Link between porphyria and fasting uncovered

The madness of King George III has been attributed to acute intermittent porphyria, an inherited genetic disorder of the heme biosynthesis pathway. Acute attacks of porphyria result in neuropsychiatric dysfunction and are often brought on by fasting or drugs, most notably sulfonamides and barbiturates. Although episodes of the disease can be treated with heme infusion and glucose, the mechanism whereby acute porphyria is precipitated remains unclear.

Figure. King George III Photo by: William L. Clements Library

New research by Christoph Handschin and colleagues reveals a missing molecular link that helps explain the mystery.1 These researchers found that fasting increases the level of a protein, proliferator-activated receptor γ coactivator 1α (PGC-1α), which is involved in creating glucose in the liver. They also found that this protein regulates a key enzyme in the heme biosynthesis pathway, 5-aminolevulinate synthase (ALAS-1). Increased levels of PGC-1α resulted in increased production of ALAS-1. This in turn led to a build-up of precursor heme molecules, which, in mice, caused acute attacks of porphyria. The discovery reveals why glucose administration is helpful, since glucose can return PGC-1α levels to normal. However, the role of PGC-1α seems to be restricted to fasting-induced porphyria, since there was no effect when barbiturates were administered.

This discovery may lead to new treatments that allow patients to regulate their weight through diet without fear of acute episodes that result from decreased energy intake.