Genetic changes in the FH gene cause vagal paraganglioma.

Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.