Two Previously Unknown Mutations Identified in Rare Case of Harderoporphyria

Researchers identified two previously unknown mutations in the coproporphyrinogen oxidase (CPOX) gene as the underlying cause of a rare form of hereditary coproporphyria, called harderoporphyria, in a 78-year old man.

The study, “Harderoporphyria: Case of lifelong photosensitivity associated with T compound heterozygous coproporphyrinogen oxidase (CPOX) mutations“ was published in the journal Molecular Genetics and Metabolism Reports.

Porphyrias are caused by an alteration to enzymes involved in the biochemical pathways responsible for oxygen transport, cellular metabolism and heme production. Heme is the red pigment that contains iron and gives blood its color. When these enzymes are altered, there is accumulation and excretion in urine and feces of intermediate molecules like porphyrins.

The most common symptom is skin sensitivity to light (photosensitivity). This is due to an accumulation of porphyrins that are themselves light sensitive in the blood or red blood cells. Other symptoms include neurological complications caused by high levels of porphyrin precursors, namely δ-aminolevulinic acid (ALA) and porphobilinogen (PBG).

A mutation in one of the CPOX gene alleles, or copies, has been associated with hereditary coproporphyria (HCP), an inherited porphyria disease. However, this is a heterogenous disease and more than 50 mutations have been described in the CPOX gene.

Coproporphyrinogen oxidase is an enzyme involved in the heme pathway and is located inside the cells’ energy factories, called mitochondria.

In this study, a team of researchers analyzed a 78-year-old Caucasian man who was evaluated for chronic skin photosensitivity. His clinical history showed that he had jaundice (yellowish discoloration of the white part of the eyes and skin) and anemia as a newborn, which required blood transfusions.

He went on to develop blisters upon sun exposure. He had mild anemia and an enlarged spleen (splenomegaly), “but developed normally and was able to participate normally in sports and other activities,” researchers said.

At age 76, he had undergone surgery to remove an asymptomatic pancreatic mass (cyst) and an enlarged spleen. Urinalysis showed high levels of porphyrins — 2,420 nmol/gram creatinine — the normal cutoff is below 300 nmol/gram creatinine.

Levels of porphyrins in the blood and feces were also high, reaching 13.4 µg/dL (normal levels below 0.9) and 875 mmol/gram, (normal levels below 300), respectively.

These symptoms were consistent with a diagnosis of harderoporphyria, a clinically distinct variant of HCP.

DNA analysis of the CPOX gene showed that the patient had two mutations — c.698A > G (p.D233G) and c.1207_1218del 12. The second mutation led to a significant deletion in part of the CPOX protein, impairing its molecular activity. Neither of the two mutations had previously been described for harderoporphyria.

Overall, the results suggest that “this very rare form of porphyria is more genetically heterogeneous than previously thought,” researchers wrote.

Harderoporphyria, they added, “should be considered as the cause of increased porphyrins and chronic photosensitivity at any age, and is recognized by finding increases in harderoporphyrin in feces and, in many cases, in [red blood cells] .”