Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact

The initial objective of this protocol is to assemble a well-documented group of patients with confirmed diagnoses of the erythropoietic protoporphyrias, including autosomal recessive Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) for clinical, biochemical, and genetic studies. The long-term objectives are (1) to conduct a longitudinal investigation of the natural history, complications, and therapeutic outcomes in people with erythropoietic protoporphyria, (2) to systematically investigate the psychological effects of the erythropoietic protoporphyrias on children and adults, and (3) to investigate the correlation between the identified genotypes and the resulting clinical presentation, also determining the possible interaction of other genetic markers.

Study Overview

• Status: Completed
• Conditions: Erythropoietic Protoporphyria; EPP; XLP; X-Linked Protoporphyria; XLPP; X-Linked Dominant Erythropoietic Protoporphyria; XLEPP; XLDP

Detailed Description

The porphyrias are a group of rare metabolic diseases that may present in childhood or adult life and are due to deficiencies of enzymes in the heme biosynthetic pathway. The most common manifestations are related to accumulation of intermediates in the pathway and usually occur as acute neurological attacks (as in the acute or hepatic porphyrias), or cutaneous photosensitivity (as in the cutaneous porphyrias, including the erythropoietic protoporphyrias). Multiple mutations have been identified in each of the porphyrias. The risk of disability or death from these disorders is significant, in part because diagnosis is often delayed due to lack of adoption of diagnostic testing in clinical practice. Moreover, the natural history of these disorders is not well described and it is not known what determines differences in outcomes. New therapies are needed. For existing therapies, high-quality evidence on short and long term efficacy and safety is generally lacking. Therefore, the purpose of this study of a large group of patients with EPP and XLP is to provide a better understanding of the natural history of these disorders, as affected by available therapies, and to aid in developing new forms of treatment. Much of the data collected on subjects as participants in the Longitudinal Study of the Porphyrias will be accessed for this study specific to the investigation of the erythropoietic protoporphyrias. To maximize the information that can be informative in our objectives, additional data will be collected, including additional biochemical findings and EPP-specific psychosocial parameters.

The Office of Rare Diseases (ORD) of the National Institutes of Health (NIH) established a Rare Diseases Clinical Research Network (RDCRN) in collaboration with other NIH Institutes and currently has funded 19 rare diseases clinical research consortia and one Data Management and Coordinating Center. The Porphyrias Consortium was created as part of the RDCRN, to study the human porphyrias. The Porphyrias Consortium is a consortium of the academic institutions listed in the participating institutions table. All Centers in the Porphyrias Consortium are participating in this study. Additional centers may be added if funding is available.

• Study Type: Observational
• Enrollment (Actual): 150

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0012
      • University of Alabama, Birmingham
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • New York
    • New York, New York, United States, 10029
      • ICAHN School of Medicine at Mount Sinai
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27106
      • Wake Forest University Health Sciences
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects will be recruited from the following resources:

1. Patients followed by one of the Investigators
2. The American Porphyria Foundation (APF)
3. The Rare Diseases Clinical Research Network (RDCRN) Contact Registry
4. Non-study Physician referrals
5. Self-referrals, including family members of individuals diagnosed with Porphyria (proband) and other individuals who may have heard about the study from other subjects or prospective subjects.
6. Medical Records Review

Description

Inclusion Criteria:

• All subjects must also be enrolled in the Longitudinal Study of the Porphyrias.
• Willing to sign informed consent form
• Biochemical findings - A marked increase in erythrocyte protoporphyrin [total erythrocyte protoporphyrin >200 ug/dL, or more than 1.5-fold increase (relative to ULN of 80 ug/dL)], with a predominance of free protoporphyrin (85-100% in EPP and 50-85% in XLP).

• Molecular findings - one of the following:

  1. A disease causing FECH mutation trans to the IVS3-48C>T low expression FECH allele
  2. Two disease-causing FECH mutations
  3. A gain-of-function ALAS-2 C-terminal deletion/exon 11 mutation (in XLP). If no mutation is found and subjects fulfill criteria 1-3 they are eligible for enrollment.

Exclusion Criteria:

• cases with elevations of porphyrins in urine, plasma or erythrocytes due to other diseases (i.e. secondary porphyrinuria or porphyrinemia), such as liver and bone marrow diseases [Gibson 2000].
• patients with a prior diagnosis of porphyria that cannot be documented by review of existing medical records or repeat biochemical or DNA testing.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Participants with Protoporphyrias; Individuals with a documented diagnosis of Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Hospital Anxiety and Depression Scale (HADS)	Questionnaire with 7 items for anxiety and 7 items for depression, each item is scored on a 4 point response 0 - 3, subscales 0-21, with full range from 0 to 42, with higher score indicating more severe anxiety or depression.	1 weeks
Illness Perception Questionnaire Revised (IPQR)	Each item is scored on a likert scale from 1 (strongly disagree) to 5 (strongly agree). Items within each domain were totaled for final domain scores. Seven domains - Timeline (score 5-25), Consequences (score 6-30), Personal Control (score 6-30), Treatment Control (score 3-15), Illness Coherence (score 5-25), Timeline-Cyclical (score 4-20), and Emotional Representations (score 6-30). A modified version without the identity component was used as it was not applicable in EPP. Higher scores domains indicate overall strong beliefs that the disease is chronic and has a negative impact.	1 week
EPP-Specific Tool	Each item was scored from 0-3 on a Likert scale. There are 2 domains: S=disease severity and Q=QoL. Total scale for each domain transferred to 0-100 scale. Higher scores for the S domain reflect lower severity, and higher satisfaction/QoL for the Q domain. Total Score from 0-100, with higher score indicating higher quality of life.	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Disturbance PROMIS Scores	Sleep Subscales: Pain Interference, Depression, Physical Function, Fatigue, Anxiety, Sleep Disturbance, Satisfaction with Social Roles, each subscale scored from 0-100 with higher score indicating more symptoms affecting sleep.	baseline

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Rare Diseases Clinical Research Network; Office of Rare Diseases (ORD)
• Investigators: Principal Investigator: Manisha Balwani, MD, ICAHN School of Medicine at Mount Sinai

Publications and helpful links

Helpful Links

• Website for the Rare Diseases Clinical Research Network (RDCRN) Porphyrias Consortium (PC)

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ACTUAL): July 1, 2019
• Study Completion (ACTUAL): July 1, 2019

Study Registration Dates

• First Submitted: September 14, 2012
• First Submitted That Met QC Criteria: September 14, 2012
• First Posted (ESTIMATE): September 20, 2012

Study Record Updates

• Last Update Posted (ACTUAL): April 17, 2020
• Last Update Submitted That Met QC Criteria: April 13, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: cutaneous; porphyria; erythropoietic; protoporphyria
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyrias; Protoporphyria, Erythropoietic
• Other Study ID Numbers: GCO 08-0959-04; U54DK083909 (U.S. NIH Grant/Contract); HSM12-00307 (OTHER: Mount Sinai School of Medicine)