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δ-Aminolevulinic-dehydratase Deficiency Porphyria

What is δ-Aminolevulinic Acid Dehydratase Porphyria (ADP)?

ADP is more severe than the other acute porphyrias and can present in childhood. It is an inherited genetic condition but is extremely rare. Only ~10 cases have been reported worldwide and all of the reported cases have been males, in contrast to the other acute porphyrias where more women have symptoms. In ADP, the gene responsible is ALAD which produces the enzyme δ-aminolevulinic acid dehydratase. Normally, the activity of this enzyme is high, much higher than that of ALA synthase-1 the enzyme immediately preceding ALAD, or HMBS, the enzyme immediately after ALAD. When activity of ALAD is severely deficient [less than ~ 10% of normal], ALA builds up and can cause symptoms similar to those seen in AIP.

How is δ-Aminolevulinic Acid Dehydratase Porphyria diagnosed?

Biochemical testing means looking for “biomarkers” in the blood or urine. To diagnose ADP, measurements of porphobilinogen (PBG), aminolevulinic acid (ALA), and total porphyrins in the urine should be done. Also porphyrins in the blood should be measured. The level of PBG in the body can vary so the best time to take samples is during an acute attack (e.g. when someone is having abdominal pain, etc). Slight elevations in porphyrins are not diagnostic of ADP; the levels need to be very high.

What are treatments for δ-Aminolevulinic Acid Dehydratase Porphyria?

Due to its extreme rarity, there are few consensus recommendations regarding the management of ADP. Most authorities recommend the same general measures as for AIP, HCP, or VP. Use of IV heme in ADP has not been very effective, and its place in therapy is uncertain. In contrast to AIP, liver transplantation has not proven to be of certain benefit in ADP, but recent results in a Dutch patient indicate that also decreasing ALA overproduction from the bone marrow by hypertransfusions, to decrease bone marrow red blood cell production, is effective.

Givosiran may also be worthy of trial; there is thus far no clinical experience with its use in ADP. It is presumed that combined liver and bone marrow transplantation would likely be curative or highly ameliorative for ADP, but this also would entail great risks of complications. It has not yet been tried in ADP.

How is δ-Aminolevulinic Acid Dehydratase Porphyria Inherited?

ADP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive means that both copies of the gene are mutated. The gene that causes ADP is called ALAD.