RESUMO
OBJECTIVE: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2). METHODS: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures. RESULTS: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05). SIGNIFICANCE: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries.
Assuntos
Epilepsia , Humanos , Resultado do Tratamento , Epilepsia/diagnóstico , Epilepsia/cirurgia , Convulsões/cirurgia , Nomogramas , Medição de RiscoRESUMO
Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/terapia , Cuidados PaliativosRESUMO
We report the case of a 42-year-old woman with paraparesis associated with transverse myelitis. For differential diagnostics detailed microbiological, cerebrospinal fluid (CSF) and neuroimaging examinations were performed. Syphilis was confirmed, but diagnosis of neurosyphilis was only probable based on the CSF microbiological test results. The beneficial treatment response to application of the therapeutic protocol for syphilis supported the supposed diagnosis of syphilis-associated myelitis in our case. In this case report we reviewed the differential diagnostic tools of myelopathies/myelitis.
Nowadays regarding to growing prevalence of syphilis worldwide physicians should face on its presence and medical consequences.
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Mielite Transversa , Neurossífilis , Sífilis , Feminino , Humanos , Adulto , Sífilis/líquido cefalorraquidiano , Sífilis/complicações , Sífilis/diagnóstico , Neurossífilis/diagnóstico , Neurossífilis/complicações , Neurossífilis/tratamento farmacológico , Diagnóstico Diferencial , PrevalênciaRESUMO
BACKGROUND: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS). OBJECTIVES: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS). METHODS: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries. RESULTS: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment. CONCLUSION: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cladribina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Imunossupressores/uso terapêutico , Estudos Retrospectivos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Comprimidos/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Sandhoff disease is a rare type of hereditary (autosomal recessive) GM2-gangliosidosis, which is caused by mutation of the HEXB gene. Disruption of the ß subunit of the hexosaminidase (Hex) enzyme affects the function of both the Hex-A and Hex-B isoforms. The severity and the age of onset of the disease (infantile or classic; juvenile; adult) depends on the residual activity of the enzyme. The late-onset form is characterized by diverse symptomatology, comprising motor neuron disease, ataxia, tremor, dystonia, psychiatric symptoms and neuropathy. METHODS: A 36-year-old female patient has been presenting progressive, symmetrical lower limb weakness for 9 years. Detailed neurological examination revealed mild symmetrical weakness in the hip flexors without the involvement of other muscle groups. The patellar reflex was decreased on both sides. Laboratory tests showed no relevant alteration and routine electroencephalography and brain MRI were normal. Nerve conduction studies and electromyography revealed alterations corresponding to sensory neuropathy. Muscle biopsy demonstrated signs of mild neurogenic lesion. Her younger brother (32-year-old) was observed with similar symptoms. RESULTS: Detailed genetic study detected a known pathogenic missense mutation and a 15,088 base pair long known pathogenic deletion in the HEXB gene (NM_000521.4:c.1417G>A; NM_000521:c.-376-5836_669+1473del; double heterozygous state). Segregation analysis and hexosaminidase enzyme assay of the family further confirmed the diagnosis of late-onset Sandhoff disease. CONCLUSION: The purpose of this case report is to draw attention to the significance of late-onset Sandhoff disease amongst disorders presenting with proximal predominant symmetric lower limb muscle weakness in adulthood.
Assuntos
Doença dos Neurônios Motores , Doença de Sandhoff , Adulto , Feminino , Hexosaminidase A/genética , Hexosaminidase B/genética , Humanos , Masculino , Mutação , Doença de Sandhoff/diagnóstico , Doença de Sandhoff/genéticaRESUMO
Cerebral calcification may be caused by several potentially treatable conditions, however, in most cases it does not receive special attention in clinical practice. From the point of view of etiology, the diseases associated with cerebral calcification can be divided into two main groups: idiopathic (mostly incurable) and secondary (potentially treatable). The first group includes mainly the hereditary diseases identified before 2021 (primary familial brain calcification subtypes, previously known as Fahr's disease or Fahr's syndrome). In contrast, the second group includes diseases with cerebral calcification that develop generally as a consequence of metabolic/endocrine/autoimmune abnormalities. The aim of our research was to present hereditary and non-hereditary etiologies associated with extensive brain calcification. We compare the detailed clinical, radiological and laboratory results of 6 patients with prominent cerebral calcification identified in our clinic in the last 3 years (idiopathic and secondary etiologies as well). Our research draws attention to the complexity of the etiologies in the context of cerebral calcification. We recommend, beside NGS-based sequence analyses, the application of array comparative genomic hybridization as well, to identify potential genetic etiologies associated with brain calcification.
