JAK Inhibition in the Aicardi-Goutières Syndrome

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ABSTRACT The associations between androgens and cardiovascular risk factors in men are controversial. A nested case-control study was used to compare the levels of cardiovascular risk factors in two groups (n ϭ 25 each) of healthy men contrasted by their plasma total testosterone (PTT) concentration, matched by age and ethnic origin. Compared to the men with normal PTT (mean Ϯ SEM, 19.8 Ϯ 0.7 nmol/L), the men with low PTT (10.1 Ϯ 0.3 nmol/L) had a significantly higher body mass index (P Ͻ 0.01), waist/hip ratio (P Ͻ 0.001), systolic blood pressure (P Ͻ 0.05), fasting and 2-h plasma glucose (P Ͻ 0.04 and P Ͻ 0.02 respectively), serum triglycerides (P Ͻ 0.001), total cholesterol (P Ͻ 0.04), low density lipoprotein cholesterol (P Ͻ 0.01), apolipoprotein B (P Ͻ 0.01), fasting and 2-h plasma insulin (both P Ͻ 0.0001), and lower values of serum high density lipoprotein cholesterol (P Ͻ 0.01) and apolipoprotein A1 (P Ͻ 0.05). After adjustment for both body mass index and waist/ hip ratio, fasting and 2-h plasma insulin and triglyceride levels remained significantly different between the two groups (P Ͻ 0.04, P Ͻ 0.001, and P Ͻ 0.03 respectively). Plasma sex hormone-binding globulin was markedly decreased in the low PTT group (P Ͻ 0.0001), whereas bioavailable testosterone was not significantly different. This case-control study provides further and stronger evidence of a negative association between PTT and plasma insulin in men, as suggested by cross-sectional studies. Because these are observational data, neither causality nor the direction of the associations among PTT, sex hormone-binding globulin, and insulin sensitivity can be determined. Intervention studies are needed to better assess the metabolic and cardiovascular benefits of androgen treatment that have been suggested by preliminary clinical trials. (J Clin Endocrinol Metab 82: 682-685, 1997) F OR A LONG time, androgens have been considered to decrease glucose tolerance, induce hyperinsulinemia, and increase cardiovascular risk in women (1) as well as in men (2). Recently, these effects have been questioned in men. Indeed, from recent cross-sectional studies in healthy men, lower plasma total testosterone (PTT) levels seem to be associated with hyperinsulinemia, decreased glucose tolerance, and a higher level of cardiovascular risk factors (3-5). To investigate the role of endogenous testosterone and sex hormone-binding globulin (SHBG) in the association between sex hormones and cardiovascular risk factors in healthy males, in 1992-1993 we selected from the large male occupation-based population examined in the Telecom Study in 1985-1987 (3, 6), two groups of men contrasted by their PTT concentrations to compare their levels of cardiovascular risk factors, plasma SHBG, and plasma bioavailable testosterone. Materials and Methods Study design This study used a nested case-control design. The levels of plasma SHBG, plasma bioavailable testosterone, and cardiovascular risk factors were compared between males with low and normal PTT. As age and ethnicity influence cardiovascular risk factors (7-9), the subjects were matched on these covariates (Ϯ1 yr for age). Selection of subjects For the low PTT group, we selected healthy men not treated for diabetes, dyslipidemia, or hypertension from the lower percentiles of the PTT distribution of the 1718 adult men who participated in the crosssectional study of 1985-1987 (3, 6). We recruited all healthy men with PTT levels of 11.8 nmol/L or less in 1985-1987 who could be traced and who agreed to be reexamined in 1992-1993. The fifth percentile of the PTT distribution in the background population was 11.8 nmol/L When a case with a confirmed low PTT level had been included, we then recruited a matched control subject, with PTT levels between 17. 3-24.3 nmol/L in 1985-1987 and 13.9 -28.4 nmol/L in 1992-1993. When several controls were available for a given case, we systematically chose the control who had been examined at the date closest to that of the case in [1985][1986][1987]. To obtain the a priori calculated sample size of 25 men by group (see Statistical methods), we contacted 147 subjects (65 with low PTT in 198

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

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

International audienceWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context

Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

International audienceTo the Editor:The Aicardi–Goutières syndrome is a genetic encephalopathy that is associated with childhood illness and death. The syndrome is hypothesized to be due to misidentification of self-derived nucleic acids as nonself and the subsequent induction of a type I interferon–mediated response that simulates an antiviral reaction.1 Endogenous retroelements, mobile genetic elements that can be transcribed to RNA and then to DNA by reverse transcription, constitute 40% of the human genome and represent a potential source of immunostimulatory nucleic acid in patients with this syndrome.

