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.

Multiple paragangliomas: a case report.

BACKGROUND: Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and genetic mechanisms underlying the pathogenesis of multiple paragangliomas remain elusive. CASE PRESENTATION: We report a case of multiple paragangliomas in a patient, manifesting as bilateral CPGL and unilateral VPGL. Tumors were revealed via computed tomography and ultrasound study and were resected in two subsequent surgeries. Both CPGLs and VPGL were subjected to immunostaining for succinate dehydrogenase (SDH) subunits and exome analysis. A likely pathogenic germline variant in the SDHD gene was indicated, while likely pathogenic somatic variants differed among the tumors. CONCLUSIONS: The identified germline variant in the SDHD gene seems to be a driver in the development of multiple paragangliomas. However, different spectra of somatic variants identified in each tumor indicate individual molecular mechanisms underlying their pathogenesis.

Mutation profiling in eight cases of vagal paragangliomas.

BACKGROUND: Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood. METHODS: The collection of VPGLs obtained from 8 patients of Russian population was used in the study. Exome library preparation and high-throughput sequencing of VPGLs were performed using an Illumina technology. RESULTS: Based on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas. SDHB variants were found in three patients, whereas SDHD was mutated in two cases. Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex. In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT). Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors. CONCLUSIONS: Results indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.

Tumor multifocality with vagus nerve involvement as a phenotypic marker of SDHD mutation in patients with head and neck paragangliomas: A 18 F-FDOPA PET/CT study.

BACKGROUND: 18 F-FDOPA PET/CT was proved to be a highly sensitive imaging method for detecting head and neck paraganglioma (HNPGL). The primary aim of the study was to evaluate the relationship between tumor characteristics and the SDHx-mutational status in a large series of patients with HNPGL evaluated by 18 F-FDOPA PET/CT. METHODS: A total of 104 patients with HNPGL (65 sporadic/39 SDHx-mutated) were included. RESULTS: In comparison to SDHB/SDC/SDHx-negative cases, patients with SDHD were younger at diagnosis and had a higher rate of multifocal, vagal, and carotid paraganglioma. In patients with SDHD, vagal paraganglia represented the primary site of tumor origin. Multicentric involvement of the vagus nerve alone or in association with other locations was found to be a typical feature of SDHD cases compared to other cases (odds ratio = 59.4). CONCLUSION: The present study shows that tumor multifocality within the vagus nerve is a phenotypic marker of SDHD mutation. This information is essential in the choice of the therapeutic strategy.

Detection of copy number variants in the horse genome and examination of their association with recurrent laryngeal neuropathy.

We used the data from a recently performed genome-wide association study using the Illumina Equine SNP50 beadchip for the detection of copy number variants (CNVs) and examined their association with recurrent laryngeal neuropathy (RLN), an important equine upper airway disease compromising performance. A total of 2797 CNVs were detected for 477 horses, covering 229 kb and seven SNPs on average. Overlapping CNVs were merged to define 478 CNV regions (CNVRs). CNVRs, particularly deletions, were shown to be significantly depleted in genes. Fifty-two of the 67 common CNVRs (frequency ≥ 1%) were validated by association mapping, Mendelian inheritance, and/or Mendelian inconsistencies. None of the 67 common CNVRs were significantly associated with RLN when accounting for multiple testing. However, a duplication on chromosome 10 was detected in 10 cases (representing three breeds) and two unphenotyped parents but in none of the controls. The duplication was embedded in an 8-Mb haplotype shared across breeds.

Autonomic dysfunction in unaffected first-degree relatives of patients suffering from schizophrenia.

Recent studies revealed cardiac autonomic dysfunction in patients with acute schizophrenia, which appears to be mainly related to reduced vagal and increased sympathetic modulation. To understand the significance of cardiac autonomic function in patients with schizophrenia, we extended these studies to relatives of patients. In this study, we assessed cardiac autonomic modulation in healthy first-degree relatives of patients with schizophrenia (n = 36) to investigate a putative genetic influence. Data were compared with control subjects matched for age, gender, and physical activity as well as to patients suffering from schizophrenia. First-degree relatives showed an attenuated, yet identical pattern in autonomic dysfunction as patients with decreased vagal modulation of heart rate, decreased baroreflex sensitivity, but no difference in blood pressure variability could be detected. The patients' relatives also showed a similar pattern in regards to QT variability. In addition, the subgroup comparison of offspring vs. siblings showed a significant difference in heart rate variability suggesting a higher degree of heritability in offspring. In conclusion, the pattern of autonomic dysfunction seen in patients and relatives might indicate underlying disease-inherent genetic vulnerability, especially because autonomic parameters are heritable. In addition, these findings may be of value to identify the high-risk group of patients' relatives in regards to serious cardiovascular events so that early preventive measures can be taken.

The facial motor nucleus transcriptional program in response to peripheral nerve injury identifies Hn1 as a regeneration-associated gene.

