DIAGNOSING PORPHYRIA - A CLINICAL AND BIOCHEMICAL SURVEY IN SWISS PATIENTS WITH ACUTE-INTERMITTENT PORPHYRIA

Minder E

 

Stadtspital Triemli, Zentrallabor, Zurich, Switzerland

 

 

Acute-intermittent porphyria is an autosomal dominant inherited disorder with incomplete penetrance. Molecular analysis showed that carriers of identical mutation of the HMB-synthase gene greatly differ in the expression of their disease. Therefore, we performed a survey in Swiss AIP patients and their latent family members to search for possible mechanisms of disease manifestation. The following questions were addressed:

(1)     To what extent does the diagnosis of acute-intermittent porphyria affect the quality of life?

(2)     Are there any detectable exogenous or endogenous factors that correlate to disease expression?

(3)     Does the biochemical profile in urine discriminate between latent and overt disease?

(4)     Is there any x-chromosomal marker that correlates to disease expression as suggested by the higher rate of symptomatic disease in females than in males?

(5)     Does an allele specific inheritance of the rate limiting enzyme ALA-synthase 1 explain the disease expression?

Twenty-one of the 40 individuals proven by molecular diagnosis to have inherited a mutation of the HMB-synthase were symptomatic. Quality of life was only affected in severely symptomatic patients. The only exogenous factor detected to correlate with overt disease was smoking. Latent mutation carriers showed lower excretion of porphyrin precursors and porphyrins in urine than symptomatic individuals. ALA (Mean ± SD) was 3.68±2.05 vs 9.30±6.55 μmol/mmol creatinine, PBG was 3.51±3.26 vs 19.4±18.7 and porphyrins were 25.1±22.0 vs 102.4± 64.3 nmol/mmol creatinine. Seven of the 19 individuals with latent disease had completely normal urinary porphyrin excretion rates, but none of 21 individuals who had experienced at least one attack  in their preceding life time. We found that the gender specific frequency of overt disease is compatible with an dominant x-chromosomal manifestation factor. This was not only true in our patient cohort, but also in recently published series of Swedish and Argentinean AIP patients. However, no significant correlation of x-chromosomal markers (10 cM) was found within the families tested. Further, we also noticed a transmission of overt disease from fathers to daughters. Both findings argue against an x-chromosomal manifestation factor. Lastly, we tested, if an allele-specific inheritance of ALA-Synthase 1 explains incomplete penetrance. Fifteen different polymorphic sites - three of them within the promotor region - of ALA synthase 1 were assayed but none of them were correlated with disease expression. [This work was supported by a grant from Hartmann-Müller Stiftung].