Erythropoietic Protoporphyria (EPP) Clinical Trial
Official title:
Quantification of the Effects of Isoniazid Treatment on Erythrocyte and Plasma Protoporphyrin IX Concentration and Plasma Aminolevulinic Acid in Patients With Erythropoietic Protoporphyria
In erythropoietic protoporphyria there is an accumulation of protoporphyrin IX in the plasma
and liver. The reason it builds up is either the last step to make heme, insertion of iron
into protoporphyrin IX, is rate limiting or there is an increase in activity in the first
step in the heme pathway.
It may be possible to decrease the amount of protoporphyrin IX made and see a decrease in
symptoms. The first step to make heme is the key step in the pathway and it uses vitamin B6
as a cofactor. If the investigators can limit the amount of vitamin B6 the investigators can
possibly reduce the activity of this rate limiting step. With decreased activity of the
enzyme it may be possible for the body to utilize all the protoporphyrin IX that is made so
that none builds up.
Clinically, both aEPP and XLEPP are characterized by painful, non-blistering cutaneous
photosensitivity with onset in early childhood. EPP is the most common porphyria in children
and the third most common in adults (after porphyria cutanea tarda and acute intermittent
porphyria). Reports of prevalence vary between 5 and 15 cases per million population.
EPP is due in most cases to decreased activity of FECH, the enzyme that catalyzes the
incorporation of ferrous iron into PPIX, the final step in the production of heme. The
pattern of inheritance is autosomal recessive. However, homozygosity for a FECH mutation is
rare. Rather, the decreased activity is a consequence of a combination of an inherited
inactivating mutation affecting one FECH allele and an intronic polymorphism that alters
splicing of the other allele. The alternative splice site, when used, produces a
non-functional FECH mRNA. The alternative splice site is used approximately 40% of the time.
Therefore, the polymorphic allele produces approximately 60% of normal FECH activity, and
for this reason, is termed hypomorphic. When the hypomorphic FECH allele is in trans with
the non-functional mutant allele the result is 30% or less of the normal FECH enzyme
activity. This subnormal FECH activity becomes rate-limiting, resulting in accumulation of
intracellular PPIX. Although the defect is presumably expressed in all tissues, the PPIX
responsible for photosensitivity derives primarily from marrow reticulocytes.
ALAS1 and ALAS2 ALAS, the first, and rate-limiting enzyme in the heme biosynthetic pathway,
catalyzes the condensation of glycine and succinyl-CoA to form ALA, and requires pyridoxal
5'-phosphate as a cofactor. ALAS in mammalian cells is localized to the mitochondrial
matrix. The enzyme is synthesized as a precursor protein in the cytosol and transported into
mitochondria. Two separate ALA synthase genes encode housekeeping (tissue-nonspecific) and
erythroid specific forms of the enzyme (ALAS1 and ALAS2, respectively). The gene for human
ALAS1 is on 3p.21 and the locus for ALAS2 the X-chromosome, at Xp11.2.
The two forms of ALAS are differentially regulated, ALAS1 is a housekeeping gene expressed
in all cells and ALAS2 is driven by erythroid specific transcription factors GATA1 and
NF-E2. Additionally, ALAS2 mRNA contains an iron-responsive element (IRE) in its
5'-untranslated region, similar to mRNAs encoding ferritin and the transferrin receptor (in
which the IRE is in the gene's 3' UTR). Gel retardation analysis showed that the
iron-responsive element in ALAS2 mRNA is functional [as evidenced by binding to iron
regulator protein 2 (IRP2)], indicating that translation of the erythroid-specific mRNA is
directly linked to the availability of iron and heme in erythroid cells.[9] In this case,
when intracellular iron concentration is relatively high, it is available for binding to
IRP2, a process that enhances ubiquitin-mediated degradation of IRP2. Under these
conditions, IRP2 is unavailable for binding to the IRE element in ALAS2, clearing the
message for efficient translation. Conversely, when intracellular iron is relatively low,
IRP2 degradation is restricted, making the protein available for binding to the IRE and
thereby blocking translation of ALAS2 mRNA.
Recently, a variant form of EPP, inherited in an X-linked pattern (XLEPP), was shown to be
due to an ALAS2 gain-of-function mutation in exon 11. The mutation results in a truncated
form of the protein that has supranormal specific activity as a result of less constrained
enzyme-substrate interactions, resulting in overproduction of PPIX. This situation is in
contrast to EPP with mutated FECH in which PPIX accumulates because of deficient heme
formation.
ALAS1 and 2 use pyridoxal phosphate (PLP) as a cofactor. PLP is a modified form of vitamin
B6. It has been shown that PLP complexes with isoniazid depleting the cofactor. This PLP
depletion has been one of the causes of sideroblastic anemia.
The investigators will test the hypothesis that depletion of PLP will lead to decreased
activity of ALAS.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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