While the pathogenetic mechanisms underlying the lesions remain unclear, it has been suggested that the accumulation of fumarate may lead to overexpression of the aldo-keto reductase enzyme, AKR1B10. It has also been found that fumarate is present in the mitochondria and in the cytoplasm. The cytoplasmic form appears to have a role in the protection of DNA from molecular injury. Fumarate has been shown to be a competitive inhibitor of prolyl hydroxylase. This inhibition leads to the stabilisation of a number of hypoxia-inducible factors which are thought to predispose to tumorigenesis. An alternative pathway for the metabolism of fumarate in the presence of these mutations has been described. Other genes involved affected by this mutation are Keap1, Nrf2 and HMOX1.
Hereditary leiomyomatosis and renal cell cancer syndrome
Menke-Hennekam syndrome
Hereditary leiomyomatosis and renal cell carcinoma
Fryns syndrome
Heerfordt syndrome
Serrated polyposis syndrome
Hereditary breast–ovarian cancer syndrome
Ehlers–Danlos syndromes