Clinical Trial: Effect of Isoniazid on Protoporphyrin Levels in Erythropoietic Protoporphyria

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Quantification of the Effects of Isoniazid Treatment on Erythrocyte and Plasma Protoporphyrin IX Concentration and Plasma Aminolevulinic Acid in Patients With Erythropoietic Prot

Brief Summary:

In erythropoietic protoporphyria there is an accumulation of protoporphyrin IX (PPIX) in the plasma and liver. The reason it builds up is either the last step to make heme, insertion of iron into PPIX, 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 PPIX 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 PPIX that is made so that none builds up.


Detailed Summary:

Clinically, both erythropoietic protoporphyria (EPP) and X-linked EPP (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 ferrochelatase (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 messenger ribonucleic acid (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.

Aminolevulinic acid synthase (ALAS), the first, and rate-limiting enzyme in the heme biosynthetic pathway, catalyzes the condensation of glycine and succinyl-Coenzyme A (succinyl-CoA) to form aminolevulinic acid (ALA), and requires pyridoxal 5'-phosphate as a cofactor
Sponsor: University of Utah

Current Primary Outcome: Change in Plasma Protoporphyrin IX Level [ Time Frame: Baseline and 3 Months ]

Plasma Protoporphyrin IX will be measured at baseline and at 3 months


Original Primary Outcome: Decrease in plasma protoporphyrin [ Time Frame: 3 months ]

Plasma protoporphyrin will be measured ever 2 weeks for 3 months.


Current Secondary Outcome: Participants With Increased Sun Sensitivity [ Time Frame: Baseline and 3 Months ]

Study participants were asked to report after 3 months if they had experienced an increase in subjective measures of sun sensitivity during the trial. Reported outcome is the number of study participants who reported increased sun sensitivity


Original Secondary Outcome: Sun sensitivity [ Time Frame: 3 months ]

Patients will be asked if there is a change in sun sensitivity


Information By: University of Utah

Dates:
Date Received: March 5, 2012
Date Started: March 2012
Date Completion:
Last Updated: November 19, 2016
Last Verified: November 2016