S2631 Porphyria Cutanea Tarda, Type 2, in a Man With a Novel UROD Mutation

Abstract

Introduction: Porphyria cutanea tarda (PCT) is usually caused by acquired defects in uroporphyrinogen decarboxylase (UROD) activity in the liver. 20% of cases occur in patients who have a genetically determined partial decrease in UROD activity. We describe a case of a man with a novel UROD mutation causing PCT type 2. Case Description/Methods: A 77-year-old man was evaluated for 6 months of painful blistering over his dorsal hands, forearms and head [Fig 1a]. His medical history was notable for hypertension, melanoma, and stroke. He reported heavy alcohol and tobacco use. He had no family history of porphyria. He worked for years at a manufacturing facility, with exposure to various industrial chemicals. More recently, he had exposure to weed killers, carburetor cleaners, and wood varnish. Exam revealed tense bullae with milia and hyperpigmented macules on dorsal hands and forearms. Biopsies revealed a subepidermal blister containing a small number of neutrophils with fibrin and evidence of festooning of the vessels consistent with porphyria. Labs revealed AST 63 U/L, ALT 64 U/L, alkaline phosphatase 54 U/L, and total bilirubin 0.8 mg/dL. Iron profile was unremarkable, and antibodies against HIV and hepatitis A, B and C were negative. Total plasma porphyrins were elevated to 13.4 mcg/dL. Fractionated urine, stool and plasma porphyrin levels were obtained [Table 1]. Urinary uro- and hepta-carboxyl porphyrins were markedly elevated, consistent with PCT. The patient was advised to start hydroxychloroquine 100 mg 3 times weekly and to avoid alcohol, tobacco use and sun exposure. Genetic testing revealed a novel mutation of UROD gene (c.224 G >C; p. Arg 75 Pro) with red blood cell UROD activity decreased by 50%. He returned to clinic 3 and 7 months after the index visit. He had stopped alcohol use, but continued smoking cigarettes. His hands were improved [Fig 1b]. Repeat urinary porphyrins showed improvement [Table 1]. The mutation in UROD is predicted to have a major effect on protein structure and function [Fig 1c]. Discussion: Inherited partial deficiency in UROD is not sufficient to cause clinically manifest PCT. Other factors that increase oxidative stress are also required. This patient has a mutation in the UROD gene not heretofore described in PCT type 2, but that we show markedly affects the structure and activity of the protein product. Nonetheless, the patient did not develop clinically manifest PCT until age 77, emphasizing the importance of acquired factors in disease pathogenesis.Figure 1.: A. Dorsal right hand at presentation B. Dorsal right hand at 7 month follow-up C. Structure of URO-D showing the substrate (yellow) in the active site located at the C-terminal end of the beta-sheets (magenta) that form the core of the TIM-barrel structure. The location of arginine 75 (Arg 75) is shown in green. Arg 75 is the penultimate residue in one of the eight corresponding alpha-helices that surround the central core. Arg 75 forms two hydrogen bonds with glutamic acid 45 (Glu 45) of the preceding helix in the structure. This hydrogen bonding network supports the overall tertiary fold of the protein in this otherwise solvent-exposed region of the protein. The UROD mutation of the patient (Arg 75 Pro) disrupts the helix with premature termination and more importantly eliminates the hydrogen bonding network.Table 1-A.: Results of Selected Laboratory Studies.Table 1-B.: Results of Selected Laboratory Studies.