous system B cell lymphoma in this patient, and interpret the development of the temporal lobe leukoencephalopathy as a likely paraneoplastic complication of smoldering myeloma.

Glioblastoma is the most common intracranial malignancy that constitutes about 50 % of all gliomas. Despite aggressive, multimodal therapy consisting of surgery, radiation, and chemotherapy, the outcome of patients with glioblastoma remains poor with 5-year survival rates of

This review presents inherited and acquired forms of mitochondrial dysfunction associated with oligodendrocytopathy and neurodegeneration in order to better understand the degenerative features of inflammatory demyelination. The recognition that various mitochondrial mechanisms are involved in the pathogenesis of multiple sclerosis leads to therapeutic considerations, re-emphasizing the importance of early neuroprotection in combination with the approved means of immune modulation.

BACKGROUND An objective demonstration of lesions disseminated in time and space remains the core of the last revision of diagnostic criteria for multiple sclerosis (MS), but this update is now empowered by a weighted use of magnetic resonance imaging (MRI), which results in an earlier and more unambiguous diagnosis ("MS," "not MS," or "possible MS"). Nevertheless, the exclusion of other entities still remains an integral element of the diagnostic process. REVIEW SUMMARY Exclusion of genetic disorders can be challenging in some cases with familial recurrence of MS, particularly when the transmission is mimicking a mendelian or a maternal pattern of inheritance. Vice versa, many forms of mendelian leukodystrophies and leukoencephalopathies present with juvenile or adult onset, progressive or relapsing-remitting courses, intrafamilial phenotypic heterogeneity and MRI signs of multifocal white matter (WM) pathology, features potentially leading to a temporary confusion with MS. With the recent availability of disease modifying medications in MS, the development of specific molecular therapies in inherited WM disorders, and the general recognition of the effectiveness of early treatments, the accuracy of initial diagnostic assessment has become critical. CONCLUSION Considering the importance of disease specific treatments, here we review the major characteristics of familial MS and some of the inheritable diseases of the WM. Although no direct genetic link between MS and these WM abnormalities is known, molecular data from the field of rare genetic disorders may also provide some experimental paradigms to a further exploration of MS.

We measured the mRNA expression levels of molecules involved in scavenging free radicals and in apoptosis within normal appearing white and gray matter (NAWM and NAGM, respectively) and chronic active plaque containing frontal lobe specimens of patients with multiple sclerosis (MS). While no regional differences were detected in the mRNA levels of free radical scavengers, Bcl-XL was higher in plaques than in NAWMs, and both Bak and Bcl-2 were found to be increased in correlation with an immune marker (beta2-microglobulin--beta2Mg) in NAWM and plaque compared with corresponding cortical regions. We did not measure a similar white-gray matter difference in the expression of the latter genes in brains of normal or Alzheimer disease controls. This finding indicates that both pro- and anti-apoptotic mechanisms are activated, not only within but also outside of plaques.

Neurodegeneration is the main pathological correlate of accumulating disability in progressive stages of Multiple Sclerosis (MS), but both histologic and imaging studies detect significant tissue loss even in early disease. These observations raise the question as to whether neurodegeneration in MS is a primary mechanism or whether it develops secondary to inflammation and demyelination. Recent data suggest that the atrophy of brain and cord is directly linked to inflammation and may partly be independent of demyelination. Released products of both residential and infiltrating immune cells can induce ultrastructural changes and cell-death by multiple mechanism. We propose that the inflammation-induced tissue response is controlled by genetic variations and to some extent involves a mitochondrion-driven mechanism in MS, similar to that described in the final pathway of other neurodegenerative disorders. Current therapeutic strategies primarily target the immune system which results in a successful down-regulation of plaque formation and of relapse rate. However, measures of clinical disability best correlate with the degree of neurodegeneration rather than with the volume of plaques, and these immune-modulating regimens may only incompletely affect the accumulating tissue loss. Considering the need for additional therapeutic strategies, we emphasize the degenerative components, and review a mitochondrial mechanism of tissue loss potentially involved in the process of MS.

