ALAD-Deficiency Porphyria (ADP)

 

What is δ-Aminolevulinic Acid Dehydratase Porphyria?

ADP is a severe disorder caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase (ALAD) which results in  an increase of 5’-aminolevulinic acid (ALA) in the liver, other tissues, blood plasma, and urine. In addition, urine coproporphyrin and erythrocyte protoporphyrin are increased. ADP generally presents with sudden attacks of severe stomach pain that last for several days.

 

Who gets δ-Aminolevulinic Acid Dehydratase Porphyria?

All of the reported cases of ADP have been males, in contrast to the other acute porphyrias. ADP is the least common of all the porphyrias with less than 10 cases documented to date. This is an autosomal recessive disease, whereas the other three acute porphyrias are autosomal dominant. Each parent of an affected individual must have a mutation in one of their ALAD  genes and both must pass their mutation on to their child.

 

What causes δ-Aminolevulinic Acid Dehydratase Porphyria?

ADP is caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase (ALAD).

 

How is δ-Aminolevulinic Acid Dehydratase Porphyria (ADP) diagnosed?

There are many laboratory tests available for the porphyrias, and it is often difficult to decide which should be chosen.  Many of these tests are expensive and the results are often difficult to interpret. When abdominal and neurological symptoms suggest an acute porphyria, the best screening tests are urinary aminolevulinic acid (ALA) and porphobilinogen (PBG). DNA testing to identify the specific mutation in an individual’s porphyria-causing gene is the most specific and sensitive test to confirm the diagnosis of a specific porphyria. Before requesting DNA testing, it is recommended that patients have biochemical testing (urinary, stool and/or plasma porphyrins and porphyrin precursors (ALA and PBG) and/or enzyme assays). However, biochemical testing may be inconclusive.

 

What are treatments for δ-Aminolevulinic Acid Dehydratase Porphyria?

Treatment is the same as in the other acute porphyrias. For the acute porphyrias, hospitalization is often necessary for acute attacks. Medications for pain, nausea and vomiting, and close observation are generally required with monitoring of salt and water balance. Harmful drugs should be stopped. Attacks are treated with either glucose loading or intravenous administration of hemin (Panhematin®). Attacks can be prevented in many cases by avoiding harmful drugs and adverse dietary practices.

 

For more information, see the Healthcare Professionals section of our web site.

 

 

PBS Documentary

 

 

Additional Reading about ALAD:

ALAD Porphyria

NORD gratefully acknowledges 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.

Synonyms of ALAD Porphyria

  • ADP
  • ALAD deficiency
  • ALA-dehydratase deficient porphyria
  • delta-aminolevulinate dehydratase deficiency
  • Doss porphyria
  • porphyria of Doss

General Discussion

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 come from the neurological and gastrointestinal systems. This disease 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.

Signs & Symptoms

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 individual. Individuals with more significant enzyme deficiency may have more severe symptoms and earlier onset. Individuals with partial deficiency will have milder symptoms, and some individuals will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.

Individuals with ALAD porphyria may have bouts or “attacks” when symptoms are intense, which are referred to as neurovisceral or acute attacks. An attack may last for several weeks. During an attack, affected individuals may experience severe abdominal cramping or pain accompanied by vomiting and constipation. During infancy, gastrointestinal abnormalities may cause an affected child to fail to grow and gain weight as expected.

Several other neurological symptoms can occur during an acute attack due to problems with the nerves outside the central nervous system (peripheral neuropathy), resulting in numbness or tingling in the hands and feet, burning pain, sensitivity to touch, and a lack of coordination. In severe cases, the motor nerves are involved, resulting in loss or partial impairment of the ability to use voluntary muscles. ALAD porphyria can also be associated with psychological changes during an acute attack. In severe cases, loss of contact from reality (psychosis) has been reported.

Additional symptoms that occur during acute attacks include a rapid heartbeat (tachycardia), high blood pressure (hypertension), seizures, and breathing (respiratory) impairment.

Causes

ALAD porphyria is caused by mutations in the ALAD gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALAD gene have a mutation. 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 two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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 is 25%. The risk is the same for males and females. 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.

The ALAD gene contains instructions for creating the enzyme aminolevulinate dehydratase (ALAD), which is necessary for the production of 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.

Mutations of the ALAD gene result in deficient levels ofporphobilinogen in the body, with accumulation of ALA, which causes the symptoms associated with ALAD porphyria.

A variety of different triggers have been identified that can precipitatean 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 suspect of triggering an acute attack.

Affected Populations

ALAD porphyria is an extremely rare disorder with few cases reported in the medical literature. Most cases have occurred in Europe. However, the disorder can potentially occur in any population. More males have been identified with ALAD porphyria than females in the medical literature, but the disorder affects probably males and females in equal numbers. Researchers suspect that some cases of ALAD porphyria go undiagnosed or misdiagnosed, making it difficult to estimate the true frequency of this disorder in the general population. 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.

Related Disorders

Symptoms of the following disorders can be similar to those of ALAD porphyria. Comparisons may be useful for a differential diagnosis.

