An overview of pathogenic variants in Acute Intermittent Porphyria in Argentina.

VARELA, LAURA; CABALLERO, ALEJANDRA; GUOLO, MARCELO; MELITO, VIVIANA; BUZALEH ANA MARIA; PARERA, VICTORIA

Bethesda, Maryland

Congreso; THE INTERNATIONAL PORPHYRIAS SYMPOSIUM 2023; 2023

American Porphyria Foundation

Acute Intermittent Porphyria (AIP) is a low penetrance, autosomal dominant disorder characterized clinically by abdominal pain, nausea, vomiting, peripheral neuropathy, and seizure which may be life-threatening. It results from a partial deficiency of hydroxymethylbilane synthase (HMBS), encoded by the HMBS gene. More than 520 variants in the HMBS gene were identified worldwide. In Argentina, AIP has a familial prevalence of 1:250,000.The aim of this study was to analyze the molecular basis of patients with AIP from unrelated families in the Argentinean population. Our investigation centered on 127 AIP patients who had been diagnosed at the CIPYP. Informed consent was signed by all patients to carry out this study. The diagnostic process encompassed a range of biochemical assessments, including measurement of urinary 5-aminolevulinic acid, porphobilinogen and porphyrin levels, assessment of plasma porphyrin index, and evaluation of blood HMBS activity. Mutations in the HMBS gene were identified by direct automated sequencing of amplified genomic DNA. The exploration of our target population yielded a striking array of 49 different pathogenic variants. Despite the genetic heterogeneity inherent to AIP, certain variants exhibited prominence within the Argentinean cohort. Notably, p.G111R (49%), p.Q34P (5.5%), p.R173W (4%), and c.202_203delCT (1.6%) were the prevailing variations. Additionally, a subset of variants remained private to specific familial contexts. Intriguingly, our study unveiled four novel pathogenic variants, discovered over the last half-decade, including p.(Leu49Cysfs*49), hitherto unreported. Encouragingly, we observed instances of compound heterozygosity in three families, alongside the occurrence of dual PAI/PCT (Porphyria Cutanea Tarda) in another family. This study offers insights into the intricate genetic landscape of AIP within the Argentinean population, underscoring the pivotal role of genetic analysis in achieving accurate diagnoses and informed medical guidance. Furthermore, the identification of previously unknown variants increases our comprehension of the genetic foundations of AIP in the Argentinean context. Genetic analysis is imperative in special cases to corroborate the diagnosis of AIP. Equally relevant is its capacity to uncover latent patients and provide guidance on potential triggering factors, thereby preventing the clinical manifestation of the disorder. By virtue of these insights, genetic analysis emerges as an indispensable tool in managing AIP, announcing a new era of precision medicine in the field.