Rare HMBS gene mutation ID’d in Mexican woman with severe AIP
She responded well to treatment with Givlaari, started in a clinical trial
A rarely reported mutation in the HMBS gene was identified as the cause of recurrent, hard-to-treat episodes of acute intermittent porphyria (AIP) in a young Mexican woman, according to a case report.
While it’s unclear whether the mutation is linked to a more severe clinical presentation, its identification “underscores the importance of expanding genetic analyses in diverse populations to improve diagnosis, management, and knowledge of the disease’s clinical implications,” the scientists wrote.
The case study, “A novel mutation c.457C > T p.Q153 in the HMBS gene in a Mexican woman with acute intermittent porphyria,” was published in Clinical Case Reports.
More than 400 disease-causing mutations identified in the HMBS gene
Acute hepatic porphyria is a group of conditions characterized by a liver deficiency in one of several enzymes needed for making heme. Heme is a component of iron-containing proteins, including hemoglobin, which carries oxygen in red blood cells.
Deficiency leads to a toxic accumulation of intermediate molecules used to make heme, known as porphyrins and their precursors, in the liver that pass into the bloodstream to cause a wide range of porphyria symptoms.
The most common and severe form of AHP, acute intermittent porphyria is caused by mutations in HMBS, which codes for an enzyme of the same name. More than 400 disease-causing HMBS mutations have been identified, affecting the activity of its resulting enzyme.
However, information is limited on disease-causing HMBS mutations, “particularly in low and middle-income countries such as Mexico,” the researchers wrote, adding that “consequently, there is uncertainty about the disease [features] in these individuals.”
Researchers at an institute in Mexico City described the case of a woman with severe AIP who was found to carry a rare HMBS mutation.
The woman, then 28, came to their clinic due to recurring episodes of intense abdominal pain, weakness in the arms and legs, uncontrollable vomiting, and insomnia, which she had been experiencing since she was 17.
“These symptoms required frequent visits to the emergency department,” the team wrote, and persisted despite testing and symptomatic treatment.
After nearly three years of almost daily symptoms, a urine test during a crisis came back positive for elevated porphobilinogen (PBG), a type of porphyrin that builds up in AIP. This result, along with her symptoms, confirmed an AIP diagnosis.
The woman was started on treatment with Normosang and Panhematin, two injectable products containing hemin, a molecule that ultimately suppresses the formation of porphyrins. This resulted in “partial improvement,” the researchers wrote.
But over the following years, she began experiencing progressively severe AIP episodes, some leading to paralysis and kidney damage. Higher-than-normal urine PBG levels also were detected even when there were no apparent symptoms.
Meanwhile, “her first cousin was also diagnosed with AIP and had a similar clinical presentation,” the team wrote.
Research needed to determine if mutation causes more severe disease
Genetic testing revealed a nonsense mutation, called c.457C>T (p.Q153), in one copy of the HMBS gene. A nonsense mutation is one that makes protein production stop earlier than it should, resulting in a shorter protein that most likely does not work properly.
This mutation “had not been previously reported in medical literature among individuals with AIP, particularly when the patient presented to us in 2009,” the researchers wrote. Last year, however, researchers in China identified the mutation exclusively in patients categorized in their 2022 published study as being of “American mixed race.”
At age 38, the woman entered a clinical trial for Givlaari, a therapy now approved in the U.S. and European Union to treat people with AHP, including AIP.
She responded well to Givlaari and continued treatment after the trial ended.
“Over the past years, her symptoms have been sporadic, and she has not required hospitalization. The patient is now 42 years old,” the researchers wrote.
This case highlights that “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,” the researchers wrote.
“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 … are related to the patient’s [genetic profile] or other demographic characteristics,” they added. “Specifically, this mutation could be a specific variant found in Mexico or the Americas.”
More research, the scientists concluded, “is necessary to establish a definitive link between this specific mutation and disease severity.”