ALA Dehydratase Deficiency Porphyria

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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]

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]

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]  

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.

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.

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

Smeeta Sinha, MD is a member of the following medical societies: Alpha Omega Alpha, Phi Beta Kappa, Sigma Xi

Disclosure: Nothing to disclose.

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

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

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

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

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

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

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

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

Thomas H Davis, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Education, American College of Physicians, New Hampshire Medical Society, Phi Beta Kappa, Society of University Urologists

Disclosure: Nothing to disclose.

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.

ALA Dehydratase Deficiency Porphyria

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