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Harderoporphyria is a rare autosomal recessive porphyria caused by biallelic loss-of-function variants in the coproporphyrinogen oxidase gene (CPOX). Affected individuals accumulate the tricarboxylic intermediate harderoporphyrinogen, leading to neonatal hemolytic anemia, hyperbilirubinemia, hepatosplenomegaly, photosensitivity and chronic porphyrin elevation. Diagnosis relies on clinical presentation, biochemical profiling of porphyrins and molecular confirmation of CPOX variants.
Genetic evidence for CPOX-related harderoporphyria includes four biallelic probands from three unrelated families with consistent phenotypes and segregation data. The first report described a Turkish infant homozygous for c.980A>G (p.His327Arg) presenting with neonatal hyperbilirubinemia, hemolytic anemia and hepatosplenomegaly; urinary porphyrins were massively elevated before fatal acute neurologic decompensation (PMID:21103937). A 78-year-old man with lifelong photosensitivity and persistent jaundice harbored two novel CPOX alleles and showed high erythrocyte and fecal harderoporphyrin levels (PMID:30828546). Two siblings from a consanguineous pedigree manifested severe microcytic anemia, cholestasis, hepatosplenomegaly and later primary adrenal and gonadal insufficiency with homozygous c.83_85del (p.Ser28Ter) (PMID:40296768).
Segregation analysis within the sibling pair confirms autosomal recessive inheritance with two additional affected relatives segregating the truncating allele. The variant spectrum includes active-site missense mutations (His327Arg), predicted damaging substitutions in residues 391–404, and early truncating alleles (p.Ser28Ter), with no healthy homozygotes reported in population databases.
Functional studies of engineered CPOX homodimers and heterodimers demonstrate that substitutions of residues R391 and K404 yield <20% of wild-type activity and marked accumulation of harderoporphyrinogen. Heterodimeric complexes with one mutant and one wild-type subunit also show severely reduced enzymatic function, supporting a loss-of-function mechanism underlying both hereditary coproporphyria and the rarer autosomal recessive harderoporphyria (PMID:24078084).
No conflicting reports have disputed the CPOX-harderoporphyria link. All identified variants disrupt enzyme dimerization or active-site integrity in concordance with clinical severity. The collective genetic and experimental data satisfy ClinGen criteria for a Strong gene-disease association.
Key Take-home: Biallelic CPOX variants cause autosomal recessive harderoporphyria via loss of enzymatic activity; molecular diagnosis enables early intervention and family counseling.
Gene–Disease AssociationStrongFour biallelic probands across three unrelated families, including segregation in two siblings, with consistent clinical phenotypes and functional data Genetic EvidenceStrongFour probands with biallelic CPOX variants including missense and truncating alleles, segregation in siblings, and recurrent active-site variants Functional EvidenceModerateIn vitro assays of mutant homodimers and heterodimers show markedly reduced CPOX activity consistent with disease mechanism (PMID:24078084) |