RESUMO
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.
Assuntos
Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Motivo Estéril alfa/genética , Adulto , Idade de Início , Autoantígenos/genética , Sequência de Bases , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/patologia , Feminino , Instabilidade Genômica , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Íntrons , Masculino , Linhagem , Células de Purkinje/patologia , Proteínas de Ligação a RNA/genética , Análise de Sequência de DNARESUMO
BACKGROUND/AIMS: Evidence on modifiable factors associated with cognitive impairment in Japanese patients is scarce. This study aimed to determine modifiable factors for cognitive impairment in a Japanese hospital-based population. METHODS: Subjects of this cross-sectional study were 1,143 patients of Sado General Hospital (Niigata, Japan) registered in the Project in Sado for Total Health (PROST) between June 2008 and September 2014. We assessed disease history, body mass index (BMI), leisure time physical activity, walking time, smoking and drinking habits, and consumption of vegetables, fruits, and green tea as predictors, with cognitive impairment defined by the Mini-Mental State Examination (score <24) as an outcome. Multiple logistic regression analysis was performed to calculate odds ratios (ORs) for cognitive impairment. RESULTS: The mean subject age was 68.9 years, and the prevalence of cognitive impairment was 21.5%. Multivariate analysis revealed that age (p < 0.001), low BMI (<21.1; OR 1.39, 95% CI 1.12-1.72), a history of stroke (p = 0.003), a history of myocardial infarction (p = 0.038), low fruit consumption (p for trend = 0.012), and low green tea consumption (p for trend = 0.032) were independently associated with a higher prevalence of cognitive impairment. CONCLUSIONS: Modifiable factors, such as low BMI, low fruit consumption, and low green tea consumption, are associated with cognitive impairment. Longitudinal studies will be needed to confirm these findings.
RESUMO
A 60-year-old man presented with progressive dementia and generalized convulsions. An initial MRI revealed a widespread high-intensity area with a mass effect in the right frontal and temporal lobes on T2-weighted images. Findings on digital subtraction angiography were normal. Serum and CSF tests showed high titers of antibodies to Treponema pallidum, which helped to distinguish neurosyphilis from glioma. He was initially treated with penicillin injection; however, it caused liver dysfunction and penicillin was switched to erythromycin. Even after antibiotic therapy for 2 months, his dementia did not improve. He underwent brain MRI four times during the treatment course, and they showed steady progression of brain atrophy in the right hemisphere. Taking these findings together, we diagnosed Lissauer form of general paresis. To the best of our knowledge, this is the first case of Lissauer form of paretic neurosyphilis, in which the progression of brain atrophy was clearly demonstrated on MRI.
Assuntos
Imageamento por Ressonância Magnética , Neurossífilis/diagnóstico , Neurossífilis/etiologia , Atrofia , Angiografia Cerebral , Córtex Cerebral/patologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Neurossífilis/complicações , Neurossífilis/patologia , Neurossífilis/fisiopatologiaRESUMO
The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/líquido cefalorraquidiano , Hipertrofia/sangue , Hipertrofia/líquido cefalorraquidiano , Meningite/sangue , Meningite/líquido cefalorraquidiano , Peroxidase/sangue , Peroxidase/líquido cefalorraquidiano , Vasculite/enzimologia , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Hipertrofia/enzimologia , Masculino , Meningite/enzimologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Vasculite/sangue , Vasculite/líquido cefalorraquidianoRESUMO
We report a 75-year-old man with a 3.5-year history of cerebral amyloid angiopathy (CAA)-related inflammation. His initial symptom was headache and sensory aphasia appeared 1 month later. Brain MRI revealed features compatible with meningoencephalitis involving the right frontal, parietal and temporooccipital lobes. A brain biopsy sample from the right parietal lobe showed thickening of the leptomeninges, and granulomatous vasculitis with multinucleated giant cells and vascular Aß deposits. No vascular lesions were evident by cerebral angiography. Serological examination revealed an elevated level of proteinase 3 anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA). The patient was treated with corticosteroids, but this was only partially and temporarily effective. Autopsy revealed marked leptomeningeal thickening with inflammatory cell infiltrates and hemosiderin deposits, many superficial predominantly small infarcts at various stages in the cerebral cortex and only a few cerebral active vasculitic lesions. Immunohistochemically, CAA showing widespread Aß-positive blood vessels with double-barrel formations was demonstrated. In conclusion, we consider that, although the association of PR3-ANCA with the pathogenesis of Aß-associated vasculitis remained unclear, the present case represents a rare example of CAA-related inflammation at the chronic stage.