Last updated:
9/25/2025
Years published: 1987, 1988, 1990, 1997, 2001, 2010, 2013, 2016, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Joseph R. Bloomer, MD, Professor of Medicine and Genetics, Director of the Liver Center, Director of the Porphyria Center, University of Alabama at Birmingham, for assistance in the preparation of this report.
Summary
ALAD porphyria is a very rare genetic metabolic disease characterized by almost complete deficiency of the enzyme delta-aminolevulinic acid (ALA) dehydratase. Deficiency of this enzyme leads to the accumulation of the porphyrin precursor ALA, which can potentially result in a variety of symptoms. Symptoms vary from one person to another but usually involve the neurological and gastrointestinal systems. ALAD porphyria is inherited as an autosomal recessive disorder.
Introduction
ALAD porphyria is in the group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins and porphyrin precursors in the body due to deficiencies of enzymes essential to the creation (synthesis) of heme, a part of hemoglobin. There are at least seven types of porphyria. The symptoms associated with the various types of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and related substances originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. ALAD porphyria is a hepatic form of porphyria.
The onset, severity and type of symptoms can vary greatly in individuals with a specific type of porphyria. This variation may depend on, in part, the amount of residual enzyme activity in each person. People with more significant enzyme deficiency may have more severe symptoms and earlier onset. People with partial deficiency will have milder symptoms and some people will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.
Reported onset ages include: birth, early childhood, adolescence (12–15 years) and late adulthood (63 years).
ALAD porphyria typically causes acute neurovisceral attacks which can last weeks and may recur. Symptoms include:
In infants, ALAD porphyria can present with vomiting, hyponatremia, growth failure and respiratory compromise. In some people, acute attacks are recurrent and disabling and can lead to severe paralysis.
Unlike some other porphyrias, skin symptoms have not been observed in ALAD porphyria.
ALAD porphyria is caused by changes (variants) in the ALAD gene. The ALAD gene contains instructions for creating the enzyme aminolevulinate dehydratase (ALAD) which is necessary to produce heme. Heme is part of hemoglobin, which is the oxygen-carrying component of red blood cells. Heme is mainly produced in the bone marrow and the liver. Eight different enzymes are necessary for the creation of heme.
Variants in the ALAD gene result in deficient levels of porphobilinogen in the body, with accumulation of ALA, which causes the symptoms associated with ALAD porphyria. At least 14 different ALAD gene variants have been reported in affected people.
A variety of different triggers have been identified that can precipitate an acute attack in individuals with ALAD porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspected of triggering an acute attack.
Inheritance
ALAD porphyria is inherited as an autosomal recessive disorder. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
ALAD porphyria is extremely rare. Fewer than a dozen cases have been reported in the medical literature to date. Cases have been reported from Germany, Sweden, the Netherlands, Belgium and the United States.
People who have one copy of an ALAD gene variant (carriers or heterozygotes) are asymptomatic but may have increased sensitivity to lead exposure, which can further inhibit ALAD. Carrier frequency in Sweden is estimated around 2%. The onset of ALAD porphyria is usually during infancy or childhood, but late-onset of the disorder (well into adult life) has also been reported.
A diagnosis of ALAD porphyria is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and specialized tests that can detect delta-aminolevulinic acid in the urine.
Biochemical tests can detect elevated urinary ALA and coproporphyrin III, elevated erythrocyte zinc protoporphyrin and severely reduced ALAD activity in red cells.
Molecular genetic testing can confirm a diagnosis of ALAD porphyria by identifying variants in the ALAD gene.
Testing should also exclude lead poisoning (blood lead levels) and tyrosinemia type 1 (urine organic acids, succinylacetone).
Because ALAD porphyria is so rare, anyone suspected of having this condition should undergo enzyme activity measurement and genetic testing.
Treatment
The treatment of ALAD porphyria is directed toward the specific symptoms that are present in each individual. Because there have been so few cases of ALAD porphyria, there is only limited information on treatment for the disorder.
