Introduction to the Porphyrias
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What are the Porphyrias?
The porphyrias are a group of disorders caused by deficiencies of specific enzymes in the pathway to make heme. Heme is an essential component of hemoglobin and many other hemoproteins in the body. Depending on which enzyme is deficient, different intermediates in the pathway accumulate. These intermediates include porphyrin precursors [δ-aminolevulinic acid (ALA) and porphobilinogen (PBG)] and porphyrins. Porphyrins are complex ring structures that are formed from four PBG molecules.
Specific porphyrias associated with deficiencies in enzymes at each step in this sequence are shown in the diagram.
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Each porphyria is due to the deficiency of a different enzyme in this pathway from Succinyl CoA and Glycine to Heme. Each porphyria has different metabolic and clinical features. The location of the change in the pathway is responsible for the distinct features of the individual porphyrias.
The terms "porphyrin" and "porphyria" are derived from the Greek word "porphuros" meaning red or purple. Porphyrins in purified form are dark red and when present in excess cause the urine to appear reddish or brown. The color change, however, is not specific to porphyria. It may be caused also by blood in the urine, by certain foods (beets, for example) and some medications (rifampin, pyridium, griseofulvin, and others).
Inheritance of the Porphyrias
Each type of porphyria involves the deficiency of a specific enzyme in the pathway of heme formation. In most porphyrias, the deficiency is due to an inherited gene defect. The exception is ‘sporadic’ PCT, in which the enzyme deficiency develops during life from a combination of environmental factors (for example, iron accumulation, acquired liver disease, alcohol, and some medications including estrogen). While the inherited gene defect in most cases results in enzyme deficiency, in one type of porphyria (XLP) it causes increased activity of the enzyme, ALA-synthase 2 (ALAS2). Other genetic differences, as well as environmental factors such as drugs, chemicals, and diet, can contribute to the development of active porphyria.
Each of the eight enzymes in the heme pathway has its own gene, located on one of the human chromosomes. However, there are two genes for the first enzyme in the pathway, 5’-aminolevulinic acid synthase, known as ALAS1 and ALAS2. The ALAS1 gene is located on chromosome 3 and functions in all cell types. The ALAS2 gene is located on the X-chromosome and is active only in cells of the bone marrow that produce hemoglobin.
Humans have 46 chromosomes which can be organized into 23 pairs. The first 22 pairs are called autosomes. Each pair of autosomes shares the same genes. The 23rd pair of chromosomes is the sex chromosomes, also known as the X and Y chromosomes. Females have two X chromosomes, and males have one X chromosome and one Y chromosome. The X and Y chromosomes have different genes. Therefore, females have 2 copies of genes on the X chromosome, while males have only one .
How a genetic disorder is inherited depends upon whether the associated gene is on an autosome (autosomal inheritance) or the X chromosome (X-linked inheritance), and also on whether one mutated copy of the gene is sufficient to cause the disease (dominant inheritance) or two are required (recessive inheritance). In an autosomal dominant disorder, one parent passes the mutation to the child, whereas in an autosomal recessive disorder, both parents must be carriers of the gene and both must pass the mutation to the child. In an X-linked disorder, inheritance depends on whether it is the mother or the father who carries the mutation. A female with the mutation may pass it to any of her children; a male with the mutation will pass it to all of his daughters but to none of his sons.
Table 1. Types of porphyria, their patterns of inheritance, and the enzyme that is deficient in each.
| Type | Inheritance |
Deficient Enzyme |
Gene | Gene Locus |
|---|---|---|---|---|
ALA-Dehydratase Porphyria (ADP) |
Autosomal recessive |
ALA-Dehydratase |
ALAD | 9q34 |
Acute Intermittent Porphyria (AIP) |
Autosomal dominant |
Hydroxymethylbilane synthase (Porphobilinogen deaminase) |
HMBS | 11q23 |
Congenital Erythropoietic Porphyria (CEP) |
Autosomal recessive |
Uroporphyrinogen III synthase |
UROS | 10q25-26 |
Porphyria Cutanea Tarda (PCT), familial form |
Autosomal dominant |
Uroporphyrinogen decarboxylase |
UROD | 1p34 |
Hepatoerythropoietic Porphyria (HEP) |
Autosomal recessive |
Uroporphyrinogen decarboxylase |
UROD | 1p34 |
Hereditary Coproporphyria (HCP) |
Autosomal dominant |
Coproporphyrinogen oxidase |
CPOX | 3q12 |
Variegate Porphyria (VP) |
Autosomal dominant |
Protoporphyrinogen oxidase |
PPOX | 1q22 |
Erythropoietic Protoporphyria (EPP) X-linked Protoporphyria (XLP) |
Autosomal recessive X-linked |
Ferrochelatase δ-Aminolevulinate synthase 2 |
PECH ALAS2 |
18q21 Xp11.21 |
* For more information about inheritance, visit Genetics 101.
The Classification of the Porphyrias
The porphyrias are generally classified as either acute or cutaneous, depending on the type of symptoms. Acute porphyrias affect the nervous system and cause acute attacks of pain in the abdomen, limbs and elsewhere, nausea and vomiting, constipation, urinary retention, confusion, hallucinations, and seizures. Most cutaneous porphyrias cause chronic blistering and scarring on sun-exposed areas of the skin. One type causes an acute form of non-blistering photosensitivity. Porphyrias are also classified as either hepatic, meaning that the excess intermediates arise largely in the liver, or erythropoietic, in which they originate in the bone marrow.
For in-depth information about each of the porphyrias, click on any of the following:
The Acute Porphyrias
- Acute Intermittent Porphyria
- Hereditary Coproporphyria
- Variegate Porphyria
- Aminolevulinate-dehydratase Deficiency Porphyria
The Cutaneous Porphyrias
- Porphyria Cutanea Tarda
- Hepatoerythropoietic Porphyria
- Congenital Erythropoietic Porphyria
- Erythropoietic Protoporphyria and X-Linked Protoporphyria
Also See: Genetics 101
