Etiology

• In human medicine the inherited porphyrias are a diverse group of errors of heme synthesis, each caused by the deficient activity of a specific enzyme in the heme pathway. Porphyrias are classified as either hepatic or erythropoietic, according to whether the excess production of porphyrin precursors and porphyrins occurs primarily in the liver or in the red cells and their precursors. As far as the Authors and Editors are aware, only erythropoietic porphyrias have been described in cattle.
• The mechanism is believed to be as follows:
  • In healthy animals, the enzyme ferrochelatase converts protoporphyrin to heme by inserting ferrous iron. This enzyme is found in the mitochondria and is one of eight enzymes involved in the heme pathway.
  • In affected homozygous animals, the ferrochelatase gene is faulty and as such this stage of the heme synthesis pathway does not occur and protoporphyrin therefore accumulates in blood and tissues.
• Another mechanism has also been described:
  • BCEP has been postulated to occur due to a rare autosomal recessive trait that results in a decrease of uroporphyrinogen III synthase (URO-synthase) activity.
  • URO-synthase is the fourth enzyme in the heme biosynthesis pathway and it normally converts hydroxymethylbilane to uroporphyrinogen III. It is found in the cytoplasm of the cell.
  • With decreased URO-synthase there is a buildup of hydroxymethylbilane in red blood cells which convert to uroporphyrinogen I.
• Regardless of the exact mechanism, the result is the same:
  • Porphyrinogen/protoporphyrin accumulate in large amounts and can become pathological.
  • Accumulations of Porphyrinogen/protoporphyrin in the bone marrow can lead to cell damage and hemolysis.
  • Porphyrinogen/protoporphyrin are released into the circulation and can be deposited in the skin, bone and other tissues. In the skin the porphyrins are photocatalytic and cytotoxic leading to cutaneous photosensitivity.
  • Exposure of the skin to sunlight leads to excitation of isomers, formation of oxygen radicals and subsequent tissue and vessel damage.
• Why do seizures occur?
  • Seizures were postulated to occur due to accumulation of δ-Aminolevulinic acid, an endogenous non-proteinogenic amino acid, which is the first compound in the porphyrin synthesis pathway. The δ-Aminolevulinic acid competitively inhibits γ-amino-butyric acid (GABA) a primary inhibitory neurotransmitter of the central nervous system.
  • However, it is now believed that although this molecule may be responsible for neuropathic pain observed in affected individuals, seizures are more likely attributed to metabolic imbalances such as hyponatremia.

Timecourse

• The condition is present from birth, but signs often only detected after exposure to sunlight or poor growth rate is detected.

Epidemiology

• The recessive genetic character is widely distributed but the clinical condition is comparatively rare.