04152 The prevalence and penetrance of acute intermittent porphyria in the mass general Brigham biobank

Total porphyrins and heme precursors were detected in urine; biochemical analysis for Hcy, folic acid, and vitamin B12 were performed in serum.ELISA or colorimetric assays were used for vitamin B6, S-adenosylmethionine (SAM), Sadenosylhomocysteine (SAH) and heme measurements.Genotyping was applied to define the inherited status for c.C677T MTHFR polymorphism.We found 14 patients (60.9%) with HHcy (>15.40mmol/L) of which 9 mild (<25mmol/L) and 5 moderate (<50mmol/L).HHcy was frequently associated with low blood concentrations of folate and values were inversely correlated as expected (r=-0.65,p=0.0008).Despite the allele distribution of MTHFR polymorphism was comparable to those in the Italian population (53% vs 50%), the Hcy average values were higher than normal even after stratification for polymorphism: 18.7 and 35.2 mmol/L for CC and TT genotype respectively.On the contrary, the average values of vitamin B12 (434.2 198.8ng/L), B6 (64.6 41.6 nmol/L) and folate (7.9 5.3 mg/L) were similar to those of healthy population.Of note, the AIP high excreters showed increased levels of B12 and significantly reduced levels of both folate and B6 compared to low excreters, but no difference in Hcy values.Finally, heme and SAM were significantly reduced (p < 0.01 and p=0.037 respectively) while SAH was increased (p= 0,014) in AIP patients compared to healthy subjects.This study confirms that HHcy is very frequent in AIP patients and that higher values are significantly associated with lower values of folic acid and the presence c.C677T MTHFR polymorphism in homozygous as expected.However, the high frequency of HHcy in AIP cohort is not directly due to a greater T allele frequency or a greater vitamins deficiency compared to the general population but rather to a pathophysiological mechanism of AIP itself.Considering that CBS is a heme-containing enzyme regulated by SAM, these results demonstrate that a combined depletion of heme and SAM metabolite is the most likely cause of HHcy in AIP cohort.