Assuntos
Doenças dos Gânglios da Base , Calcinose , Doenças Neurodegenerativas , Encéfalo/diagnóstico por imagem , Calcinose/complicações , Calcinose/diagnóstico por imagem , Calcinose/genética , Hibridização Genômica Comparativa , HumanosRESUMO
BACKGROUND AND PURPOSE: Although vertigo is one of the most common complaints, intracranial malignant tumors rarely cause sudden asymmetry between the tone of the vestibular peripheries masquerading as a peripheral-like disorder. Here we report a case of simultaneous temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting as acute unilateral vestibular syndrome, due to the reawakening of a primary gastric signet ring cell carcinoma. Purpose - Our objective was to identify those pathophysiological steps that may explain the complex process of tumor reawakening, dissemination. The possible causes of vestibular asymmetry were also traced. METHODS: A 56-year-old male patient's interdisciplinary medical data had been retrospectively analyzed. Original clinical and pathological results have been collected and thoroughly reevaluated, then new histological staining and immunohistochemistry methods have been added to the diagnostic pool. RESULTS: During the autopsy the cerebrum and cerebellum was edematous. The apex of the left petrous bone was infiltrated and destructed by a tumor mass of 2x2 cm in size. Histological reexamination of the original gastric resection specimen slides revealed focal submucosal tumorous infiltration with a vascular invasion. By immunohistochemistry mainly single infiltrating tumor cells were observed with Cytokeratin 7 and Vimentin positivity and partial loss of E-cadherin staining. The subsequent histological examination of necropsy tissue specimens confirmed the disseminated, multi-organ microscopic tumorous invasion. Discussion - It has been recently reported that the expression of Vimentin and the loss of E-cadherin is significantly associated with advanced stage, lymph node metastasis, vascular and neural invasion and undifferentiated type with p<0.05 significance. As our patient was middle aged and had no immune-deficiency, the promoting factor of the reawakening of the primary GC malignant disease after a 9-year-long period of dormancy remained undiscovered. The organ-specific tropism explained by the "seed and soil" theory was unexpected, due to rare occurrence of gastric cancer to metastasize in the meninges given that only a minority of these cells would be capable of crossing the blood brain barrier. CONCLUSION: Patients with past malignancies and new onset of neurological symptoms should alert the physician to central nervous system involvement, and the appropriate, targeted diagnostic and therapeutic work-up should be established immediately. Targeted staining with specific antibodies is recommended. Recent studies on cell lines indicate that metformin strongly inhibits epithelial-mesenchymal transition of gastric cancer cells. Therefore, further studies need to be performed on cases positive for epithelial-mesenchymal transition.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células em Anel de Sinete/secundário , Carcinomatose Meníngea/secundário , Neoplasias Gástricas/secundário , Osso Temporal/patologia , Vertigem/etiologia , Carcinoma de Células em Anel de Sinete/patologia , Transição Epitelial-Mesenquimal , Humanos , Metástase Linfática/patologia , Masculino , Carcinomatose Meníngea/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/patologiaRESUMO
Diffuse midline gliomas, H3 K27M-mutant, World Health Organization (WHO) grade IV represent a distinct glioma entity with a predominantly paediatric presentation and remarkably poor prognosis. This report presents a case of a 73-year-old woman with a diffuse midline glioma, H3 K27M-mutant, WHO grade IV with a remarkable longitudinal extension, extending from the cervical myelon to the basal ganglia. On imaging, the lesion was predominantly suggestive of inflammatory oedema, and it was clinically associated with progressive hemi- and later tetraparesis with severe autonomic and bulbar symptoms. Laboratory examinations suggested a generalized inflammatory process; however, neither infectious nor autoimmune aetiology could be confirmed. Biopsy was deemed unfeasible given the critical localization. Presuming a seronegative autoimmune encephalomyelitis, high-dose corticosteroid therapy and plasma exchanges were conducted, resulting in a modest but transient relief. The patient passed away two months after hospitalization. Neuropathological examination of the lesion revealed a high-grade diffuse glioma with H3 K27M mutation (grade IV). Although originally considered as a paediatric entity, our case confirms reports from recent years that diffuse midline gliomas, H3 K27M-mutant, WHO grade IV can occur in adults, even among the elderly, and can mimic inflammatory alterations, posing diagnostic difficulty. Our case is one of the oldest patients reported with this pathology, the oldest with an extensive diffusely infiltrating growth pattern, and with the most extensive lesion reported in adulthood.
Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Histonas/genética , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Diagnóstico Diferencial , Feminino , Glioma/genética , Glioma/patologia , Humanos , Inflamação/diagnóstico , Inflamação/patologiaRESUMO
OBJECTIVE: The prevalence of xeroderma pigmentosum (XP) is quite low in Europe, which may result in a delay in determining the appropriate diagnosis. Furthermore, some subtypes of XP, including XPA, may manifest themselves with quite severe neurological symptoms in addition to the characteristic dermatological lesions. Accordingly, the aim of the current study is to highlight the predominant neurological aspects of XPA, as well as mild-to-moderate dermatological signs in a Hungarian family with 5 affected siblings. CASE REPORTS: The symptoms of the Caucasian male proband started to develop at 13-14 years of age with predominantly cerebellar, hippocampal, and brainstem alterations. His elder sister and three younger brothers all presented similar, but less expressed neurological signs. The diagnostic work-up, including clinical exome sequencing, revealed 2 novel compound heterozygous mutations (p.Gln146_Tyr148delinsHis, p.Arg258TyrfsTer5) in the XPA gene. Surprisingly, only mild-to-moderate dermatological alterations were observed, and less severe characteristic ophthalmological and auditory signs were detected. CONCLUSIONS: In summary, we present the first family with genetically confirmed XPA in the Central-Eastern region of Europe, clearly supporting the notion that disturbed function of the C-terminal region of the XPA protein contributes to the development of age-dependent neurologically predominant signs. This case series may help clinicians recognize this rare disorder.
Assuntos
Mutação/genética , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/genética , Proteína de Xeroderma Pigmentoso Grupo A/genética , Xeroderma Pigmentoso/diagnóstico por imagem , Xeroderma Pigmentoso/genética , Adulto , Evolução Fatal , Feminino , Humanos , Hungria , Masculino , Doenças do Sistema Nervoso/complicações , Linhagem , Fenótipo , Xeroderma Pigmentoso/complicaçõesAssuntos
Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Cognição , Mutação de Sentido Incorreto , Ataxias Espinocerebelares/congênito , Adulto , Encéfalo/diagnóstico por imagem , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Ataxias Espinocerebelares/psicologiaRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of the motor neurons. To date, 126 genes have been implicated in ALS. Therefore, the heterogenous genetic background of ALS requires comprehensive genetic investigative approaches. METHODS: In this study, DNA from 28 Hungarian ALS patients was subjected to targeted high-throughput sequencing of the coding regions of three Mendelian ALS genes: FUS, SETX, and C9ORF72. RESULTS: A novel heterozygous missense mutation (c.791A>G, p.N264S) of the SETX gene was identified in a female patient presenting an atypical ALS phenotype, including adult onset and lower motor neuron impairment. No further mutations were detected in the other Mendelian ALS genes investigated. CONCLUSION: Our study contributes to the understanding of the genetic and phenotypic diversity of motor neuron diseases (MNDs). Our results also suggest that the elucidation of the genetic background of MNDs requires a complex approach, including the screening of both Mendelian and non-Mendelian genes.
Assuntos
Esclerose Lateral Amiotrófica/genética , Mutação de Sentido Incorreto , RNA Helicases/genética , Idoso , Proteína C9orf72 , DNA Helicases , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Enzimas Multifuncionais , Fenótipo , Proteínas/genética , Proteína FUS de Ligação a RNA/genéticaRESUMO
AARS2 gene (NM_020745.3) mutations result in two different phenotypic diseases: infantile mitochondrial cardiomyopathy and late-onset leukoencephalopathy. The patient's first symptoms appeared at the age of 18 years with behavioral changes and psychiatric problems. Some years later, extrapyramidal symptoms, cognitive impairment, nystagmus, dysarthria and pyramidal symptoms also developed. The brain magnetic resonance imaging (MRI) indicated extensive white matter abnormalities. The diagnosis of AARS2 gene mutations causing leukodystrophy was confirmed by genetic testing. Segregation analysis confirmed the compound heterozygous state of the patient. Histological examination of the biopsy did not prove specific pathological alterations. The clinical phenotype of our patient was compared with seven previously described patients suffering from leukoencephalopathy caused by AARS2 mutations. We have documented a new, nonsense AARS2 gene mutation (c.578T>G, p.Leu193*) and a known missense mutation (c.595C>T, p.Arg199Cys) associated with leukoencephalopathy in a male patient. Clinical features, imaging characteristics and genetic testing are presented, and histological data from an AARS2-related leukodystrophy patient are described for the first time.
