ALA Dehydratase Deficiency Porphyria

Updated: Dec 29, 2017
  • Author: Smeeta Sinha, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

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]

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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]

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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.

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