Vogt Koyanagi Harada syndrome in a 15-year-old girl, steroids side effects and recurrences

Background. Vogt-Koyanagi-Harada Syndrome is rare in childhood and is usually seen between the 2nd and 5th decades. We present a 15-year-old girl with findings of incomplete Vogt-Koyanagi-Harada Syndrome. Case. In the first visit, anterior chamber inflammation, vitritis, serous retinal detachment and papillitis were observed in her both eyes. She also had neurological symptoms such as a headache. During the systemic treatment period, some of the side effects related to steroids emerged. Additionally, the symptoms and findings of the disease relapsed while the steroid dose was reduced. Conclusion. Early diagnosis and selection of an individualized appropriate treatment provided good clinical and visual results without any serious complications in our case

Neuromuscular disease genetics in under-represented populations: increasing data diversity

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses \u27solved\u27 or \u27possibly solved\u27 ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% \u27solved\u27 and ∼13% \u27possibly solved\u27 outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally

SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis

As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The 4 SEC24 proteins (A–D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently known only for SEC24D. Here, we reported that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with 4 affected individuals. We showed that knockout of sec24C in zebrafish recapitulated important aspects of the human phenotype. SEC24C-deficient fibroblasts displayed alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also affected the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggested a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation

Gangliosides: The Double-Edge Sword of Neuro-Ectodermal Derived Tumors

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to the number of sialic acid residues, which can be also modified by O-acetylation. Both ganglioside expression and sialic acid modifications can be modified in pathological conditions such as cancer, which can induce either pro-cancerous or anti-cancerous effects. In this review, we summarize the specific functions of gangliosides in neuro-ectodermal derived tumors, and their roles in reprogramming the lipidomic profile of cell membrane occurring with the induction of epithelial-mesenchymal transition

Étude des mécanismes de biosynthèse de la forme O-acétylée du GD2 dans le cancer du sein

Le ganglioside GD2, ré-exprimé dans les cancers d’origine neuro-ectodermique, a été caractérisé comme un antigène oncofetal constituant une cible pour l’immunothérapie. L’anticorps anti-GD2 dinutuximab (Unitixin, TM) a récemment obtenu l’agrément de la Food Drug Administration et de l’Agence Européenne du Médicament pour le traitement des neuroblastomes pédiatriques. Cependant, l’utilisation de cet anticorps se heurte à de forts problèmes de toxicité due à l’expression du GD2 dans les nerfs périphériques sains. La forme O-acétylée du GD2 (OAcGD2) n’est exprimé que dans les tissus cancéreux représentant ainsi une cible thérapeutique moins toxique que le GD2. Les activités de la société OGD2 Pharma, partenaire de ce projet, sont axées sur le développement d’anticorps thérapeutiques dirigés contre le GD2 O-acetylé. L’anticorps développé cible spécifiquement au GD2 O-acetylé sans réaction croisée avec GD2. Dans le cancer du sein, les gangliosides complexes, notamment le GD2 et sa forme O-acetylé sont ré-exprimés. Cette expression est corrélée à un mauvais pronostic chez les patientes atteintes de cancer du sein. L’objectif principale de ma thèse est d’identifier les mécanismes moléculaires régissant l’O-acétylation du GD2 dans le cancer du sein afin de mettre en évidence l’intérêt thérapeutique et diagnostique du ciblage de cet antigène.O-Acetylated GD2 (OAcGD2) ganglioside is neo-expressed in neuroectodermal derived tumors as neuroblastoma and breast cancer. This oncofetal marker is an essential target for immunotherapy. Dinutuximab (Unitixin TM), a therapeutic antibody targeting GD2 has recently obtained Food Drug Administration and European Medicines Agency approval for neuroblastoma treatment. Nevertheless, Dinutuximab causes toxicity due to the expression of GD2 on peripheral nerve fibers. In that way, targeting OAcGD2 seems more beneficial because of absence of this antigen in normal tissues. The activities of OGD2 Pharma Company, partner of this project, are focused on therapeutic antibody development against OAcGD2. OGD2 Pharma developed an antibody specifically targeting OAcGD2 with no cross reaction with GD2. Absent from the normal mammary gland, complex gangliosides especially GD2 and its O-acetylated form have been detected in breast cancer. This expression is correlated with poor patient outcome. The aim of this thesis project was to decipher the molecular mechanisms of OAcGD2 biosynthesis, expression and its role in breast cancer, in order to highlight the therapeutic and diagnostic value of targeting OAcGD2 in breast cancer

O-acetylated Gangliosides as Targets for Cancer Immunotherapy

O-acetylation of sialic acid residues is one of the main modifications of gangliosides, and modulates ganglioside functions. O-acetylation of gangliosides is dependent on sialyl-O-acetyltransferases and sialyl-O-acetyl-esterase activities. CAS1 Domain-Containing Protein 1 (CASD1) is the only human sialyl-O-acetyltransferases (SOAT) described until now. O-acetylated ganglioside species are mainly expressed during embryonic development and in the central nervous system in healthy adults, but are re-expressed during cancer development and are considered as markers of cancers of neuroectodermal origin. However, the specific biological roles of O-acetylated gangliosides in developing and malignant tissues have not been extensively studied, mostly because of the requirement of specific approaches and tools for sample preparation and analysis. In this review, we summarize our current knowledge of ganglioside biosynthesis and expression in normal and pathological conditions, of ganglioside O-acetylation analysis and expression in cancers, and of the possible use of O-acetylated gangliosides as targets for cancer immunotherapy

Gangliosides: The Double-Edge Sword of Neuro-Ectodermal Derived Tumors

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to the number of sialic acid residues, which can be also modified by O-acetylation. Both ganglioside expression and sialic acid modifications can be modified in pathological conditions such as cancer, which can induce either pro-cancerous or anti-cancerous effects. In this review, we summarize the specific functions of gangliosides in neuro-ectodermal derived tumors, and their roles in reprogramming the lipidomic profile of cell membrane occurring with the induction of epithelial-mesenchymal transition.</jats:p

O-acetylated Gangliosides as Targets for Cancer Immunotherapy

O-acetylation of sialic acid residues is one of the main modifications of gangliosides, and modulates ganglioside functions. O-acetylation of gangliosides is dependent on sialyl-O-acetyltransferases and sialyl-O-acetyl-esterase activities. CAS1 Domain-Containing Protein 1 (CASD1) is the only human sialyl-O-acetyltransferases (SOAT) described until now. O-acetylated ganglioside species are mainly expressed during embryonic development and in the central nervous system in healthy adults, but are re-expressed during cancer development and are considered as markers of cancers of neuroectodermal origin. However, the specific biological roles of O-acetylated gangliosides in developing and malignant tissues have not been extensively studied, mostly because of the requirement of specific approaches and tools for sample preparation and analysis. In this review, we summarize our current knowledge of ganglioside biosynthesis and expression in normal and pathological conditions, of ganglioside O-acetylation analysis and expression in cancers, and of the possible use of O-acetylated gangliosides as targets for cancer immunotherapy.</jats:p