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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