ALA Dehydratase Deficiency Porphyria
- Author: Smeeta Sinha, MD; Chief Editor: Emmanuel C Besa, MD more...
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.
ALAD deficiency porphyria (ADP) is characterized by autosomal recessive inheritance and only neurologic 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. 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 ALAD deficiency porphyria (ADP), termed plumboporphyria, because the heavy metal is a potent inhibitor of ALAD.[1]
Epidemiology
Frequency
United States
Only 1 case of ALA dehydratase (ALAD) has been reported in the United States.[7]
International
ALAD deficiency porphyria (ADP) is extremely rare, with only 7 confirmed cases worldwide.
Mortality/Morbidity
All 7 known patients with ALAD deficiency porphyria (ADP) had highly variable symptomatology, 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
ALAD deficiency porphyria (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.
Sex
No known sexual predilection exists for ALAD deficiency porphyria (ADP), but 6 of the 7 reported cases occurred in males.
Age
The onset of ALAD deficiency porphyria (ADP) typically occurs at birth or during childhood, although late-onset disease has been recognized.
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