Therapy Follows Diagnosis: Old and New Approaches for the Treatment of Acute Porphyrias, What We Know and What We Should Know

Abstract

Heme, iron protoporphyrin IX, is one of life's most central molecules. Hence, availability of the enzymatic machinery necessary for its synthesis is crucial for every cell. Consequently, inborn errors of porphyrin metabolism that compromise normal synthesis, namely the family of porphyrias, undermine normal cellular metabolism given that heme has functions in catalytic centers, signal transduction and functional regulation and its synthesis is fully integrated into the center of intermediary metabolism. Very often, diagnosis of porphyrias is difficult and therefore delayed. Therapy can be as complicated. Over the last 50 years, several strategies have been developed: because of its integration with other parts of intermediary metabolism, the infusion of glucose (glucose effect) was one of the first attempts to counterbalance the dysregulation of porphyrin synthesis in porphyrias. Since heme synthesis is impaired, infusional replacement of heme was the next important therapeutic step. Recently, siRNA technology has been introduced in order to downregulate 5-ALA-synthase 1, which contributes to the patho-physiology of these diseases. Moreover, other novel therapies using enzyme protein replacement, mRNA techniques or proteostasis regulators are being developed.

Keywords: 5-ALA; acute intermittent porphyria; givosiran; glucose effect; heme; heme arginate; panhematin; variegate porphyria.

Figure 1

Human cystathionine-ß-Synthase (a Homotetramer): the protein backbone of a dimer is represented as ribbons, while heme (in a pocket, see arrows), pyridoxal phosphate and the so-called CXXC oxidoreductase motif are drawn as ball and stick models. The iron in the porphyrin moiety is shown as a red dot. (adapted from [4]) Copyright 2002 with permission from American Chemical Society).

Figure 2

Biosynthesis of heme: the first four enzymes occur in tissue specific isoenzyme forms. d-ALA = d-aminolevulinic acid, PBG = porphobilinogen, HMB = hydroxymethylbilane, Uro III = Uroporphorinogen III, Copro III = Coproporphorinogen III, Proto = Protoporphyrin (ogen) IX. The enzyme defects in the four acute porphyrias are shown.

Figure 3

Integration of heme biosynthesis into carbohydrate, lipid and protein metabolism. Heme synthesis uses succinyl-CoA (cataplerosis), which is replenished by the TCA cycle (anaplerosis).

Figure 4

Signs and symptoms (in Percentages) during acute attacks in a German cohort of 62 patients (57 AIP, 5 VP) with acute porphyrias [16].

Figure 5

PGC-1-Alpha as a meeting point for the regulation of heme biosynthesis by fasting, glucose and iron (see text for details). Arrow up = increase, arrow down = decrease.