Changes in Heart, Kidney Function May Be Undiagnosed Fabry Disease

Researchers write about man with long clinical history of heart, kidney problems

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A long clinical history of cardiac alterations, including heart valve impairments, without an apparent cause and accompanied by kidney dysfunction may be a sign of undiagnosed Fabry disease, a case report suggests.

The report, “Transcatheter Tricuspid Valve Replacement for Anderson Fabry Disease With Severe Tricuspid Regurgitation,” was published in CASE.

Fabry disease, also Anderson Fabry disease, is caused by mutations in the GLA gene, which contains instructions for making an enzyme called alpha-galactosidase A (alpha-gal A).

Lack or insufficient activity of alpha-gal A leads to certain fatty molecules building up — particularly globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) — across several organs, including the kidneys, brain, heart, eye, and skin.

Heart disease is common with Fabry disease. In fact, a hallmark is the enlargement and excessive thickness of the heart’s left lower pumping chamber (left ventricle). Severe tricuspid regurgitation, wherein the valve between the heart’s two right chambers doesn’t close properly, causing blood to leak backward, is rare in Fabry disease, however.

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A history of heart, kidney problems

Researchers at the Naval Military Medical University, China described the case of a 54-year-old man who was hospitalized due to swelling in both legs and abdominal distension, symptoms that had lasted for more than a year, but worsened in the last three months.

His clinical history included cardiac pacemaker surgery at age 39, as well as a kidney transplant and mitral valve replacement. The mitral valve regulates the passage of blood from the heart’s upper left chamber (left atrium) to the left ventricle. He had no family history of cardiovascular or kidney disease.

At admission, he had a normal blood pressure and heart rate. A diastolic murmur — a “whoosh” when the heart muscle relaxes between beats — was heard, possibly due to valve regurgitation.

Lab work revealed signs of poor kidney function, as shown by elevated creatinine levels and a low glomerular filtration rate, which assesses how well the kidneys are filtering.

He also had levels of heart failure markers, including the N-terminal b-type natriuretic peptide precursor (NT-proBNP) and the B-type natriuretic peptide (BNP).

The lessons from this case are that the constellation of unexplained progressive [left ventricle] wall thickness or LV hypertrophy [enlargement], valvular abnormalities, and multiorgan involvement should trigger the differential diagnosis of [Fabry disease].

A transthoracic echocardiogram (TTE), a noninvasive imaging heart test, showed the walls of both ventricles and two upper chambers (atria) were unusually thick.

Systolic pressure in his pulmonary artery was slightly elevated and his mitral valve was working normally. Systolic pressure is the pressure blood exerts on arteries when the heart beats.

At age 48, the man developed severe tricuspid regurgitation. He was not eligible for a second open chest surgery, but was for interventional tricuspid valve surgery, a minimally invasive procedure to replace the tricuspid valve.

No obvious valve regurgitation or leakage was seen after the surgery and the new valve worked normally, as shown in a follow-up heart scan. The man’s symptoms eased, swelling in both legs disappeared, and he only had mild shortness of breath after exertion.

Diagnosing Fabry disease

At a one year follow-up visit, he reported fatigue and shortness of breath after physical activity, which rest alleviated.

Heart scans showed the volume of the left atrium was twice as large as on previous scans. The thickness of the right ventricle’s wall remained stable, while the interventricular septal diameter — the space between both ventricles — and the posterior wall diameter were thicker than before surgery.

These findings led the researchers to suspect Fabry disease.

“Our patient had many characteristic features of AFD [Anderson Fabry disease] including progressively increased LV [left ventricle] and RV [right ventricle] wall thickness, which was initially but incorrectly presumed to be due to aging and renal dysfunction,” the researchers wrote.

Genetic tests confirmed a mutation in the GLA gene. He also had elevated levels of lyso-Gb3.

The patient started treatment with Fabrazyme, an enzyme replacement therapy (ERT) approved to treat Fabry disease, in January 2022 (45 mg, four times daily). His fatigue, asthma, leg swelling, and shortness of breath eased after treatment.

Lab work confirmed a drop in lyso-Gb3 levels and kidney function improvements, as shown by decreased creatinine levels and an increase in the glomerular filtration rate. Also, his heart imaging parameters improved, supporting the positive effects of ERT beyond kidney function.

“The lessons from this case are that the constellation of unexplained progressive LV [left ventricle] wall thickness or LV hypertrophy [enlargement], valvular abnormalities, and multiorgan involvement should trigger the differential diagnosis of [Fabry disease],” the researchers wrote.