Porphyria is a group of at least eight metabolic disorders that arise as a result of a malfunction in one of the eight steps in the body’s synthesis of a complex molecule called heme. Heme is essential for the transport of oxygen to cells in the body. If any step in the synthesis of heme is blocked, an intermediate chemical accumulates in the cell, resulting in oxygen depletion. Those intermediate chemicals, known as porphyrins or porphyrin precursors, are the substances of which heme is composed.
There are two general categories of porphyrias, those that affect the skin and those that affect the nervous system. The former are called cutaneous porphyrias. The latter are called acute porphyrias. Because the symptoms of the various porphyrias may resemble symptoms of other disorders, diagnosis may be difficult.
Each type of porphyria represents a deficiency of a specific enzyme needed for the synthesis of heme. Treatment is specific to the type of porphyria. The porphyrias are inherited conditions, but don’t all follow the same mode of inheritance.
Acute Intermittent Porphyria
Abdominal pain is the most common complaint in acute intermittent porphyria. In addition, some of the following symptoms occur with varying frequency: pain in the arms and leg, generalized weakness, vomiting, confusion, constipation, tachycardia, fluctuating blood pressure, urinary retention, psychosis, hallucinations, and seizures. The muscle weakness may progress to respiratory paralysis, necessitating artificial respiration. Porphobilinogen is elevated during the attack but may be consistently high in some patients. Urine may exhibit a purple-red color. Unlike other forms of porphyria, sun sensitivity is not present in this type.
Variegate Porphyria
Variegate porphyria is characterized by abrasions, blisters, and erosions of the skin which are commonly seen during the second and third decade. These lesions tend to heal slowly, often leaving pigmented or slightly depressed scars. The patients experience sensitivity to light and fragility of skin exposed to the sun. Although in many patients manifestations remain limited to the skin, episodes similar to those of acute porphyria are not uncommon. Therefore, the symptoms, drugs, precautionary measures, and treatment described for acute intermittent porphyria are applicable to variegate porphyria.
Hereditary Coproporphyria
The large amounts of coproporphyrin present in hereditary coproporphyrin makes the patient sensitive to sunlight, but skin disease is rarely severe in this type of porphyria. Clinically it resembles variegate porphyria except that a larger percentage of affected individuals exhibit few symptoms. Other symptoms are similar to those listed for acute intermittent porphyria.
Protoporphyria
Protoporphyria can have mild to severe light sensitivity and burning on exposure to the sunlight. Usually, the symptoms subside in twelve to twenty-four hours and heal without significant scarring or discoloration to the skin. The skin lesions may also progress to a chronic stage persisting for weeks and healing with a superficial scar. These manifestations generally begin in childhood. They are more severe in the summer and can recur throughout life. Affected skin, at times, exhibits the fragility or blister formation seen in other photosensitizing types of porphyria. Hepatobiliary dysfunction may be associated with significant liver damage.
Porphyria Cutanea Tarda
In porphyria cutanea tarda, exposed skin shows abnormalities similar to those found in variegate porphyria. They range from slight fragility of the skin to persistent scarring and disfiguration. Due to fragility of the skin, minor trauma may induce blister formation. Areas of increased and decreased pigment content may be noted on the skin. Blistering of light exposed skin and increased hair growth, especially on the face, are also characteristic.
Congenital Erythropoietic Porphyria
This is a very rare disease with approximately 150 patients reported in the world. congenital erythropoietic porphyria is often manifested shortly after birth with dark urine and sunlight sensitivity causing blistering and skin fragility. Later, brownish, fluorescent teeth, increased hair growth, and pronounced scarring may occur. In some cases, loss of fingers and toes and cartilage from ears or nose may be noted.
ALA-D Porphyria
ALA-D porphyria symptoms usually arise from effects on the nervous system and/or the skin. Sometimes, the cause of the nervous system symptoms is not clear. Skin manifestations include burning, blistering, and scarring of the sun exposed areas. The disease usually manifests after puberty, and more commonly occurs in women. The most common symptom is severe abdominal pain. Other characteristics are nausea, vomiting, rapid heart rate, increased blood pressure, confusion and/or seizures, and the passing of ALA (delta- aminolevulinic acid) in the urine.
The porphyrias are a group of inherited disorders caused by deficiencies of enzymes needed in particular steps in the synthesis of the heme molecule. Of the seven distinct disorders that make up the porphyrias, four are transmitted as autosomal dominant traits, two are transmitted as autosomal recessive traits and one is transmitted in a more complex manner.
The following summarizes the mode of inheritance and the location of the genetic abnormality associated with each specific type of porphyria:
Acute Porphyrias
ALA-D porphyria; autosomal recessive; 9q34
Acute intermittent porphyria; autosomal dominant;11q24.1-q24.2
Hereditary coproporphyria; autosomal dominant; 3q12
Variegate porphyria; autosomal dominant; 1q21-23
Non-Acute Porphyrias
Congenital erythropoietic porphyria; autosomal recessive; 10q25.2-q26.3
Porphyria cutanea tarda; complex genetic transmission; 1p34
Erythropoietic protoporphyria; autosomal dominant; 18q21.3
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p34” refers to band 34 on the short arm (p) of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
The prevalence of porphyria remains unknown, but clinicians suggest that a range of 1 per 500-50,000 of population is probable. Some forms of porphyria are more common in specific populations including, for example, in Finland.
