Clinical, Genetic, and Pathological Studies in Two Brothers with Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures: A Case Report

Introduction: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive disorder caused by biallelic pathogenic variants in the ADPRS gene. Since its first description in 2018, less than fifty cases have been reported worldwide, but thus far, without histopathology of the nervous system. Case Presentation: We summarize the clinical, paraclinical, and genetic characteristics of the disease in the proband, and the pathological workup in his older brother who passed away more than a decade ago. The characteristics of CONDSIAS in the two brothers overlapped with those of Friedreich ataxia. A final clarification of the diagnosis was made possible by whole exome sequencing (WES) that identified the homozygous pathogenic variants in the ADPRS gene. Conclusion: CONDSIAS is a rare disorder with highly variable presentation. Based on solely clinical and even pathological workup, establishing a definite diagnosis may be challenging. In the two brothers, we observed clinical and histopathological features of the disease suggesting, though not completely fulfilling, the diagnosis of Friedreich’s ataxia. WES allowed us to rapidly identify the underlying genetic abnormality and to make a shortcut to the right diagnosis amongst recessive ataxias. As of today, no specific treatment for CONDSIAS is available. Repurposing of certain approved modalities that also target the affected pathway in CONDSIAS recently arose, though as yet without proven success. Knowing the biological relevance of the affected gene product offers potential targets for the development of disease-modifying drugs for this highly disabling disease in the near future

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

Background: Immune evasion in glioblastoma (GBM) shields cancer cells from cytotoxic immune response. Methods: We investigated CpG methylation in promoters, genes, and pathways in 22 pairs of formalin-fixed paraffin-embedded sequential (FFPE) GBM using restricted resolution bisulfite sequencing (RRBS) and bioinformatic analyses. Results: Gene ontology revealed hypermethylation in elements of the innate and adaptive immune system when recurrent GBM samples (GBMrec) were compared to control (CG) and primary GBM samples (GBMprim). Higher methylation levels of the IL-7 signaling pathway and response to IL-7 were found in GBMrec suggesting a progressive blockade of the IL-7 driven T cell response in sequential GBM. Analyses of the Cancer Genome Atlas array-based data confirmed hypermethylation of the IL-7 pathway in recurrent compared with primary GBM. We also quantified DNA CpG methylation in promoter and gene regions of the IL-7 ligand and IL-7 α-receptor subunit in individual samples of a large RRBS-based sequential cohort of GBM in a Viennese database and found significantly higher methylation levels in the IL-7 receptor α-subunit in GBMrec compared with GBMprim. Conclusions: This study revealed the progressive suppression of the IL-7 receptor-mediated pathway as a means of immune evasion by GBM and thereby highlighted it as a new treatment target

On the Boundary of Exploratory Genomics and Translation in Sequential Glioblastoma

OMICS methods brought significant advancements to the understanding of tumor cell biology, which transformed the treatment and prognosis of several cancers. Clinical practice and outcomes, however, changed significantly less in the case of glioblastoma (GBM). In this study, we aimed to assess the utility of whole exome (WES) sequencing in the clinical setting. Ten pairs of formalin-fixed, paraffin-embedded (FFPE) GBM specimens were obtained at onset (GBM-P) and at recurrence (GBM-R). Histopathological and molecular features of all samples supported the diagnosis of GBM based on WHO CNS5. WES data were filtered, applying a strict and custom-made pipeline, and occurrence of oncogenic and likely oncogenic variants in GBM-P, GBM-R or both were identified by using the VarSeq program version 2.5.0 (Golden Helix, Inc.). Characteristics and recurrence of the variants were analyzed in our own cohort and were also compared to those available in the COSMIC database. The lists of oncogenic and likely oncogenic variants corresponded to those identified in other studies. The average number of these variants were 4 and 5 out of all detected 24 and 34 variants in GBM-P and GBM-R samples, respectively. On average, one shared oncogenic/likely oncogenic variant was found in the pairs. We assessed the identified variants’ therapeutic significance, also taking into consideration the guidelines by the Association for Molecular Pathology (AMP). Our data support that a thorough WES analysis is suitable for identifying oncogenic and likely oncogenic variants in an individual clinical sample or a small cohort of FFPE glioma specimens, which concur with those of comprehensive research studies. Such analyses also allow us to monitor molecular dynamics of sequential GBM. In addition, careful evaluation of data according to the AMP guideline reveal that though therapeutic applicability of the variants is generally limited in the clinic, such information may be valuable in selected cases, and can support innovative preclinical and clinical trials