Background: Chronic progressive external ophthalmoplegia (CPEO) may be related to primary nuclear DNA or mitochondrial (mt)DNA mutations. The A3243G mtDNA point mutation most frequently causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, but also has been associated with other phenotypes including CPEO, migraine, seizure, diabetes, and sensorineural hearing loss. Case description: We report a 38-year-old white man with seizures and progressive difficulties of infantile origin including CPEO, sensorineural hearing loss, cataracts, migraines, multiple endocrinopathy, myopathy, and cardiomyopathy. Moderate hearing loss in association with CPEO, diabetes mellitus, or migraines were noted in the proband's maternal grandmother, great aunt, mother, and three sisters, suggesting either an autosomal dominant or maternal inheritance. Detailed histological and biochemical analysis of the proband's biopsied muscle specimen revealed severe abnormalities compatible with a mitochondrial disease. MtDNA analysis excluded large-scale deletions, but revealed a heteroplasmic A to G transition at nt3243 in 56.4% and 27.4% of molecules in muscle and white blood cells, respectively. Conclusion: We discuss possible causes of this intrafamilial heterogeneity of phenotypes associated with the A3243G mtDNA mutation.

Since the first description of multiple sclerosis (MS) as an inheritable disease by Eichhorst [1] accumulating epidemiological observations support a genetic hypothesis. Population, family and twin studies have revealed that Mendelian transmission of a single susceptibility gene would not be compatible with the observed patterns of inheritance. Like most other common diseases, MS is a complex trait, defined by several genes, each probably exerting a relatively small effect. Complex interactions among susceptibility genes and the environment are believed to contribute to a predisposition to dysregulation of inflammatory pathways, demyelination and tissue degeneration in the central nervous system (CNS). Natural history and pathological studies, however, define that MS represents a spectrum rather than a single entity of inflammatory demyelination. Despite a growing need for identifying molecular markers of biological subtypes of MS, only limited information is available for genotype-phenotype correlations. Four full genome scans using polymorphic microsatellite markers in nuclear and multiplex MS families indicated several chromosomal regions of susceptibility. With the recently discovered, highly abundant single nucleotide polymorphisms (SNPs) and family-based association methods, the means are now available to confine these relatively large regions of interest to candidate genes and susceptibility alleles. The currently available SNP maps favor indirect association studies based on linkage disequilibrium between marker and disease alleles. Here, we review available genetic data in MS, and introduce an additional strategy which correlate genetic markers with major biological components of the disease such as autoimmunity and neurodegeneration. This approach may yield important insights with utility in clinical practice.