Facial nerve axotomy (FNA) is a well-established experimental model of motoneuron regeneration. After peripheral nerve axotomy, a sequence of events including glial activation and axonal regrowth leads to functional recovery of the afflicted pool of motoneurons. Using microarray analysis we identified an increase in the expression of 60 genes (at a false discovery rate of 0.1, genes were significant P < 0.004) within the facial nucleus as a consequence of nerve injury. In situ hybridization analysis validated the increased expression of many of these axotomy-induced genes. One specific gene, encoding a unique primary amino acid sequence, termed hemopoietic- and neurologic-expressed sequence-1 (Hn1), was evaluated more extensively using several additional nerve injury paradigms. Hn1 mRNA was upregulated in injured facial motoneurons in both rats and mice. Sustained upregulation of Hn1 mRNA was evident after nerve resection whereas levels of Hn1 mRNA returned to baseline in animals subjected to nerve crush or nerve transection. Hn1 was also increased in the dorsal motor nucleus and the nucleus ambiguous after vagus nerve axotomy, another regeneration model. No upregulation of Hn1 expression was observed, however, in two nonregeneration models: FNA in newborn rats and rubrospinal tractotomy. Hn1 mRNA was ubiquitous in the developing central nervous system whereas its expression in adult brain was confined to neurons of the hippocampus, cortex and cerebellum. These findings identify Hn1 as a gene associated with nervous system development and nerve regeneration.

Management of vagal paraganglioma: is operative resection really the best option?

BACKGROUND: Vagal paragangliomas cannot be resected without sacrifice of the vagal nerve. The risk of bilateral vocal cord palsy has been reason to postpone treatment of this benign and slow growing neoplasm in hereditary cases. Postponement could be considered for solitary cases as well. METHODS: An institute-based review of 48 patients with vagal paragangliomas over the past 30 years was performed. RESULTS: Forty-eight patients with 58 vagal paragangliomas were studied. All but 4 patients had multiple paragangliomas and should be considered hereditary cases. The 10 patients that underwent an operation lost the vagal nerve; 60% of them had additional cranial nerve palsy postoperatively. In the group of patients who were followed for an average period of 8.5 years, 3 patients (8%) developed cranial nerve palsy. CONCLUSIONS: Aggressive treatment of vagal paragangliomas leads to unnecessary early loss of vagal nerve function. A period of clinical and radiologic follow-up preceding an operation may lead to prolonged preservation of voice and swallowing functions in these patients, without grave consequences for other lower cranial nerves.

Cardiovascular autonomic control in myotonic dystrophy type 1: a correlative study with clinical and genetic data.

The autonomic nervous system has been evaluated in myotonic dystrophy with contradictory results and its relationship with heart disturbances remains unclear. Twenty-three patients with myotonic dystrophy type 1 were investigated by a battery of six cardiovascular autonomic tests and power spectral analysis of heart rate variability. Although 15 patients (65%) revealed abnormal or borderline results in some tests, only one patient had a definite autonomic damage, as indicated by two or more abnormal tests. As a group, myotonic dystrophy type 1 patients showed a significant reduction of heart rate variability during deep breathing (P < 0.0001). The exclusive involvement of parasympathetic tests suggests that a mild vagal dysfunction occurs in some myotonic dystrophy type 1 patients. The results indicate that such autonomic abnormalities are not: (1) part of a peripheral neuropathy; (2) related to cytosine-thymine-guanine repeat size or breathing pattern. Power spectral analysis showed a reduction of supine low-frequency band, which is, but not exclusively, a marker of sympathetic activity. It was inversely correlated to disease duration (P < 0.04), suggesting a progression as the disease advances. A low-frequency power, recorded after standing, was significantly associated (P < 0.02) with presence of heart involvement. Our findings suggest that a mixed, especially parasympathetic, autonomic dysfunction may occur in myotonic dystrophy type 1, although it is not a major finding. It could play a role in the occurrence of cardiac abnormalities, or increase the risk of sudden cardiovascular events.

Neurotrophin-4 deficient mice have a loss of vagal intraganglionic mechanoreceptors from the small intestine and a disruption of short-term satiety.

Intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs) are the two putative mechanoreceptors that the vagus nerve supplies to gastrointestinal smooth muscle. To examine whether neurotrophin-4 (NT-4)-deficient mice, which have only 45% of the normal number of nodose ganglion neurons, exhibit selective losses of these endings and potentially provide a model for assessing their functional roles, we inventoried IGLEs and IMAs in the gut wall. Vagal afferents were labeled by nodose ganglion injections of wheat germ agglutinin-horseradish peroxidase, and a standardized sampling protocol was used to map the terminals in the stomach, duodenum, and ileum. NT-4 mutants had a substantial organ-specific reduction of IGLEs; whereas the morphologies and densities of both IGLEs and IMAs in the stomach were similar to wild-type patterns, IGLEs were largely absent in the small intestine (90 and 81% losses in duodenum and ileum, respectively). Meal pattern analyses revealed that NT-4 mutants had increased meal durations with solid food and increased meal sizes with liquid food. However, daily total food intake and body weight remained normal because of compensatory changes in other meal parameters. These findings indicate that NT-4 knock-out mice have a selective vagal afferent loss and suggest that intestinal IGLEs (1) may participate in short-term satiety, probably by conveying feedback about intestinal distension or transit to the brain, (2) are not essential for long-term control of feeding and body weight, and (3) play different roles in regulation of solid and liquid diet intake.

Paroxysmal vagal overactivity, apparent life-threatening event and sudden infant death.

The possibility of reversible cardiac asystoly due to paroxysmal vagal overactivity (VO) has been well studied, first in adults, then in children, and finally in breath-holding spells. Few studies deal with infants and the incidence of VO among preterm, apparent life-threatening event (ALTE) and sudden infant death syndrome (SIDS). In this review, we summarize data acquired during the past 20 years leading to the diagnosis of VO in infants. We describe the clinical aspects of VO in infants and young children such as Holter-ECG and oculocardiac reflex criteria. The familial aspect of VO and its possible link with SIDS (a new risk factor?) are discussed. Finally, whether or not to treat infants with symptomatic VO is discussed.