SDHAF2 (PGL2-SDH5) and Hereditary Head and Neck Paraganglioma

Abstract

Purpose: Hereditary head and neck paraganglioma (HNPGL) syndromes are associated with mutations in the SDHD(PGL1), SDHC(PGL3), and SDHB(PGL4) genes encoding succinate dehydrogenase subunits. We recently described mutations in a previously uncharacterized human gene, now called SDHAF2, and showed that this was the long-sought "imprinted" PGL2 gene. Here, we present a new branch of the Dutch SDHAF2 (PLG2-SDH5) family.Experimental Design: The SDHAF2 family has been collected over a 30-year period. The family described here was linked to PGL2 and at-risk family members were invited to participate in this study. Patients were investigated and treated dependent on tumor size and localization. All family members have now been analyzed for the SDHAF2 mutation status.Results: Among the 57 family members, 23 were linkage positive including 7 risk-free carriers (maternal imprinting). Of the 16 at-risk individuals, 11 had a total of 24 tumors with primarily carotid (71%) and vagal locations (17%). Multifocality of tumors was prominent (91%). Malignancy was not detected. The average age at onset was 33 years, and many patients (42%) were asymptomatic prior to screening. SDHAF2 mutation analysis confirmed the findings of the previously performed linkage analysis without detection of discrepancies.Conclusions: We established the SDHAF2 mutation status of PGL2 family members. Phenotypic characterization of this family confirms the currently exclusive association of SDHAF2 mutations with HNPGL. This SDHAF2 family branch shows a young age at onset and very high levels of multifocality. A high percentage of patients were asymptomatic at time of detection.

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

“…Also with these lower estimates, the need for expanded family testing and referral of heterozygous mutation carriers to a surveillance program remains unchanged. This should also be considered in the families of patients with bi-allelic mutations in SDHD and SDHA that also have been described with a dual role, with mitochondrial disease in patients with bi-allelic mutations and risk of paraganglioma/pheochromocytoma and cancer in heterozygotes (Ricketts et al 2010;Kunst et al 2011;Welander et al 2011;Renkema et al 2015).…”

SdhE Is a Conserved Protein Required for Flavinylation of Succinate Dehydrogenase in Bacteria

“…In humans, mutations within the sdhE homologue (SDH5) increase susceptibility to tumor formation, specifically paraganglioma (30,46). This genetically amenable bacterial system provides a unique opportunity to study the conserved mechanism of SdhE/DUF339 proteins, which will have implications for central metabolism and might also further our understanding of mitochondrial diseases.…”

La génétique des paragangliomes et des phéochromocytomes

“…Les premières données montrent que les mutations de SDHAF2 semblent associées à une symptomatologie souvent multifocale et à un jeune âge d'apparition de la maladie [27]. Toutefois, de nombreux sujets chez lesquels la mutation SDHAF2 a été détectée par le dépistage génétique semblaient asymptomatiques au moment du diagnostic, suggérant une pénétrance faible de la maladie [28]. Bien que la participation du gène SDHAF2 à la génétique des PGL/PCC semble relativement mineure, le génotypage de ce gène devrait donc être considéré chez un patient atteint de PGL de la tête et du cou, qu'il existe ou non une histoire familiale dans la branche paternelle, pour lequel un dépistage des gènes SDHD, SDHB et SDHC s'est avéré négatif, mais dont la tumeur n'exprime pas SDHB en immunohistochimie.…”