The basic defect cannot presently be treated, but significant effort is being directed toward treating the underlying mechanisms that cause symptoms. Porphyria is diagnosed through blood, urine, and stool tests.
Some people who are identified as having inherited porphyria do not have symptoms. It is important for those people, as well as for those who have symptoms, to be aware of preventive measures that may help them avoid episodes of porphyria symptoms. These preventive measures include avoidance of certain drugs and alcohol for some types of porphyria. For some people, they may also include avoidance of exposure to sunlight because sun sensitivity can occur with some types of porphyria. More specific information on these preventive measures is available from the American Porphyria Foundation (see Resources section of this report).
Some of the drugs that affected individuals may need to avoid include barbiturates, tranquilizers, birth control pills, sedatives, and alcohol.
An orphan drug formerly known as Hemin, now called Panhematin (hemin for injection), is approved for use as a treatment for various forms of porphyria and is administered intravenously. It is extremely potent, and its use typically follows a period of glucose therapy that has not produced the desired results. Panhematin is manufactured by Recordati Rare Diseases Inc.
Information on current clinical trials is posted on the Internet at http://www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Information about current research on porphyria also is available from the American Porphyria Foundation. (See contact information and web site in the Resources section of this report.)
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Anderson KE. Acute Intermittent Porphyria, ALA-Dehydratase-Deficient Porphyria, Congenital Erythropoietic Porphyria, Porphyria Cutanea Tarda, Variegate Porphyria and Hereditary Coproporphyria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:490-95.
Mathews-Roth MM. Erythropoietic Porphyria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:495-96.
Anderson KE, Sassa S, Bishop DF, et al. Disorders of Heme Synthesis. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3024-62.
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:185-200.
Berkow R, ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:933-36.
Menkes JH, Pine Jr JW, et al., eds. Textbook of Child Neurology. 5th ed. Williams & Wilkins. Baltimore, MD; 1995:129.
REVIEW ARTICLES
Foran SE, Abel G. Guide to the porphyrias. A historical and clinical perspective. Am J Clin Pathol. 2003;119 Suppl:S86-93.
Lecha M, Herrero C, Ozalla D. Diagnosis and treatment of the hepatic porphyrias. Dermatol Ther. 2003;16:65-72.
Murphy GM. Diagnosis and management of the erythropoietic porphyrias. Dermatol Ther. 2003;16:57-64.
Downey DC. The porphyrin pathway: the final common pathway? Med Hypotheses. 2002;59:615-21.
Nordmann Y, Puy H. Human hereditary hepatic porphyrias. Clin Chim Acta. 2002;325:17-37.
Aggarwal N, Bagga R, Sawhney H, et al. Pregnancy with acute intermittent porphyria: a case report and review of the literature. J Obstet Gynaecol Res. 2002;28:160-62.
Ahmed I. Childhood porphyrias. Mayo Clin Proc. 2002;77:825-36.
Badminton MN, Elder GH. Management of acute and cutaneous porphyrias. Int J Clin Pract. 2002;56:272-78.
Lambrecht RW, Bonkovsky HL. Hemochromatosis and porphyria. Semin Gastrointest Dis. 2002;13:109-19.
Sassa S, Akagi R, Nishitani C, et al. Late-onset porphyrias: what are they? Cell Mol Biol (Noisy-le-grand). 2002;48:97-101.
Murphy GM. Diseases associated with photosensitivity. J Photochem Photobiol B. 2001;64.
Elder GH, Hift RJ. Treatment of acute porphyria. Hosp Med. 2001;62:422-25.
Deacon AC, Elder GH. ACP Best Practice No 165: frontline tests for the investigation of suspected porphyria. J Clin Pathol. 2001;54:5000-07.
Shaw PH, Mancini AJ, McConnell JP, et al. Treatment of congenital erythropoietic porphyria in children by allogenic stem cell transplantation: a case report and review of the literature. Bone Marrow Transplant. 2001;27:101-05.
FROM THE INTERNET
About Porphyria. American Porphyria Foundation. 2003. 10pp.
www.porphyriafoundation.com/overview.html
Information for Patients. PORPHYRIA BOOKLET. 2003.
www.porphyria-europe.com/EN/00-Info_Patients/Info_Patients_sommaire.asp
A Guide to Porphyria. Canadian Porphyria Foundation, Inc.
www.cpf-inc.ca/guide.htm
Porphyria. MedlinePlus. Medical Encyclopedia. Page last updated: 05 January 2004. 4pp.
www.nlm.nih.gov/medlineplus/ency/article001208.htm
Porphyria. National Digestive Diseases Information Clearinghouse. March 2003. 4pp.
http://digestive.niddk.nih.gov/ddiseases/pubs/porphyria
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