ALA Dehydratase Deficiency Porphyria

Updated: Jan 29, 2020
  • Author: Smeeta Sinha, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

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 (compared with asymptomatic carriers who have 50% of normal enzyme activity). [5]

ADP was first described in 1979 and, to date, less than 10 cases have been identified and confirmed by gene mutation analysis. [6]

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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, 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.

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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Etiology

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 less than 3% of normal in homozygotes and 50% of normal in heterozygotes. [5]

Precipitants of the acute attack include the following [9] :

  • Decreased caloric intake

  • Dehydration

  • Alcohol

  • Drugs that induce the cytochrome P-450 system: Classically unsafe drugs include barbiturates (eg, phenobarbital),  phenytoin, griseofulvin, sulfonamides, and valproic acid.

  • Estrogen or progesterone use

  • Acute physical and psychologic stressors

  • Infection

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Epidemiology

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 

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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Prognosis

The 7 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. [10]

A patient who presented with late-onset porphyria died from a comorbid hematologic malignancy.

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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 Further Inpatient Care).

The American Porphyria Foundation Website contains lists of safe and unsafe medications and other pertinent information for patients with porphyria diseases (www.porphyriafoundation.com).

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