Assuntos
Alanina-tRNA Ligase/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Mutação de Sentido Incorreto/genética , Substância Branca/anormalidades , Adulto , Transtornos Cognitivos/genética , Feminino , Testes Genéticos , Humanos , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Insuficiência Ovariana Primária/genéticaRESUMO
Cerebrotendinous xanthomatosis (CTX) is a rare, genetically determined error of metabolism. The characteristic clinical symptoms are diarrhea, juvenile cataracts, tendon xanthomas and neuropsychiatric alterations. The aim of this study is to present a pair of identical adult twins with considerable differences in the severity of phenotype. With regards to neuropsychiatric symptoms, the predominant features were severe Parkinsonism and moderate cognitive dysfunctions in the more-affected individual, whereas these alterations in the less-affected patient were only very mild and mild, respectively. The characteristic increase in the concentrations of serum cholestanol and the lesion volumes in dentate nuclei in the brain assessed with magnetic resonance imaging were quite similar in both cases. The lifestyle conditions, including eating habits of the twin pair, were quite similar as well; therefore, currently unknown genetic modifiers or certain epigenetic factors may be responsible for the differences in severity of phenotype. This case series serves as the first description of an identical twin pair with CTX presenting heterogeneous clinical features.
Assuntos
Gêmeos Monozigóticos , Xantomatose Cerebrotendinosa/fisiopatologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Fenótipo , Xantomatose Cerebrotendinosa/diagnóstico por imagem , Xantomatose Cerebrotendinosa/patologiaRESUMO
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.
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Encéfalo/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Ferro/metabolismo , Mutação , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Alopecia/diagnóstico , Alopecia/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/genética , Encéfalo/patologia , Ceruloplasmina/genética , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Fosfolipases A2 do Grupo VI/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/terapia , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/terapia , Oxigenases de Função Mista/genética , Distrofias Neuroaxonais/metabolismo , Distrofias Neuroaxonais/terapia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Transferases/genéticaRESUMO
INTRODUCTION: The proven pathological alterations in the kynurenine pathway of tryptophan metabolism, either in preclinical models of neurological and psychiatric disorders or in human samples themselves, elicited numerous attempts to restore the altered balance via pharmaceutical manipulation of the pathway. AREAS COVERED: The aim of the authors was to conduct a review of relevant scientific data on enzyme inhibitors of the kynurenine pathway, with special attention to pipeline drug development strategies based on relevant patent literature, covering the period of 2012-2015. Considering the magnitude of the topic, only the most prominent examples of lead compounds and substances necessary to enlighten structure activity relationships were reported. EXPERT OPINION: Although the clinical and preclinical data are reassuring, there is a lack of applicable drugs in daily clinical practice. However, the recent determination of enzyme structures considerably promoted the development of potent inhibitors, most of them having been designed as a structural analog of the natural enzyme substrate. Especially, the inhibition of indolamine 2,3-dioxygenase in central nervous system tumors, the inhibition of kynurenine aminotransferase in cognitive dysfunction, and the inhibition of kynurenine 3-monooxygenase in neurodegenerative disorders, such as Huntington's disease, each show great promise.
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Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Cinurenina/metabolismo , Animais , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Inibidores Enzimáticos/química , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Patentes como Assunto , Relação Estrutura-Atividade , Triptofano/metabolismoRESUMO
BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. METHODS: We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. RESULTS: Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1. CONCLUSION: This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.
