UROD – Hepatoerythropoietic Porphyria

Hepatoerythropoietic porphyria (HEP) is a rare, autosomal recessive cutaneous porphyria characterized by profound uroporphyrinogen decarboxylase (UROD) deficiency leading to marked accumulation of polycarboxylated porphyrins in urine and tissues. Clinically, HEP presents in infancy or early childhood with extreme photosensitivity, skin fragility in sun-exposed areas, hypertrichosis, erythrodontia, and pink urine. Variability in severity ranges from mild cutaneous findings without overt photosensitivity to classic blistering lesions and systemic manifestations such as arthritis and developmental delay. Diagnosis relies on biochemical assays showing <10% of normal UROD activity and confirmed by molecular genetic testing of the UROD gene.

More than 15 probands across >10 unrelated families have been reported with biallelic UROD variants (PMID:12071824; PMID:15491440; PMID:20479301; PMID:21668429). Autosomal recessive inheritance is confirmed by homozygous and compound heterozygous presentations. Segregation was observed in two sibships, representing at least five additional affected relatives (PMID:1634232; PMID:20479301). No studies have refuted the association, and heterozygous carriers remain asymptomatic or present with late-onset familial porphyria cutanea tarda.

Over 30 distinct UROD variants have been described, including ~25 missense substitutions, 8 truncating mutations (nonsense and frameshift), and 4 canonical splice-site changes. A recurrent missense p.Gly281Glu variant is prevalent among Spanish families (PMID:8644733). One well-characterized variant, c.138T>G (p.Phe46Leu), was identified homozygously in a 5-year-old proband with mild HEP (PMID:12071824). Additional pathogenic alleles include p.Val166Ala, p.Gly170Asp, and essential splice-site mutations, underscoring the allelic heterogeneity of HEP.

Functional studies of recombinant UROD mutants consistently demonstrate loss-of-function. Prokaryotic expression of p.Phe46Leu and other missense mutants resulted in <10% of wild-type enzymatic activity (PMID:12071824; PMID:15491440). Site-directed mutagenesis of P62L and Y311C variants showed subnormal activity and increased thermolability (PMID:8644733). The G170D mutant exhibited 17–60% residual activity, correlating with milder biochemical phenotypes (PMID:21668429). Truncating and splice-site alleles abolish catalytic function, confirming haploinsufficiency as the pathogenic mechanism.

The robust genetic evidence of autosomal recessive inheritance, consistent multigenerational segregation, and concordant functional assays establish UROD deficiency as the definitive cause of hepatoerythropoietic porphyria. Molecular diagnosis via UROD sequencing differentiates HEP from related porphyrias, enables carrier detection, and permits prenatal exclusion. Genotype–phenotype correlations inform prognosis, as residual enzyme activity often predicts disease severity. Genetic counseling should be offered to affected families, and heterozygous carriers monitored for late-onset familial porphyria cutanea tarda.

Key Take-home: Homozygous or compound heterozygous UROD variants cause hepatoerythropoietic porphyria through loss-of-function, and targeted UROD genetic testing is critical for definitive diagnosis, family planning, and management.

References

• Archives of dermatology • 2002 • Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. PMID:12071824
• The British journal of dermatology • 2004 • Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. PMID:15491440
• Archives of dermatology • 2010 • Hepatoerythropoietic porphyria misdiagnosed as child abuse: cutaneous, arthritic, and hematologic manifestations in siblings with a novel UROD mutation. PMID:20479301
• The British journal of dermatology • 2011 • Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. PMID:21668429
• Human genetics • 1992 • Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria. PMID:1634232
• American journal of human genetics • 1996 • Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. PMID:8644733
• The Journal of investigative dermatology • 1994 • Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. PMID:8176248
• Dermatology (Basel, Switzerland) • 1990 • Uroporphyrinogen decarboxylase deficiency in hepatoerythropoietic porphyria: further evidence for genetic heterogeneity. PMID:2322500

Evidence Based Scoring (AI generated)