Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria

Abstract

IMPORTANCE Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.OBJECTIVE To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP. DESIGN, SETTING, AND PARTICIPANTSA prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database. MAIN OUTCOMES AND MEASURES Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP. RESULTS Of the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3-48T>C, and only 1 patient had 2 FECH mutations.Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients' mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 μg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 μg/dL; P Յ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 μg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 μg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 μg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.CONCLUSIONS AND RELEVANCE These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a fra...

Evaluating quality of life tools in North American patients with erythropoietic protoporphyria and X‐linked protoporphyria

“…Comparisons of responses for each tool between sex (males vs females) and disease (EPP vs XLP) were unremarkable. Characteristics of this cohort have been previously reported, however only the portion who completed these tools is reported here . Of the 202 patients, 104 completed the IPQR, 103 completed the HADS, 107 completed the EPP‐Specific tool, and 193 completed the PROMIS‐57; 101 patients completed all of the tools.…”

“…Each site's Institutional Review Board approved the study and informed consent was obtained. Study procedures were described previously . All patients included had a confirmed diagnosis of EPP with significantly elevated ePPIX.…”

“…Sun‐exposed skin, typically on the face and dorsum of the hands, reacts with tingling, burning, and/or itching that may progress rapidly to severe pain, erythema, and swelling . Severity is variable, but most patients can only tolerate <30 minutes of sun exposure . The pain can be excruciating, does not respond well to analgesics, including opioids, and may last for days .…”

Erythropoietic protoporphyria in an adult with sequential liver and hematopoietic stem cell transplantation: A case report

“…11 Given the severity of this patient's phenotype characterized by symptoms and protoporphyrin levels, we conclude that he bears an uncharacterized mutation leading to EPP (Table 1). 11 Given the severity of this patient's phenotype characterized by symptoms and protoporphyrin levels, we conclude that he bears an uncharacterized mutation leading to EPP (Table 1).…”

Liver metabolomics in a mouse model of erythropoietic protoporphyria

“…EPP results from the defective mutation of the gene encoding ferrochelatase (FECH), the enzyme that is responsible for the final step of heme synthesis [2–4]. FECH catalyzes the insertion of a ferrous iron into protoporphyrin IX (PPIX) to form heme, which mainly occurs in the bone marrow and liver [2, 5, 6]. The defective mutation of the FECH gene reduces FECH activity and leads to PPIX accumulation in the bone marrow, erythrocytes, plasma, and liver.…”