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

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
[Anderson, 2001]. 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 [Sood 2008]. 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.

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.