Porphyria Cutanea Tarda Type II/Hepatoerythropoietic Porphyria via the UROD Gene

Porphyria Cutanea Tarda (PCT) type II is metabolic disorder due to impairment of the fifth enzyme, uroporphyrinogen decarboxylase (UROD), in the heme biosynthetic pathway and is the most common form of porphyria affecting about 5-10 in 100,000 individuals. It is characterized by cutaneous photosensitivity resulting in blistering. Patients may also exhibit skin friability after minor trauma, facial hypertrichosis, hyperpigmentation, and pseudoscleroderma. Individuals with PCT type II have an increased risk for hepatocellular carcinoma. Symptom onset is typically in the fourth or fifth decade of life and is more common in men. There are three clinically indistinguishable types of PCT: type 1-sporadic, type II- familial with presence of UROD mutation, and type III- familial without presence of UROD mutation. PCT type II has relatively low penetrance with susceptibility being influenced by several factors including presence of HFE mutations, alcohol consumption, hepatitis C or HIV infection, smoking, or oral estrogen use (Sampietro et al. 1999). Genetic testing is helpful in confirming diagnosis of PCT subtypes and from other porphyria related disorders. Standard treatments typically involve monitoring of urinary porphyrin levels and phlebotomies to reduce iron stores. Avoidance of susceptibility factors and increased surveillance for hepatocellular carcinoma are also common for patients with PCT (Liu et al. 2013).

Hepatoerythropoietic porphyria (HEP) is the autosomal recessive form of PCT type II with affected individuals having biallelic mutations in the UROD gene. Clinical symptoms mirror congenital erythropoietic porphyria with skin blistering occurring in areas of sun exposure. Symptom onset primarily occurs in infancy and may include increased hair growth on sun exposed skin, reddish colored urine, and brownish colored teeth. Fewer than 100 cases have been reported to date with males and females being equally affected. Similar susceptibility factors for PCT type II also may exacerbate symptoms in HEP (Liu et al. 2013).

PCT type II and HEP are inherited in autosomal dominant and recessive manners respectively through mutations in the UROD gene. PCT type II is a low penetrant disorder with clinical presentation of the disease being influenced by several susceptibility factors (Liu et al. 2013). Missense variants affecting UROD transcript stability are the most frequently identified causative variant and are found throughout the coding region (Phillips et al. 2001). Although less common, splicing alterations, small insertions/deletions, and nonsense variants have also been found in patients with PCT type II (Aarsand et al. 2009). In HEP, typically patients have a null and missense mutation in the UROD gene. Homozygosity for null alleles is lethal (Phillips et al. 2007). Mutations in the HFE gene have been shown to enhance disease severity (Mendez et al. 1998; Aarsand et al. 2009).

The UROD gene encodes the uroporhyrinogen decarboxylase enzyme which catalyzes the conversion of uroporphyrinogen II to coproporphyringen III in the heme metabolic pathway. In tissues with impaired UROD activity, primarily blood and liver, oxidized porphyrins accumulate and are released into the plasma and deposited in the skin. When protoporphyrin accumulates in tissues it becomes photo-activated resulting in excess energy to be transferred to oxygen. This leads to heightened reactive oxygen species causing cellular damage and disease (Phillip et al. 2007).

In a patient cohort containing both sporadic and familial PCT, mutations in the UROD gene were identified in 131 of 248 patients (Aarsand et al. 2009). Analytical sensitivity is >95% as large deletions cannot be detected by this method and have been reported in a few cases (Mendez et al. 1998; Liu et al. 2013).

This test provides full coverage of all coding exons of the UROD gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).