A Novel Mutation c.457C>T p.Q153 in the HMBS Gene in a Mexican Woman with Acute Intermittent Porphyria

Introduction:Acute intermittent porphyria (AIP) represents an autosomal dominant disorder stemming from a partial deficiency in the enzymatic activity of porphobilinogen deaminase, which is also referred to as hydroxymethylbilane synthase (HMBS), the third enzyme involved in the synthesis of heme. This deficiency leads to the accumulation of toxic heme metabolites, namely aminolevulinic acid (ALA) and porphobilinogen (PBG) (1) The precise mechanisms through which porphyrin precursors trigger the symptoms of AIP are not fully understood (1,2)AIP presents with a range of clinical manifestations that can be categorized into three distinct phases: the prodromal phase, the visceral symptom phase, and the neurological phase. Prominent clinical symptoms encompass the occurrence of acute neurovisceral episodes, marked by intense abdominal pain, mental disturbances, and heightened sympathetic activity (2)Acute attacks of porphyria can be precipitated by a range of factors, encompassing alcohol ingestion, stress, fasting, menstruation, surgical procedures, infection, and the administration of certain drugs (1,3). Preliminary assessment for AIP involves the detection of markedly elevated porphyrin levels in urinary, stool or serum during an acute attack, followed by subsequent genetic analysis to confirm the presence of HMBS gene mutations (4). The management of AIP encompasses a comprehensive approach that includes the management of acute attacks, prevention of future episodes, long-term monitoring, and the treatment of associated complications (2).Among the various acute porphyrias, AIP is recognized as a prevalent condition on a global scale, being both the most common and severe form among the acute hepatic porphyrias (5) AIP affects both males and females, however, in the context of AIP episodes, females tend to experience more severe impacts in terms of higher frequencies of attacks, longer durations of attacks, and an increased likelihood of requiring hospitalization (6).The HMBS gene is situated at the chromosomal position 11q23.3 and has been linked to more than 400 pathogenic mutations (5). Individuals harboring pathogenic variants of the HMBS gene, regardless of their symptomatic or latent status, are prone to experiencing acute attacks. Furthermore, chronic complications such as hepatocellular carcinoma, hypertension, and chronic renal failure can manifest in both symptomatic individuals with AIP and those who are asymptomatic but carry pathogenic HMBS variants (7).To date, limited knowledge exists regarding certain variants of pathogenic HMBS, particularly in low and middle-income countries such as Mexico. Consequently, there is uncertainty about the disease behavior in these individuals. Further research is warranted to address these gaps and enhance our understanding of AIP management in this specific patient population.