fumarates and Metabolic-Diseases

Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations.. We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations.. PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites.. Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations.. SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases.. Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Citric Acid Cycle; Female; Follow-Up Studies; Fumarates; Germ-Line Mutation; Humans; Male; Metabolic Diseases; Middle Aged; Paraganglioma; Pheochromocytoma; Sensitivity and Specificity; Succinate Dehydrogenase; Succinic Acid; Young Adult

Safety and efficacy of fumaric acid esters (FAE) in patients with psoriasis requiring treated comorbidit condition were investigated.. Data collected from 7 dermatology centers were used for a retrospective analysis of patients treated continuously with FAE for at least 6 weeks who required at least one medication for a comorbid condition. The records were analyzed at baseline and after 1, 3, 6, 12 and 24 months of therapy. Safety parameters were monitored and the severity of skin symptoms was assessed by 'Physician's Global Assessment' (PGA).. A total of 69 patients with moderate to severe psoriasis and a mean duration of 27.4 months of continuous treatment were included in the study. In less than 5% were interactions between FAE and co-medications observed. Changes of hepatic, renal or hematological laboratory parameters were usually insignificant and required a modification of FAE treatment in less than 12% of the cases. The percentage of patients documented as markedly improved or clear was 61% after 6 months, 77% after 12 months, and 75% after 24 months of therapy.. In patients with moderate to severe psoriasis on co-medications, FAE were effective and safe without any noteworthy drug interactions.

Topics: Cardiovascular Diseases; Comorbidity; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Germany; Humans; Male; Metabolic Diseases; Middle Aged; Prevalence; Psoriasis; Retrospective Studies; Risk Assessment; Treatment Outcome