Fabry may be underdiagnosed contributor to heart disease: Case
South African man with HCM later found to also have rare inherited disease
The case of a South African man diagnosed with hypertrophic cardiomyopathy (HCM), a disease of the heart muscle, who was later found to also have Fabry disease, suggests the rare inherited condition may be an underdiagnosed contributor to HCM, per a report.
The researchers say this case “demonstrates the importance of screening for [genetic] variants in patients with apparent HCM.”
The man’s Fabry disease was found nine years after his HCM diagnosis, when genetic testing — not widely available in the region the patient lived — was ultimately done, highlighting “the role of research and humanitarian programs in clinical practice in resource-limited settings,” the team wrote.
Reviewing his medical history, doctors found that the man had been experiencing other signs of Fabry disease for decades, but it wasn’t until the genetic testing was performed that he was able to get the right diagnosis and treatment.
“These findings indicate that FD [Fabry disease] may represent an important, but underdiagnosed, contributor to HCM in South Africa,” the researchers wrote.
The case report, “Identification of an Ultra-Rare GLA Frameshift Variant in a South African Family With Hypertrophic Cardiomyopathy: A Case Report,” was published in the journal Cureus.
Man found to have had Fabry 9 years after heart disease diagnosis
In Fabry disease, mutations in the GLA gene lead to a lack of functional alpha-galactosidase A (alpha-Gal A) enzyme. Consequently, a fatty substance that alpha-Gal A normally breaks down, called globotriaosylceramide or Gb3, toxically accumulates throughout the body, leading to a wide range of symptoms.
Cardiac issues are common in Fabry patients and may include left ventricular hypertrophy (LVH), in which the heart’s left ventricle — which normally pumps blood out to the body — becomes thick and enlarged, and the heart has a harder time pumping blood.
When LVH is seen as the main feature of Fabry, without obvious involvement of other organs, it may be mistaken for the more common HCM. While it also involves a thickening of the left ventricle, HCM occurring on its own is a distinct cardiac condition.
Fabry patients may receive cardiac medications such as those used to treat HCM, but the cornerstone of disease care is enzyme replacement therapy, or ERT. As its name suggests, ERT supplies the body with a version of the missing alpha-Gal A enzyme. It thus is critical to accurately distinguish between isolated HCM and Fabry with cardiac manifestations.
In this case, the patient had been diagnosed with HCM at age 53, when he experienced atrial fibrillation, or an irregular and rapid heartbeat, and a stroke, in which blood flow to the brain is disrupted. His mother also had been diagnosed with HCM.
A further review of the patient’s medical history showed that the man had experienced symptoms consistent with Fabry disease for decades.
In his mid 20’s, he was treated for recurrent collapsed lungs. Then, in his late 40’s, he experienced a transient ischemic attack (TIA), sometimes known as a mini-stroke. Both lung disease and TIAs are known features of Fabry disease.
After being diagnosed with HCM, the patient continued to experience a number of health issues, including progressive cardiac problems, worsening shortness of breath, and signs of chronic kidney disease. He also had another TIA, as well as symptoms of nerve damage with erectile dysfunction, intermittent pain, and worsening anxiety.
Many conditions underdiagnosed in regions with limited resources, per team
Nine years after the HCM diagnosis, the man developed signs of heart failure. This prompted clinicians to perform genetic testing, which revealed a very rare mutation in the GLA gene (c.774_775delAC) that was also found in the patient’s mother. A blood test showing that alpha-Gal A enzyme activity was reduced confirmed the Fabry diagnosis.
The patient was started on ERT. The researchers indicated that they don’t expect the treatment to reverse the existing heart disease, because such treatments have a limited ability to clear Gb3 from heart cells.
Rather, “the aim of treatment is to preserve the function of organs more responsive to ERT such as the kidneys and lungs,” the researchers wrote.
After a year, the man’s kidney, lung, and heart function have remained stable, and he has reported that his anxiety and fatigue are reduced.
“This case demonstrates the importance of exploring the medical history of patients presenting with HCM in more detail, as noncardiac disease may precede cardiac presentation,” the researchers wrote, noting that testing for GLA mutations may also be warranted when unexplained LVH is present.
[Fabry] is likely to be underreported in South Africa, with patients receiving inappropriate treatment, if any, for their condition. … [This case emphasizes] the need for genetic testing to become routine in all healthcare settings, where identification of rare genetic diseases can have profound impacts on patient management and family screening programs.
The study also highlights the challenges of diagnosing and treating rare diseases like Fabry in resource-limited areas.
Genetic testing was not readily available where the man lived, and as such, his testing had been performed as part of a genetic research project. Likewise, due to its cost, ERT is not easily accessible. This man became the first adult to receive Fabry ERT in the state sector of South Africa through a humanitarian program sponsored by Sanofi, which markets the ERT Fabrazyme (agalsidase beta), according to the researchers.
Overall, the team noted, Fabry “is likely to be underreported in South Africa, with patients receiving inappropriate treatment, if any, for their condition.”
Cases such as this one “[emphasize] the need for genetic testing to become routine in all healthcare settings, where identification of rare genetic diseases can have profound impacts on patient management and family screening programs,” the researchers wrote.
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