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Adenosina Trifosfatases/genética , Predisposição Genética para Doença/genética , Metaloendopeptidases/genética , Polimorfismo de Nucleotídeo Único/genética , Paraplegia Espástica Hereditária/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Biologia Computacional , Feminino , Proteínas de Ligação ao GTP/genética , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Hungria , Lactente , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Proteínas/genética , Paraplegia Espástica Hereditária/epidemiologia , Paraplegia Espástica Hereditária/fisiopatologia , Espastina , Adulto JovemRESUMO
OBJECTIVES: Different methods of open or minimally invasive thymectomies have been recommended for the treatment of myasthenia gravis (MG). We compared the results of standard transsternal thymectomy (TS) and two different types of minimally invasive thymectomies [video-assisted thoracoscopic extended thymectomy (VATET) and classic Video-Assisted Thoracoscopic Surgery (cVATS)] performed at the same department. METHODS: During three different time periods 71 patients (60 female and 11 male; mean age 31 [range, 14-84] years) underwent thymectomy for MG. Twenty-three underwent standard transsternal thymectomy (January 1995 - September 2004), 22 VATET (September 2004 - August 2009), and 26 cVATS (September 2009 - December 2011) thymectomy for the right side. Operative data, MG- and surgery-related postoperative morbidity and early improvement of MG during the initial 1-year follow-up period were compared among the three methods. RESULTS: There were no perioperative deaths during the study period. Operative time was 112, 211, and 116 minutes (p = 0.001) in the TS, VATET and cVATS, respectively, and the length of hospital stay was 8.9, 5.6, and 4.0 (p = 0.001) days. Postoperative MG-related neurological morbidity affected 21.7%, 18.2%, and 7.7% (p = 0.365) of the patients and the surgery-related morbidity rate was 4.3%, 13.7%, and 0% (p = 0.118) in the TS, VATET and cVATS groups, respectively. Symptom improvement rates were 91.3%, 94.7%, and 87.5% (p = 0.712), and complete remission rates were 13%, 10.5%, and 11.5% (p = 0.917) after TS, VATET and cVATS thymectomies, respectively. CONCLUSIONS: In terms of operative time and hospital stay the best results were found after cVATS. The use of a less invasive surgical intervention resulted in less surgical-, and MG related neurological complications. The improvement of MG symptoms was excellent and results were similar after different types of thymectomies.
RESUMO
Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1 alpha (PGC-1α) is involved in the regulation of mitochondrial biogenesis, respiration, and adaptive thermogenesis. The full-length PGC-1α (FL-PGC-1α) comprises multiple functional domains interacting with several transcriptional regulatory factors such as nuclear respiratory factors, estrogen-related receptors, and PPARs; however, a number of PGC-1α splice variants have also been reported recently. In this study, we examined the expression levels of FL-PGC-1α and N-truncated PGC-1α (NT-PGC-1α), a shorter but functionally active splice variant of PGC-1α protein, in N171-82Q transgenic and 3-nitropropionic acid-induced murine model of Huntington's disease (HD). The expression levels were determined by RT-PCR in three brain areas (striatum, cortex, and cerebellum) in three age groups (8, 12, and 16 weeks). Besides recapitulating prior findings that NT-PGC-1α is preferentially increased in 16 weeks of age in transgenic HD animals, we detected age-dependent alterations in both models, including a cerebellum-predominant upregulation of both PGC-1α variants in transgenic mice, and a striatum-predominant upregulation of both PGC-1α variants after acute 3-nitropropionic acid intoxication. The possible relevance of this expression pattern is discussed. Based on our results, we assume that increased expression of PGC-1α may serve as a compensatory mechanism in response to mitochondrial damage in transgenic and toxin models of HD, which may be of therapeutic relevance.
Assuntos
Doença de Huntington/genética , Fatores de Transcrição/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Doença de Huntington/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nitrocompostos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Propionatos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismoRESUMO
In the advanced Parkison's disease (PD) the late complications of levodopa therapy have to be considered: motor and/or non-motor fluctuations with or without disturbing dyskinesias. The non-motor fluctuations often influence the quality of life (QoL) in a much more negative way compared with the motor symptoms. In the treatment of advanced PD there are several device-aided methods - deep brain stimulation, apomorphine pump, levodopa/carbidopa intestinal gel (LCIG) - to improve the symptoms, the QoL, sometimes even in an individual, tailored custom form. The LCIG therapy was introduced in Hungary in 2011. Here we summarize the data of our patients: we have tested almost 60 patients and in 43 cases we have started this treatment. We analyze the duration of illness, levodopa therapy, motor and non-motor fluctuation of patients and present our experiences with the test phase and the chronic LCIG therapy via PEG/PEJ implantation. We paid attention to the surgery and device - depending side effects. Our experiences are similar to the international data. In patients selection ,,the right treatment, to the right patient, in the right time" is of importance.