JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study

International audienceThe paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery

Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases

International audienceObjective: Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome , with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. Methods: We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative geno-mic hybridization (CGH). Results: We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%

Additional file 5: of Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Clinical pictures of patients #8 (A) and #9 (B) (mutated in ERCC8(CSA)). (PPTX 403 kb

Surveillance on classical swine fever virus persistently infected farms and phenotypic alterations of peripheral blood mononuclear cells of swine after virus infection

中 文 摘 要豬瘟為豬之急性病毒性疾病，經常造成 嚴重的經濟損失。豬瘟病毒之持續性感染現象為豬瘟防疫及清除工作上所 需克服之難題。為配合政府豬瘟清除計畫之執行及了解豬瘟病毒在豬瘟污 染場中持續感染狀況，以病理學配合RT-PCR檢查，長期監控三場豬瘟污染 之一貫作業養豬場之病弱保育豬隻潛在感染豬瘟狀況，並配合豬瘟抗體 ELISA檢測，以了解豬場之群體免疫力。結果顯示，在持續一年的監控期 間，豬場內雖沒有典型豬瘟病例發生，但仍能持續從病弱豬隻中發現疑似 豬瘟病變及可檢測出豬瘟病毒RNA存在，證明豬瘟病毒確能在病弱豬群間 長期潛伏感染。由血清ELISA檢測結果，亦顯示在正常豬瘟活毒疫苗免疫 計畫下，仍有少數豬隻未呈現抗體反應，而易暴露於豬瘟病毒感染之威脅 下。進一步延續田間監控之試驗，在實驗室條件下，觀察免疫豬隻遭受野 外強毒攻毒後之細胞性免疫反應與淋巴次族群之變化情形，並探討豬瘟病 毒在免疫後耐過豬隻中持續性感染情形。結果指出，免疫過的豬隻在經豬 瘟病毒攻擊後，淋巴細胞對 concanvalin A 刺激引起的增殖反應，在大 部分豬隻皆不受到影響，但在少部份免疫反應不良之個體，呈現輕微抑制 的現象。在淋巴細胞次族群的變化方面，經免疫過的豬隻IgM+、CD4-CD8+ 、CD4+CD8-及CD4+CD8+淋巴細胞有暫時性抑制後上升的現象，但在不同免 疫方式下其改變有些許不同。其中以哺乳前免疫加六週齡免疫組在豬瘟病 毒攻擊後，血液中淋巴次族群的變化較小。免疫過的豬隻在攻毒後一個月 ，仍可以RT-PCR檢測出豬瘟病毒存在於淋巴臟器中，顯示免疫豬隻仍有帶 野外毒之可能。綜合各實驗結果，豬瘟病毒在豬場病弱保育豬隻及正常免 疫豬群中可長期持續感染。因此，加強豬瘟污染場之監控，完整的免疫計 畫，並配合病弱豬淘汰，有助於將豬瘟病毒由豬場中清除。AbstractClassical swine fever ( CSF ) is a highly contagious disease of swine and leads to severe economic losses. The persistence of CSF virus (CSFV) infection is the major problem in the control and eradication of the disease. In corresponding to the CSFV eradication program in Taiwan and the investigation of CSFV persistence in pig farms, a monitoring system of pathological examination and reverse transcriptase - polymerase chain reaction ( RT-PCR ) method focused on weak nursing pigs were undertaken on three CSFV contaminated farms. Over one-year monitoring, there was no typical clinical CSF case, however, presumable pathological lesions and positive reaction of RT-PCR for CSFV could be persistently detected in those random samples from all three pig farms. Moreover, a serological survey on these pig farms with routine LPC vaccination programs also indicated that there were still some portions of pigs lack of CSF ELISA antibody response, which might be susceptible for CSFV infection. Following monitoring study of CSF virus persistence, the alteration of subpopulations of peripheral blood mononuclear cells, lymphoproliferative responses, and virus persistence were carried on pigs with three different CSF vaccination programs and control pigs, which were challenged with virulent CSFV ( 2*10^7 pfu). The results indicated that the lymphoproliferative function of most vaccinated pigs was not significantly affected, however, the function in a few vaccinated pigs with poor immune response was partially impaired. The alterations of lymphocyte subpopulations, including, IgM+, CD4-CD8+, CD4+CD8-, and CD4+ CD8+ lymphocytes showed slight decrease during early phase of infection and then returned to normal level later. Pigs vaccinated before consumption of colostrum and booosted at 6-week-old showed the less effect on these alterations and less clinical signs after CSFV challenge. However, virulent virus RNA from recovered pigs could be detected by RT-PCR method over 1 month after CSFV challenged (2*107 pfu). Conclusively, CSFV could long term persistence in weak nursing pigs in CSFV contaminated pig farms. Therefore, to eradicate CSFV from contaminated pig farms, an intensive CSF vaccination program and a monitoring system on CSF persistence by RT-PCR combined with a strict culling strategy might be required