Apport pronostique de l' imagerie par résonance magnétique (IRM) de diffusion précoce dans les encéphalites aiguës de l' enfant

Nous avons étudié l apport pronostique en terme de séquelles neurologiques de l IRM de diffusion cérébrale précoce dans les encéphalites aiguës de l enfant. Notre hypothèse de travail était qu une restriction de la diffusion à la phase aiguë, témoignant d un œdème cytotoxique, serait une indication d un pronostic neurologique plus péjoratif qu une diffusion augmentée et a fortiori normale. Les dossiers de 25 patients ont été repris de façon rétrospective, avec analyse de leur IRM cérébrale de diffusion initiale (calcul du coefficient ADC dans 7 régions d intérêt), et leur devenir a été évalué à l aide des données de suivi en consultation, des données concernant leur scolarité et leur prise en charge rééducative, ainsi que par l échelle de Vineland pour 20 d entre eux et l échelle de BRIEF pour 8 d entre eux. Nous avons mis en évidence des corrélations significatives entre type d atteinte à l imagerie de diffusion précoce et devenir neurocognitif des patients, notamment pour le domaine du langage, mais également en terme de scolarité. Notre travail souligne donc l importance de réaliser une séquence de diffusion en IRM précocément dans les encéphalites aiguës de l enfant, et montre également l intérêt d un suivi prolongé de ces patients.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Unilateral predominance of abnormal movements: A characteristic feature of the pediatric anti-NMDA receptor encephalitis?

Anti-NMDA receptor encephalitis is a treatable autoimmune disease characterized by cognitive, motor and psychiatric features that primarily affects young adults and children. We present a case of a 7-year-old boy with asymmetrical (mainly right hemibody) and abnormal polymorphic movements without concomitant scalpictal EEG changes but had background slowing predominating over the left hemisphere. This report illustrates previous descriptions of asymmetric presentation of abnormal movements in pediatric anti-NMDA receptor encephalitis and emphasizes the importance of video-EEG interpreted within the overall clinical context, to differentiate epileptic from non-epileptic abnormal movements in patients with autoimmune encephalitis

Deep phenotyping unstructured data mining in an extensive pediatric database to unravel a common KCNA2 variant in neurodevelopmental syndromes

International audiencePurpose: Electronic health records are gaining popularity to detect and propose interdisciplinary treatments for patients with similar medical histories, diagnoses, and outcomes. These files are compiled by different nonexperts and expert clinicians. Data mining in these unstructured data is a transposable and sustainable methodology to search for patients presenting a high similitude of clinical features.Methods: Exome and targeted next-generation sequencing bioinformatics analyses were performed at the Imagine Institute. Similarity Index (SI), an algorithm based on a vector space model (VSM) that exploits concepts extracted from clinical narrative reports was used to identify patients with highly similar clinical features.Results: Here we describe a case of "automated diagnosis" indicated by Dr. Warehouse, a biomedical data warehouse oriented toward clinical narrative reports, developed at Necker Children's Hospital using around 500,000 patients' records. Through the use of this warehouse, we were able to match and identify two patients sharing very specific clinical neonatal and childhood features harboring the same de novo variant in KCNA2.Conclusion: This innovative application of database clustering clinical features could advance identification of patients with rare and common genetic conditions and detect with high accuracy the natural history of patients harboring similar genetic pathogenic variants

Patients with dravet syndrome in the era of stiripentol: A French cohort cross-sectional study

OBJECTIVE: The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS). METHODS: We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2.5 to 22 years. RESULTS: Seizure onset ranged from 2 to 9 months (mean 5 months). Treatment started at a mean age of 7 months with valproate (VPA) as first therapy in 83% of patients. STP was prescribed in 96% at an average age of 20 months. At last follow-up (up to 22 years, median 8 years), 96% were still receiving STP, with VPA and clobazam (CLB) in 91%. Additional therapies were prescribed in 72% of patients. Most patients (96%) continued to have clonic or tonic-clonic seizures but they were brief (3/month) in 38% of patients, monthly (1-3/month) in 40%, and yearly in the remaining patients. None presented with daily seizures. Seizure frequency at last visit was related to the age of treatment initiation, the age of last SE, and SCN1A mutation type. CONCLUSIONS: Triple therapy with STP, VPA, and CLB was maintained long-term by 96% of this large DS cohort because the reduced frequency and severity of seizures STP provided when added to CLB and VPA was durable. Nevertheless, only a few patients achieved seizure freedom and persisting seizures remains a concern in the majority of patients