Lead poisoning occurs when lead accumulates in the tissues of the body. This accumulation may occur slowly over months or years. The symptoms of lead poisoning vary depending upon the amount of lead exposure and the age of an affected individual. Lead poisoning can potentially cause behavioral changes such as irritability and sluggishness, and neurological abnormalities including poor coordination, convulsions, altered mental status, and disease of the nerves outside the central nervous system (peripheral neuropathy). Lead poisoning can also cause nonspecific symptoms including fever, joint pain, abdominal pain, nausea, vomiting and constipation. Lead inhibits the ALAD enzyme and can cause a clinical picture similar to ALAD porphyria. (For more information on this disorder, choose “heavy metal poisoning” as your search term in the Rare Disease Database.)

Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder that is caused by lack of the enzyme fumaryl acetoacetate hydrolase, which is needed for the break-down of the amino acid tyrosine. Failure to break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. There is also accumulation of succinylacetone, which is a potent inhibitor of ALA dehydratase. Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to severe liver disease, cirrhosis, and hepatocellular carcinoma if left untreated. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed. (For more information on this disorder, choose “tyrosinemia” as your search term in the Rare Disease Database.)

Acute intermittent porphyria (AIP) is a rare genetic metabolic disorder that is caused by deficiency of the enzyme porphobilinogen deaminase (PBG). This enzyme deficiency results in the accumulation of porphyrin precursors ALA and PBG in the body. The enzyme deficiency by itself is not sufficient to produce symptoms of the disease. Additional factors such as hormones, drugs and dietary changes trigger the appearance of symptoms. Symptoms of AIP may include severe abdominal pain, constipation, muscle weakness, rapid heartbeat (tachycardia), high blood pressure (hypertension), behavioral changes, seizures and disease of the nerves outside the central nervous system (peripheral neuropathy). Acute intermittent porphyria is inherited as an autosomal dominant trait. (For more information on this disorder, choose “acute intermittent porphyria” as your search term in the Rare Disease Database.)

Variegate porphyria is a rare genetic metabolic disorder that is caused by deficiency of the enzyme protoporphyrinogen oxidase. This leads to the accumulation of porphyrins and porphyrin precursors in the body, which, can potentially result in a variety of symptoms. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Common skin (cutaneous) symptoms include hypersensitivity to sunlight with formation of blisters in sun-exposed areas. Common neurological symptoms include muscle weakness, muscle pain, convulsions, and behavioral issues. Affected individuals may also have gastrointestinal symptoms such as abdominal pain and vomiting. Variegate porphyria is caused by mutations in the PPOX gene. This genetic mutation is inherited as an autosomal dominant trait. Some individuals who inherit this mutation do not develop any symptoms. (For more information on this disorder, choose “variegate porphyria” as your search term in the Rare Disease Database.)

An acquired form of ALAD porphyria has also been described in which six diabetic patients with advanced renal disease developed a syndrome similar to acute intermittent porphyria after initiation of treatment with erythropoietin. The symptoms varied but resolved in all patients when erythropoietin was stopped, and reappeared in four patients when erythropoietin was restarted. In all of the patients, the enzyme ALA dehydratase was low. (For more information on this disorder, see Hedger et al. Compr Ther. 2006 Fall; 32(3): 163-71. PMID:17435269)

Diagnosis

A diagnosis of ALAD porphyria is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation and of specialized tests that can detect delta-aminolevulinic acid in the urine.

Molecular genetic testing can confirm a diagnosis of ALAD porphyria by identifying the characteristic genetic mutation that causes the disorder.

Standard Therapies

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 Food and Drug Administration (FDA) for the treatment of acute porphyria. The drug known as Panhematin® (hemin for injection) is usually given to treat an acute attack. The drug is manufactured by:

Recordati Rare Diseases, Inc.
100 Corporate Drive
Lebanon, NJ 08833
Tel. 908-236-0888

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 may be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at 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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

NORD Member Organizations

Other Organizations

References

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
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

Sinha S, Gascon P, Schwartz RA, Shumate MJ. ALA Dehydratase Deficiency Porphyria. Medscape Reference, Last Update March 26, 2015. Available at: http://emedicine.medscape.com/article/198248-overview Accessed April 12, 2016.

National Digestive Diseases Clearinghouse. Porphyria. Last Update February 2014. Available at:http://digestive.niddk.nih.gov/ddiseases/pubs/porphyria/ Accessed April 12, 2016.

Deybach JC. Porphyria due to ALA dehydratase deficiency. Orphanet. Last Update February 2009. Available at: http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=14678&Disease_Disease_Search_diseaseGroup=Porphyria-due-to-ALA-dehydratase-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Porphyria-due-to-ALA-dehydratase-deficiency&title=Porphyria-due-to-ALA-dehydratase-deficiency&search=Disease_Search_Simple Accessed April 12, 2016.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 612740; Last Update: 02/27/2012. Available at:http://omim.org/entry/612740 Accessed April 12, 2016.

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