Discussion:
Genetic testing plays a confirmatory role in diagnosing acute porphyria and is also useful for screening family members, enabling genetic counseling and future trigger avoidance (4). Analysis of exomic and genomic databases has revealed a substantially increased prevalence of pathogenic HMBS variants in individuals who do not present any apparent symptoms, indicating the presence of unidentified modifying genes or environmental factors (5). The estimated clinical penetrance of mutations in the HMBS gene is around 0.5-1% in the general population, with certain families showing higher penetrance ranging from 10-30%. Multiple HMBS mutations lead to loss of function, with most being considered ”private” and affecting only a single or few families. However, certain founder mutations inherited across generations have been identified, such as HMBS c.593G>A (p.W198X) in Sweden and Norway, or c.331G>A (p.G111R) in Argentina (5). Founder effects can significantly increase the prevalence of Acute Intermittent Porphyria (AIP) in specific regions. For instance, southeastern Spain has a prevalence of 17.7 cases per million, while in Sweden, it reaches 23 cases per million. Notably, northern Sweden has an astonishing prevalence of 192 cases per million (5).
The detected mutation c.457C>T in exon 9 is a nonsense mutation that results in a premature translational stop codon at amino acid position 153 of the HMBS gene. This mutation, recently classified as pathogenic based on a single submission to the National Center for Biotechnology Information, had not been previously reported in medical literature among individuals with acute intermittent porphyria, particularly when the patient presented to us in 2016 (8). In 2022, a study conducted in China examined the prevalence of pathogenic HMBS variants and identified the c.457C>T mutation. Interestingly, this mutation was detected in a single allele and was found exclusively in individuals categorized as ”American mixed race” (9).
Acute intermittent porphyria has been rarely reported in Mexico, and the exact incidence and prevalence of the condition are unknown. This characterization is relevant because different mutations can be associated with more severe clinical symptoms (10). Based on our literature review, there is a lack of information regarding the prevalence and genetic variants of porphyria in Mexican patients. As a result, the implications of this specific variant at a population level remain unknown. It remains unclear whether the atypical features of this case, such as frequent recurrences and resistance to treatment, which led to the patient’s enrollment in a clinical trial with interference RNA, are related to the patient’s genotype or other demographic characteristics. Specifically, this mutation could be a specific variant found in Mexico or the Americas.
We conclude that expanding access to genetic analyses in patients and their family members is necessary. Future studies will help characterize the clinical implications of this and other genetic variants in the pathogenesis of acute intermittent porphyria.
Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.
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