Winning Abstracts from the 2007 Medical Student Abstract Competition: Porphyria Cutanea Tarda (Pct): Mutations and Sequence Variants in the Uroporphyrinogen Decarboxylase (Uro-D) Gene in Sporadic Patients..
Eric Gehrie, Mount Sinai School of Medicine
Porphyria cutanea tarda (PCT), the most common disorder of heme biosynthesis, typically presents with characteristic light-induced blistering skin lesions. Familial PCT (F-PCT) is an autosomal dominant disorder and patients have germline uroporphyrinogen decarboxylase (URO-D) mutations, half-normal erythrocyte and decreased hepatic URO-D activities. In contrast, sporadic PCT (S-PCT) patients have normal UROD genes and erythrocyte URO-D activities, but have decreased hepatic URO-D activity presumably due to the specific inhibition of the hepatic enzyme. Both familial and sporadic forms are precipitated by environmental factors including alcohol, iron overload, and viral infections (e.g., HCV). S-PCT and F-PCT can be diagnosed biochemically by markedly elevated urinary heptacarboxylate porphyrin levels.
To determine if URO-D single nucleotide polymorphisms (SNPs) or rare sequence variants predispose to S-PCT, the entire ~3.5 kb URO-D gene and 1000 bases upstream and downstream were sequenced in 24 sporadic patients who had no affected relatives, and 25 unrelated normal individuals.
Surprisingly, two previously identified URO-D coding mutations, R142X and a complex mutation (g645del1053ins10), were identified in 2 (8.3%) unrelated S-PCT patients, indicating that they actually had F-PCT. At-risk relatives have been counseled and offered testing. In addition, studies of a known F-PCT family revealed a novel URO-D mutation (H331R). Among the 22 S-PCT patients, 8 SNPs were identified at gDNA -293 (4 patients), -263 (9), -175 (1),496 (9), 1562 (2), 1772 (2), 1835 (9), and 2892 (9). The three F-PCT patients had 5 SNPs at gDNA -263 (2), 496 (10), 1835 (2), 2892 (2), and 3236 (1). In the 25 control patients, 7 SNPs were identified at gDNA -293 (6), -263 (10), 496 (10), 1562 (2), 1772 (2), 1835 (10), and 2892 (10).
This is the first report of germline mutations in presumed S-PCT patients, indicating that these manifesting patients either had de novo mutations or F-PCT that masqueraded as S-PCT due to the low penetrance of the germline mutations. Therefore, biochemically confirmed S-PCT patients should be screened by mutation analysis. In addition, no sequence variants or SNPs were identified in the URO-D gene that predisposed patients to S-PCT.
Students: Join ACP for Free
Benefits of Membership for Students: ACP's free Medical Student Membership includes benefits designed especially to meet students' needs.
Join Now: Sign-up today and begin enjoying the benefits of ACP Medical Student Membership.
Find a Residency
Search ACP's Internal Medicine Residency Database for information on all internal medicine residency programs in the U.S. and Canada. (ACP Members only)
Have questions about the new ABIM MOC Program?
One Click to Confidence - Free to members
ACP Smart Medicine is a new, online clinical decision support tool specifically for internal medicine. Get rapid point-of-care access to evidence-based clinical recommendations and guidelines. Plus, users can easily earn CME credit. Learn more