Saturday 4 February 2006
Porphyrias refer to a group of uncommon inborn or acquired disturbances of porphyrin metabolism.
Porphyrins are pigments normally present in hemoglobin, myoglobin, and cytochromes.
The classification of porphyrias is based on both clinical and biochemical features. The five major types are:
(1) congenital erythropoietic porphyria
(2) erythrohepatic protoporphyria
(3) acute intermittent porphyria
(4) porphyria cutanea tarda
(5) mixed porphyria
Cutaneous manifestations consist of urticaria and vesicles that heal with scarring and that are exacerbated by exposure to sunlight. The primary alterations by light microscopy are a subepidermal vesicle with associated marked thickening of the walls of superficial dermal vessels.
The pathogenesis of these alterations is not well understood, although serum proteins, including immunoglobulins, typically form glassy deposits in the walls of superficial dermal microvessels.
|ALA synthase||Glycine, succinyl CoA||D-Aminolevulinic acid||3p21.1||18.104.22.168||MIM.125290||none|
|ALA dehydratase||D-Aminolevulinic acid||Porphobilinogen||9q34||22.214.171.124||MIM.125270||ALA-Dehydratase deficiency|
|PBG deaminase||Porphobilinogen||Hydroxymethyl bilane||11q23.3||126.96.36.199||MIM.176000||acute intermittent porphyria|
|Uroporphyrinogen III synthase||Hydroxymethyl bilane||Uroporphyrinogen III||10q25.2-q26.3||188.8.131.52||MIM.606938||congenital erythropoietic porphyria|
|Uroporphyrinogen III decarboxylase||Uroporphyrinogen III||Coproporphyrinogen III||1q34||184.108.40.206||MIM.176100||porphyria cutanea tarda|
|Coproporphyrinogen III oxidase||Coproporphyrinogen III||Protoporphyrinogen IX||3q12||220.127.116.11||MIM.121300||coproporphyria|
|Protoporphyrinogen oxidase||Protoporphyrinogen IX||Protoporphyrin IX||1q22||18.104.22.168||MIM.600923||variegate porphyria|
|Ferrochelatase||Protoporphyrin IX||Heme||18q21.3||22.214.171.124||MIM.177000||erythropoietic protoporphyria|
Porphyria is diagnosed through spectroscopy and biochemical analysis of blood, urine, and stool. In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway.
In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to lead poisoning or hereditary tyrosinemia type I.
In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, respiratory and P450 liver cytochromes.
Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias because most heme synthesis enzymes, even dysfunctional enzymes, have enough residual activity to assist in heme biosynthesis.
The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces).
There are eight enzymes in the heme biosynthetic pathway, four of which, the first one and the last three, are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria.
Hepatic porphyrias (acute porphyrias) are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth.
Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. All other porphyrias are either skin- or nerve-predominant.