Nearly 6000 autoptic studies were carried out during the last 50 years at the Laboratory of Neuropathology, Markusovszky University Teaching Hospital, Hungary.The aim of the authors was to present those previously frequent and often fatal conditions that can be prevented or treated today.Retrospective analyses of the neuropathological documentations.Measles-related subacute sclerosing panencephalitis caused death in 13 cases, the last occurred in 1991. The mandatory vaccination against the causative virus has eliminated this severe neurological complication. Fourteen lives were lost due to herpes simplex encephalitis, including the last case seen in 1999. Feasibility of early diagnosis and the availability of acyclovir therapy resulted in better outcome without fatality. Tuberculous meningitis still occurred in most recent years, although only sporadically. Recognition of this condition is not straightforward due to its rarity, and considerations for this disease are often omitted from the routine differential diagnosis. The generally low mortality rates in tick borne encephalitis further dropped after the introduction of vaccination. Altogether only 8 such cases were documented. The last fatal cases of neurolues were seen in the 1990s. However, syphilis itself has not disappeared, and the number of cases with newly acquired infection continues to rise. The introduction of intrathecal methotrexate and radiotherapy made possible the prevention or effective treatment of meningeal leukosis. A careful coordination of these treatment modalities, however, is important as nervous system complications may develop in the form of disseminated necrotizing leukoencephalopathy that is also reflected in the records.The 50-year neuropathology documentation reflects changes in the occurrence of diseases, and it calls attention to those disorders which can be prevented or treated today, but may represent diagnostic challenges.Bevezetés: A Markusovszky Egyetemi Oktatókórház Neuropatológiai Laboratóriumában az elmúlt 50 évben közel 6000 esetben történt autopsziás vizsgálat. Célkitűzés: A szerzők célja azon korábban gyakori, magas mortalitású betegségek bemutatása, amelyek ma már megelőzhetőek vagy kezelhetőek. Módszer: A neuropatológiai dokumentáció retrospektív áttekintése. Eredmények: A morbilli vírusa okozta szubakut szklerotizáló panencephalitis miatt 13 beteg halt meg, az utolsó haláleset 1991-ben volt. A kötelező védőoltás bevezetése vetett véget a halálos megbetegedésnek. Herpes simplex encephalitis miatt 14-en vesztették életüket, az utolsó 1999-ben. A korai diagnosztizálás feltételeinek javulása és az aciclovirkezelés tette lehetővé a halálesetek elkerülését. Meningitis basilaris tuberculosa szórványosan, de az utóbbi években is előfordult. Felismerése nem könnyű, ritkasága miatt kikerült a rutindiagnosztika gondolatmenetből. Kullancsencephalitisben a védőoltások elérhetővé válása folyamatosan tovább csökkentette a különben is ritka, összesen 8 esetben dokumentált halálos esetek számát. Fatális kimenetelű neuroluessel az 1990-es években találkoztak utoljára, de a syphilis nem tűnt el, sőt a friss fertőzések száma emelkedik. A meningiosis leukaemica kivédését az intrathecalis methotrexat adása és radioterápia tette lehetővé, amelyek alkalmazása azonban óvatosságot igényel, a szerzők esetei között is jegyzett disszeminált nekrotizáló leukoencephalopathia kialakulásának lehetősége miatt. Következtetések: A Neuropatológiai Laboratórium 50 éves dokumentációja tükrözi a betegségek előfordulásának változásait, és felhívja a figyelmet azokra a kórképekre, amelyek ma már megelőzhetők vagy kezelhetők, de diagnosztikus kihívást is jelenthetnek. Orv. Hetil., 2014, 155(43), 1722–1728.

Aim: To report a child with an extensive tumor invading multiple anatomical structures within the left side of her neck. Material and methods: Presentation of a case including patient’s history, physical exam, molecular data, MRI imaging, histopathology and molecular genetics. Results: The life-threatening compression as well as the dislocation of the trachea required meticulous surgical removal of the tumor. Histology revealed a plexiform neurofibroma related to a frame shift mutation in the NF1 gene. Conclusion: Surgical removal of this extensive tumor saved the patient’s life. The long term success of management will be related to the effectiveness of the maintenance therapy that currently includes interferon-α2a. This report highlights unique aspects of a rare but life threatening condition in a young girl.

Glioblastoma is the most common intracranial malignancy and constitutes about 50 % of all gliomas. Both inter-tumor and intra-tumor histological heterogeneity had been recognized by the early 1980-ies. Recent works using novel molecular platforms provided molecular definitions of these tumors. Based on comprehensive genomic sequence analyses, The Cancer Genome Atlas Research Network (TCGA) cataloged somatic mutations and recurrent copy number alterations in glioblastoma. Robust transcriptome and epigenome studies also revealed inter-tumor heterogeneity. Integration and cluster analyses of multi-dimensional genomic data lead to a new classification of glioblastoma tumors into subtypes with distinct biological features and clinical correlates. However, multiple observations also revealed tumor area-specific patterns of genomic imbalance. In addition, genetic alterations have been identified that were common to all areas analyzed and other alterations that were area specific. Analyses of intra-tumor transcriptome variations revealed that in more than half of the examined cases, fragments from the same tumor mass could be classified into at least two different glioblastoma molecular subgroups. Intra-tumor heterogeneity of molecular genetic profiles in glioblastoma may explain the difficulties encountered in the validation of oncologic biomarkers, and contribute to a biased selection of patients for single target therapies, treatment failure or drug resistance. In this paper, we summarize the currently available literature concerning inter- and intra-tumor molecular heterogeneity of glioblastomas, and call attention to the importance of this topic in relation to the growing efforts in routine molecular diagnostics and personalized therapy.

