ALAS2

ALAS2 stands for delta-aminolevulinic acid synthase 2, a mitochondrial enzyme that catalyzes the first and rate-limiting step of heme biosynthesis in erythroid cells: glycine plus succinyl-CoA → delta-aminolevulinic acid (ALA), with pyridoxal phosphate as a cofactor. It is encoded by the ALAS2 gene on the X chromosome and is the erythroid-specific isoform, in contrast to ALAS1, which is expressed in most tissues.

Regulation and localization: ALAS2 is targeted to mitochondria and contains regulatory elements that permit iron-dependent control of translation in erythroid cells. An iron-responsive element in the 5' UTR mediates regulation by iron regulatory proteins, linking ALA production to cellular iron availability. Expression increases with erythroid differentiation, and heme feedback helps coordinate overall heme synthesis.

Clinical significance: Mutations in ALAS2 cause X-linked sideroblastic anemia (XLSA), a disorder of impaired mitochondrial heme synthesis leading to iron accumulation in erythroid precursors and ring sideroblasts. Clinically, XLSA presents with microcytic anemia of variable severity and can include iron overload. Some patients respond to pyridoxine (vitamin B6) therapy, reflecting the enzyme’s dependence on this cofactor, while others do not.

Genetics and diagnosis: ALAS2 is inherited in an X-linked pattern, so males are often more severely affected and female carriers may be asymptomatic or mildly affected due to X-inactivation. Diagnosis integrates peripheral blood counts, bone marrow examination for ring sideroblasts, iron studies, and genetic testing for ALAS2 variants.