ALA Dehydratase Deficiency Porphyria

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Background

Porphyrias are diseases caused by enzymatic defects in the biosynthetic pathway of heme; sensorimotor neuropathy and cutaneous photosensitivity may manifest, depending on where in the pathway the insult occurs. Delta-aminolevulinic acid dehydratase (ALAD), also known as porphobilinogen synthase, catalyzes the second step of heme synthesis. Deficiency of this enzyme produces ALAD deficiency porphyria (ADP), an extremely rare cause of acute porphyria.

ADP is characterized by autosomal recessive inheritance and only neurovisceral manifestations.[1, 2, 3, 4] It was first described in 1979 and, to date, only a few cases have been identified and confirmed by gene mutation analysis.[5]

Pathophysiology

ALAD catalyzes the conversion of 2 molecules of delta-aminolevulinic acid (ALA) into the cyclic compound porphobilinogen (PBG). In ALAD deficiency porphyria (ADP), deficient ALAD activity leads to a build-up of upstream intermediates in the metabolic pathway.[4, 6] ALA accumulates in the body and is subsequently excreted in increased amounts in the urine.[1, 2, 3]

Decreased heme production de-represses ALA synthetase and further increases ALA levels. Urine coproporphyrin III and erythrocyte protoporphyrin IX levels are also elevated, although the pathogenesis of these findings is not understood.[7] Tissue accumulation of ALA, a neurotoxin, produces neurovisceral symptoms.

ALA synthetase activity is also closely associated with cytochrome P-450 activity. Induction of the P-450 system by exogenous agents causes ALA accumulation and predisposes patients to acute attacks of porphyria.

Lead poisoning may produce a clinical picture that mimics ADP. This condition is termed plumboporphyria, because the heavy metal is a potent inhibitor of ALAD.[1]

Epidemiology

Frequency

ADP is extremely rare. Only 7 confirmed cases of ALA dehydratase deficiency porphyria (ADP) have been reported worldwide, with only one of them in the United States.[8]  

Mortality/Morbidity

Patients with ADP have had highly variable presentations, ranging from failure to thrive in an infant to the development of a polyneuropathy in a 63-year-old man. Recurrent attacks of neurovisceral symptoms may be life threatening.

Race-, Sex-, and Age-related Demographics

ADP occurs too rarely to determine the frequency in specific races. Of the 7 known cases, 6 were identified in Europe: 3 of the patients are of German lineage, 2 are Swedish, and 1 is Belgian. The seventh case was reported in the United States.

No known reason for a sexual predilection exists for ADP. However,  6 of the 7 reported cases occurred in males.

The onset of ADP typically occurs at birth or during childhood. However, late-onset disease has been recognized.

History

ALAD deficiency porphyria (ADP) is an acute hepatic porphyria that produces only neurovisceral signs and symptoms. Heterozygotes are asymptomatic.

The clinical manifestations mimic those seen in acute intermittent porphyria, as follows:

Exacerbation of symptoms occurs with stress, decreased calorie intake, and alcohol consumption. Note: This form of porphyria is not associated with cutaneous photosensitivity

The clinician should rule out the following:

Physical

On physical examination, patients with ALAD deficiency porphyria (ADP) may show evidence of abdominal tenderness or neuropathy.[9] Autonomic neuropathy, including tachycardia and systemic arterial hypertension, are common presenting signs during acute attacks. Bulbar and respiratory muscle paresis can occur. Muscle hypotonia of the arms and legs is noted in some patients.

Causes

ALAD deficiency porphyria (ADP) is an autosomal recessive porphyria due to mutations in the ALAD gene on chromosome band 9q34. The heterogeneity of the mutations accounts for the varied phenotypes in the 7 studied cases. Erythrocyte ALAD activity is 1% of normal in homozygotes and 50% of normal in heterozygotes.

Precipitants of the acute attack include the following:

Laboratory Studies

Findings on laboratory studies in patients with delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP) are as follows:

Hyponatremia and hypomagnesemia are both risk factors for development of seizures, which occur in 20-30% of acute attacks.[10]

Other Tests

DNA analysis to identify mutations in the ALAD gene is the most specific test for ALAD deficiency porphyria (ADP).

Approach Considerations

Treatment of the acute attack of ALAD deficiency porphyria (ADP) should begin by removing the precipitating factors. This includes discontinuing drugs that induce the cytochrome P-450 system, promptly treating infections, and maintaining a high-carbohydrate intake.

Treatment considerations are as follows:

Liver transplantation has not been shown to be useful in treating ADP.[11]

Diet

Patients with ALAD deficiency porphyria (ADP) should maintain a diet high in carbohydrates, consuming at least 300 g of glucose daily. Glucose inhibits ALA synthetase, thus decreasing ALA levels.

Medication Summary

Specific treatments for acute attacks of ALAD deficiency porphyria (ADP) include heme replacement with intravenous hematin and carbohydrate loading with intravenous dextrose.[12, 13] Hematin, the ferric hydroxylated form of heme, should be administered within 24 hours for severe ADP attacks, or for mild symptoms that fail to improve after 24 hours.

Hemin (Panhematin)

Clinical Context:  Previously known as hematin (hematin is a term used to describe chemical reaction products of hemin and sodium carbonate solution). Enzyme inhibitor derived from processed RBCs and an iron-containing metalloporphyrin. Decreases production of ALA synthetase, thus decreasing ALA levels. DOC for acute attacks of ALAD deficiency porphyria (ADP).

Class Summary

Metalloporphyrin agents reduce morbidity and prevent complications: Attacks of porphyria may progress to irreversible neuronal damage. Hemin therapy is used to prevent an attack from causing neuronal degeneration; it is not effective in repairing neuronal damage.

Further Inpatient Care

Some common medications that are known to be safe for use in ALAD deficiency porphyria (ADP) include the following:

Deterrence/Prevention

The mainstay of ALAD deficiency porphyria (ADP) outpatient therapy is to prevent future acute attacks. Patients should be counseled to avoid the following:

 

Prognosis

See the list below:

Patient Education

See the list below:

Author

Smeeta Sinha, MD, Resident Physician, Department of Dermatology, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Thomas H Davis, MD, FACP, Associate Professor, Fellowship Program Director, Department of Internal Medicine, Section of Hematology/Oncology, Geisel School of Medicine at Dartmouth

Disclosure: Nothing to disclose.

Acknowledgements

Mark J Shumate, MD, MPH Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, Emory University School of Medicine

Mark J Shumate, MD, MPH is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

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