The inborn errors of
heme biosynthesis, the
porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include
DNA-based diagnoses for all the
porphyrias, new understanding of the pathogenesis of the acute
hepatic porphyrias, identification of the
iron overload-induced inhibitor of hepatic uroporphyrin
decarboxylase activity that causes the most common
porphyria,
porphyria cutanea tarda, the identification of an X-linked form of
erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific
5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic prophyrias. Knowledge of these advances is relevant for hematologists because they administer the
hematin infusions to treat the acute attacks in patients with the acute
hepatic porphyrias, perform the chronic phlebotomies to reduce the
iron overload and clear the dermatologic lesions in
porphyria cutanea tarda, and diagnose and treat the
erythropoietic porphyrias, including chronic
erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene
therapies for congenital
erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.