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\begin{document}

\title{A Novel Mutation c.457C\textgreater{}T p.Q153 in the HMBS Gene in a
Mexican Woman with Acute Intermittent Porphyria}



\author[1]{Jose Malagon-Rangel}%
\author[1]{Jose Gabriel-Solis}%
\author[1]{Luis Fernando Zavala-Jonguitud}%
\author[2]{Martín Basile-Alvarez}%
\author[3]{Andrea Malagón-Liceaga}%
\affil[1]{Hospital de Especialidades Centro Médico Nacional Siglo XXI}%
\affil[2]{Universidad Nacional Autónoma de México}%
\affil[3]{Universidad Nacional Autonoma de Mexico}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\textbf{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.

\textbf{Case report:}

We present the case of a Mexican woman who started experiencing
recurring episodes of intense abdominal pain, weakness in her upper and
lower extremities, uncontrollable vomiting, and insomnia at the age of
17. These symptoms required frequent visits to the emergency department.
Despite undergoing normal biochemical and imaging tests, not responding
to pain relief medications, and even undergoing abdominal surgery for
suspected acute appendicitis, her symptoms persisted. After enduring
nearly three years of almost daily symptoms, an episode of elevated
urine porphobilinogen during a crisis finally confirmed the diagnosis of
acute intermittent porphyria.

Treatment with hematin derivatives (Normosang\selectlanguage{ngerman}®, Panhematin®) was
initiated, resulting in partial improvement. However, subsequent years
witnessed progressively severe crises, some accompanied by paralysis and
kidney injury. Remarkably, elevated urine porphobilinogen was even
detected during asymptomatic periods. Notably, her first cousin also
received a diagnosis of acute intermittent porphyria with a similar
clinical presentation.

A molecular genetic study was conducted at a reference center in
Belgium. All coding exons (1, 3-15), including parts of the adjacent
intronic sequences and regions of the 5´- and 3´-UTR of the HMBS gene,
were PCR-amplified from genomic DNA. The amplicons underwent direct
sequencing using capillary electrophoresis and the BigDye technology
(Applied Biosystems). Data alignment and comparison with the wildtype
sequence (NM\_000190.3) were performed using the GenBank Database. This
analysis revealed a heterozygous state mutation, c.457C\textgreater{}T
(p.Q153, exon 9, HMBS gene).

At the age of 28, she enrolled in a clinical trial for Givosiran, an RNA
interference therapeutic targeting ALAS1 mRNA. Remarkably, she exhibited
a remarkable response to the treatment and continued it even after the
trial. Over the past years, her symptoms have been sporadic, and she has
not required hospitalization.

\textbf{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\textgreater{}A (p.W198X) in Sweden
and Norway, or c.331G\textgreater{}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\textgreater{}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\textgreater{}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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