Myasthenia gravis exacerbation after melatonin administration: case series from a tertiary referral centre

Background: Myasthenia gravis is an autoimmune disease mediated by antibodies against proteins associated with the postsynaptic membrane of the neuromuscular junction. Several drugs may trigger an exacerbation of the disease. Melatonin supplements are widely used for the treatment of insomnia as they are well tolerated with few side effects. The role of melatonin in the immune system and its effects in autoimmune disorders remain uncertain. Case presentation: We identified three patients in our referral centre from 2014 to 2019 who presented a worsening within days or weeks of starting melatonin. Two of them stopped the treatment without clinical improvement in the next week. Increasing dose of corticosteroids did not lead to clinical improvement in the next month and one of the patients was finally administered intravenous immunoglobulins. Conclusion: Melatonin may trigger exacerbations of myasthenia gravis, probably due to an upregulation of the adaptive immune system and an interaction with the corticosteroids and other immunosuppressant treatments. We consider that melatonin should be administered with caution in these patients

Intravenous immunoglobulins may prevent prednisone-exacerbation in myasthenia gravis

Corticosteroids may produce a paradoxical worsening of myasthenia gravis (MG) symptoms within the first weeks of treatment. We therefore wanted to assess the hypothesis that a prior infusion of intravenous immunoglobulin (IVIG) may have a protective effect. Our primary objectives were to show that the coadministration of immunoglobulins and glucocorticoids is safe and effective for controlling myasthenic symptoms, and to compare the exacerbation rate with this approach and historical practice without IVIG. We recruited 45 patients with generalized MG who required corticosteroids for the first time and we gave all IVIG before starting the full doses of prednisone. Monitoring was performed with validated scales, questionnaires, and blood tests over a 6-week period. Only 4.4% had severe adverse effects related to IVIG and 86.7% improved clinically. Notably, only 2.2% had a paradoxical symptom exacerbation in the first weeks of starting prednisone, which was statistically lower than the 42% reported in a historical series. We conclude that adjuvant therapy with IVIG when starting prednisone for the first time in patients with generalized MG is safe and effective. Given that the rate of paradoxical worsening was lower than that previously reported, the addition of IVIG may have a protective effect against such exacerbations

Eculizumab as a promising treatment in thymoma-associated myasthenia gravis

Myasthenia gravis is a chronic autoimmune disorder caused by antibodies directed against the neuromuscular junction. Some patients may have an associated thymoma, which confers a worse prognosis. Eculizumab, a monoclonal antibody that inhibits the activation of terminal complement, has recently been approved for the treatment of refractory generalized myasthenia gravis. This is an early case report of thymoma-associated refractory myasthenia gravis successfully treated with eculizumab in a real-world setting

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Hypomyelinating leukodystrophy; Inborn errors of metabolism; PhosphoinositolLeucodistrofia hipomielinizante; Errores innatos del metabolismo; FosfoinositolLeucodistròfia hipomielinizant; Errors innats del metabolisme; FosfoinositolPhosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.We thank the CERCA Program/Generalitat de Catalunya for institutional support. This study was supported by grants from the Hesperia Foundation, the Asociación Española contra las Leucodistrofias (ALE-ELA España), the Autonomous Government of Catalonia (SGR 2017SGR1206 and PERIS program URD-Cat SLT002/16/00174) and the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759 to A.P.). This study was also funded by Fundació La Marató de TV3 (595/C/2020) as well as Instituto de Salud Carlos III (FIS PI20/00758 to C.C.) (co-funded by European Regional Development Fund. ERDF, a way to build Europe). This study was also funded by the Instituto de Salud Carlos III (Rio Hortega, CM18/00145 to V.V.; PFIS, FI18/00141 to L.P.; and Sara Borrell, CD19/00221 to E.V.), co-funded by European Social Fund. ESF investing in your future; the Ministerio de Ciencia e Innovación y Universidades (Juan de la Cierva, FJCI-2016-28811 to E.V.), and the Center for Biomedical Research on Rare Diseases (CIBERER to M.R.). Sequencing and analysis of Patient 5 were performed by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung and Blood Institute grants UM1 HG008900 and R01 HG009141 and the Chan Zuckerberg Initiative to the Rare Genomes Project. This work was in part supported by the association ‘Connaître les Syndromes Cérébelleux’ (CSC). This research received funding specifically appointed to the Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell’istruzione, dell’università e della ricerca-MIUR) under the programme ‘Dipartimenti di Eccellenza 2018-2022’ Project code D15D18000410001. Whole-exome sequencing was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). D.R.A. and A.P. are members of the Undiagnosed Disease Network International (UDNI)

A novel mutation in the GFAP gene expands the phenotype of Alexander disease

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist. Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by WES. A candidate variant was functionally tested in an astrocytoma cell line. Results: The novel variant in GFAP N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterized so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models. Conclusion: We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander Disease type II, probably associated with alternative pathogenic mechanisms, i.e. astrocyte enlargement. GFAP analysis should be considered in adult-onset neurologic presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases

Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?

Background Friedreich ataxia is the most common inherited ataxia in Europe and is mainly caused by biallelic pathogenic expansions of the GAA trinucleotide repeat in intron 1 of the FXN gene that lead to a decrease in frataxin protein levels. Rarely, affected individuals carry either a large intragenic deletion or whole-gene deletion of FXN on one allele and a full-penetrance expanded GAA repeat on the other allele.Case presentation We report here a patient that presented the typical clinical features of FRDA and genetic analysis of FXN intron 1 led to the assumption that the patient carried the common biallelic expansion. Subsequently, parental sample testing led to the identification of a novel intragenic deletion involving the 5'UTR upstream region and exons 1 and 2 of the FXN gene by MLPA.Conclusions With this case, we want to raise awareness about the potentially higher prevalence of intragenic deletions and underline the essential role of parental sample testing in providing accurate genetic counselling

Ciencias humanas y sociales en las movilizaciones sociales

En esta ocasión en Antropovoces tratamos dos temas coyunturales que han estado sonando bastante en esta semana. Por una parte, hablamos con el grupo Janus sobre su proyecto y cómo las comunidades indígenas perciben la universidad y qué cambios genera la educación en sus respectivas comunidades. Por otra parte, también tratamos el tema de la marcha por la educación del 10 de octubre y cómo nuestra universidad se involucró en este tema en defensa de la educación pública y su respectiva financiación

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España

Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. Patients and methods: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. Results: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials. (c) 2021 Sociedad Espanola de Neurologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/)

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population