The aim of this review is to highlight recent observations concerning the pathogenesis of acute and chronic inflammatory demyelinating diseases in the central nervous system. Without attempting to provide a didactic classification or a complete survey, we emphasize the discriminative nature of new clinical, imaging, and immunopathologic data, which, even in the absence of specific molecular markers, modify our views about the nosologic relations among these overlapping clinicopathologic entities. In the light of new findings, multiple sclerosis may represent a spectrum of demyelinating diseases rather than a single entity.

Soluble products of activated immune cells include reactive oxygen species (ROS) and nitric oxide (NO) with a high potential to induce biochemical modifications and degenerative changes in areas of inflammation in the central nervous system (CNS). Previously, we demonstrated an increased production of ROS by activated mononuclear cells (MNC) of patients with multiple sclerosis (MS) compared to those of controls, and development of oxidative damage to total DNA in association with inflammation in chronic active plaques. The current study aimed to determine whether mitochondrial (mt)DNA is affected by oxidative damage, and whether oxidative damage to mitochondrial macromolecules (including mtDNA) is associated with a decline in the activity of mitochondrial enzyme complexes. Using molecular and biochemical methods we demonstrate a trend for impaired NADH dehydrogenase (DH) activity and a possible compensatory increase in complex IV activity in association with oxidative damage to mtDNA in chronic active plaques. Immunohistochemistry confirms the increase of oxidative damage to DNA predominantly located in the cytoplasmic compartment of cells in chronic active plaques. These observations suggest that oxidative damage to macromolecules develops in association with inflammation in the CNS, and may contribute to a decline of energy metabolism in affected cells. As observed in neurodegenerative diseases of non-inflammatory origin, decreased ATP synthesis can ultimately lead to cell death or degeneration. Therefore, elucidation of this pathway in MS deserves further studies which may identify neuroprotective strategies to prevent tissue degeneration and the associated clinical disability.

IgG binding to multiple protein constituents in lysates of Jurkat cells was detected by Western blot in sera of patients with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The distribution patterns of bands with sera tested against protein lysates from normal Jurkat cells or from Jurkat cells exposed to apoptosis or oxidative stress inducing conditions were similar in most patients, but with inter-individual differences. The number of bands with sera of both patient populations far exceeded those (0 or 2 bands) detected with sera of healthy controls. Proteinase K, RNase and DNase pre-treatment of cell lysates suggested a protein nature for all of the antigens and a ribonucleoprotein (RNP) nature for some of the antigens recognized by serum IgG of MS and SLE patients. Only two MS patients had positive anti-nuclear antibody (ANA) titers, while all of them had positive Western blots. In addition to similarities, dissimilarities were also recognized between the humoral immune responses in MS and SLE. No IgG molecules were detected against phosphorylated proteins in the sera of MS patients, while multiple phosphoproteins were recognized by IgG molecules of SLE patients in immunoprecipitation experiments. These data suggest that in addition to ANA, the sera of MS patients contain autoantibodies directed against multiple intracellular proteins. The protein recognition patterns of immunoglobulins in MS share similarities, but also have distinct features when compared to those in SLE. The biological significance of these autoantibodies in MS remains to be understood.

Aims of the symposium The permanent acquirement and clinical application of exponentially growing new scientific discoveries are demanding tasks for academic neurologists. To facilitate the overview of recent developments in basic and clinical sciences of inflammatory demyelination we invited seven internationally recognized experts in multiple sclerosis (MS) to discuss their most recent works. These lectures allowed the audience to formulate a modern concept of MS by integrating data from studies on molecular pathogenesis, genetics, MRI characteristics and clinical trials. The audience was invited from the broader medical community including graduate and medical students, neurology residents, private practitioners, academic neurologists, clinical and research specialists of MS.