Avoidance of triggering factors such as alcohol, certain drugs, fasting and low carbohydrate diets is recommended for affected individuals. The specific drugs that may need to be avoided in one person can differ from the drugs that need to be avoided in another. More information on these preventive measures and a list of drugs that may potentially need to be avoided are available from the American Porphyria Foundation (see Resources section of this report).
Two standard treatments for acute porphyrias in general are intravenous infusions of hemin and supplementation with glucose. However, these therapies have not been universally effective in treating individuals with ALAD porphyria.
Hemin is an orphan drug that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute porphyria. The drug known as hemin for injection (Panhematin) is usually given to treat an acute attack.
If hemin cannot be obtained quickly enough, glucose administration both orally and intravenously (which has similar effect to hemin) may be used to treat individuals with ALAD porphyria.
Additional drugs may be used to treat affected individuals during an acute attack including pain medications such as opiates, beta-adrenergic blocking agents such as propranolol to treat a rapid heartbeat, sedatives to calm nerves, drugs that reduce nausea and vomiting (anti-emetics) and anti-seizure medications (anti-convulsants). In addition, intravenous fluid replacement may be necessary during an acute attack to ensure that proper fluid and electrolyte levels are maintained.
Individuals with ALAD porphyria should carry Medic Alert bracelets or wallet cards.
Genetic counseling is recommended for affected individuals and their families.
The American Porphyria Foundation provides a listing of experts, testing and centers of excellence in porphyrias. In addition, the International Porphyria Network supports clinical research and offers information on porphyria for patients and healthcare providers.
In 2020, treatment with weekly blood transfusions and hydroxyurea was successfully attempted in one affected person.
Liver transplantation, which benefits other porphyrias and Givosiran, an RNAi therapy used in other acute porphyrias, were not effective when tried in patients with ALAD porphyria.
Information on current clinical trials is posted on the Internet at https://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/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Strachan T and Read A. Human Molecular Genetics. 4th Edition. Garland Science, Taylor and Francis Group, LLC; New York, NY; 2011.
Lichtman MA, Beutler E, Kipps TJ, Selisohn U, et al. Eds. Williams Hematology. 7th ed. McGraw-Hill Companies. New York, NY; 2006:813-816.
JOURNAL ARTICLES
Neeleman RA, van Beers EJ, Friesema EC, et al. Clinical Remission of Delta-Aminolevulinic Acid Dehydratase Deficiency Through Suppression of Erythroid Heme Synthesis. Hepatology. 2019;70(1):434-436. doi:10.1002/hep.30543
Jaffe EK, Stith L. ALAD porphyria is a conformational disease. Am J Hum Genet. 2007;80:329-337.
Hedger RW, Wehrmacher WH, French AV. Porphyria syndrome associated with diabetic nephrosclerosis and erythropoietin. Compr Ther 2006; 32(3) 163-171.
Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. 2006;134:281-292.
Akagi R, Kato N, Inoue R, Anderson KE, Sassa S. delta-aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations. Mol Genet Metab. 2006;87:329-326.
Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Int Med 2005; 142:439-450.
Doss MO, Stauch T, Gross U, et al. The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany. J Inherit Metab Dis. 2004;27:529-536.
INTERNET
Chiang, da Costa Dourado. Porphyria Overview. Medscape Reference. Last Update March 28, 2025. Available at: https://emedicine.medscape.com/article/198248-overview Accessed Sept 22, 2025.
National Digestive Diseases Clearinghouse. Porphyria. Last Update July 2020. Available at: https://www.niddk.nih.gov/health-information/liver-disease/porphyria Accessed Sept 22, 2025.
Porphyria due to ALA dehydratase deficiency. Orphanet. Last Update March 2024. Available at: https://www.orpha.net/en/disease/detail/100924 Accessed Sept 22, 2025.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: Johns Hopkins University. Porphyria, Acute Hepatic. Entry No: 612740. Last Update: 02/27/2012. Available at: https://omim.org/entry/612740 Accessed Sept 22, 2025.
Anderson KE. ALA dehydratase porphyria. UpToDate. Wolters Kluwer; June 25, 2024. Available at: https://www.uptodate.com/contents/ala-dehydratase-porphyria Accessed Sept 22, 2025.
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