What is ALAD (Aminolevulinic Acid Dehydratase)?

ALAD: Aminolevulinic Acid Dehydratase

ALAD (Aminolevulinic Acid Dehydratase) is an enzyme in the heme biosynthesis pathway that catalyzes the second step, converting two molecules of delta-aminolevulinic acid (ALA) into porphobilinogen (PBG). 1, 2

Biochemical Function and Characteristics

• ALAD is a cytoplasmic, zinc-dependent enzyme with essential thiol groups required for its activity 3
• It catalyzes the condensation of two molecules of delta-aminolevulinic acid (ALA) to form porphobilinogen (PBG), which is a critical step in heme synthesis 2, 3
• The enzyme has a measured Km of 333 μM for ALA and a Vmax of 19.3 μM/h, with average activity in healthy individuals of 277 μmol/L erythrocyte lysate/hour 4

Clinical Significance

• Deficiency of ALAD leads to ALAD porphyria (ALAD-P), one of the acute hepatic porphyrias (AHPs) 1
• ALAD porphyria is an extremely rare autosomal recessive disorder with fewer than a dozen reported cases worldwide 1, 5
• ALAD deficiency can be classified into three categories:
  • Genetic ALAD porphyria (inherited enzyme defect)
  • Tyrosinemia type I (producing succinylacetone, a potent ALAD inhibitor)
  • Environmental inhibition (by toxins such as lead, trichloroethylene, and styrene) 2

Diagnostic Considerations

• In ALAD porphyria, only ALA is elevated in urine (without elevated PBG), distinguishing it from other acute hepatic porphyrias 1
• When only ALA is elevated in urine, clinicians should check lead levels and urine organic acids to rule out lead poisoning and hereditary tyrosinemia 1
• Diagnosis of ALAD deficiency can be confirmed by genetic testing for pathogenic variants in the ALAD gene 1
• The tandem mass spectrometric assay can detect ALAD enzyme deficiency, which typically causes a 95-99% reduction in activity 4

Clinical Presentation of ALAD Deficiency

• Presents with acute neurovisceral symptoms similar to other acute hepatic porphyrias 1
• Clinical manifestations include severe abdominal pain, nausea, vomiting, constipation, muscle weakness, neuropathy, tachycardia, and hypertension 1
• Most reported cases of genetic ALAD porphyria had compound heterozygous ALAD mutations resulting in very low residual enzyme activity and symptom onset early in life or adolescence 5

Treatment Approach

• Treatment of acute attacks in ALAD porphyria includes:
  • Discontinuation of porphyrinogenic drugs and chemicals
  • Administration of intravenous dextrose and hemin
  • Use of analgesics and antiemetics 1
• Intravenous hemin has been effective in most reported cases for treatment and prevention of acute neurological symptoms 5
• Long-term monitoring is essential due to potential complications including chronic kidney disease, hypertension, and hepatocellular carcinoma 1

Research Insights

• Recent evidence shows that ALAD porphyria involves induction of hepatic 5-aminolevulinic acid synthase-1 (ALAS1), similar to other acute hepatic porphyrias 5
• The liver appears to be an important source of excess ALA in ALAD porphyria, although bone marrow may also contribute 5
• ALAD is evolutionarily conserved, with homologs found across species including parasites like Plasmodium falciparum 6

Clinical Monitoring

• Patients with ALAD deficiency require regular monitoring of:
  • Liver enzymes, creatinine and eGFR
  • Blood pressure
  • Symptoms of neuropathy
  • Screening for hepatocellular carcinoma in appropriate cases 1