Practice Essentials
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] In ADP the enzymatic activity is less than 3% of normal (asymptomatic carriers have 50% of normal enzyme activity). [5]
ADP was first described in 1979 and, to date, fewer than 10 cases have been identified and confirmed by gene mutation analysis. [6]
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, 7] 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. [8] 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.
A review of the disease progression among the eight reported cases found an elevation in circulating levels of the rate-limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) and response to treatment with hemin. The authors concluded that this finding suggests that the liver is an important source of excess ALA in ADP, although the marrow may also be a contributor. [9]
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]
Etiology
ALAD deficiency porphyria (ADP) is an autosomal recessive porphyria that results from mutations in the ALAD gene on chromosome band 9q34. The heterogeneity of the mutations accounts for the varied phenotypes in the studied cases. [10] Erythrocyte ALAD activity is less than 3% of normal in homozygotes and 50% of normal in heterozygotes. [5]
Precipitants of the acute attack include the following [11] :
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Decreased caloric intake
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Dehydration
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Alcohol
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Drugs that induce the cytochrome P-450 system: Classically unsafe drugs include barbiturates (eg, phenobarbital), phenytoin, griseofulvin, sulfonamides, and valproic acid
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Estrogen or progesterone use
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Acute physical and psychologic stressors
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Infection
Epidemiology
ADP is extremely rare. Only 8 confirmed cases of ALA dehydratase deficiency porphyria (ADP) have been reported worldwide, with only one of them in the United States. [11]
ADP occurs too rarely to determine the frequency in specific races. Of the 8 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. [12]
No known reason for a sexual predilection exists for ADP. However, all 8 cases occurred in males.
The clinical onset of ADP typically occurs at birth or during childhood. However, late-onset disease has been recognized.
Prognosis
The 8 reported patients with ALAD deficiency porphyria (ADP) had markedly differing clinical courses. 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.
Neurovisceral attacks can recur throughout adulthood in otherwise healthy individuals.
A Swedish boy who had experienced severe ALAD deficiency porphyria (ADP) attacks refractory to treatment since birth underwent liver transplantation at age 6. A modest improvement in symptoms was noted, but the child died from pneumonia at age 9. [13]
A patient who presented with late-onset porphyria died from a comorbid hematologic malignancy.
Patient Education
Patients with ALAD deficiency porphyria (ADP) should be informed about the triggers of acute ALAD deficiency porphyria (ADP), as well as safe medications (as discussed in Medication).
The American Porphyria Foundation Web site contains lists of safe and unsafe medications, along with other pertinent information for patients with porphyria diseases.
