New GLA gene mutation tied to heart-focused Fabry disease

Doctors identified a previously unreported mutation in the GLA gene as the cause of Fabry disease in a woman whose disease mainly affected the heart.

The woman received an implantable cardioverter-defibrillator to help protect against dangerous heart rhythm oscillations and later began enzyme replacement therapy with Fabrazyme (agalsidase beta). She tolerated the treatment well and remained clinically stable during follow-up.

The case “illustrates how an integrated precision-medicine approach may facilitate the interpretation of novel GLA variants and support individualized cardiovascular care,” researchers wrote in a case report.

The report, “Case Report: Fabry cardiomyopathy associated with a novel truncating GLA variant, c.837_838delinsAT, p.(Gln280Ter),” was published in the journal Frontiers in Medicine. 

Fabry disease is caused by mutations in the GLA gene that contains instructions for producing alpha-galactosidase A (alpha-Gal A), an enzyme that normally helps break down certain fatty molecules inside cells. When this enzyme does not function properly, fatty substances — such as globotriaosylceramide (Gb3) and lyso-Gb3 — can accumulate in tissues throughout the body. Over time, that buildup can damage organs including the heart, kidneys, and nervous system.

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More than 2,200 GLA mutations have been described, ranging from disease-causing to harmless to uncertain significance. This heterogeneity means that when previously unreported mutations are identified, clinicians need to consider genetic findings alongside biochemical and clinical evidence to assess the likelihood that they cause Fabry disease.

Heart involvement can be particularly important in people with Fabry and may be the dominant manifestation in women. It can include thickening of the heart’s main pumping chamber, scarring of heart tissue, abnormalities in the heart’s electrical system, and abnormal heart rhythms (arrhythmias).

Researchers in Argentina described a newly identified GLA mutation in a 52-year-old woman with longstanding heart muscle thickening (hypertrophic cardiomyopathy), the cause of which had remained unclear.

The woman had arrhythmias and reported fatigue and palpitations. She had no known family history of cardiomyopathy, sudden cardiac death, Fabry disease, or kidney disease.

An echocardiogram (an ultrasound test that creates images of the heart) showed moderate to severe thickening of the wall of the left ventricle, the heart’s main pumping chamber. Despite the thickening, the heart’s pumping ability remained preserved.

Cardiac MRI confirmed diffuse thickening, particularly near the tip of the heart. It also showed that certain areas of the heart muscle had been replaced by scar tissue (fibrosis). The researchers said the extent of fibrosis suggested advanced Fabry cardiomyopathy and increased risk of arrhythmias.

Based on the findings, doctors referred the woman to a specialized Fabry disease program.

Blood work showed that alpha-Gal A activity was reduced, while lyso-Gb3 levels were markedly elevated. Genetic testing identified a previously unreported GLA mutation, which was initially classified as likely disease-causing. It was absent from major population databases, and its predicted effect was consistent with loss of GLA function. The woman’s reduced enzyme activity, high lyso-Gb3, and characteristic clinical findings provided additional evidence that the mutation was disease-causing.

Further evaluation identified cornea verticillata, a characteristic whorl-like pattern of deposits in the cornea that can occur in Fabry disease. The woman’s kidney function remained normal, with no significant protein loss in the urine or abnormalities on kidney ultrasound.

Because extensive heart muscle thickening and fibrosis raised concern about life-threatening arrhythmias, doctors placed an implantable cardioverter-defibrillator, a small device that monitors the heartbeat and can deliver an electrical discharge to restore a normal rhythm if needed.

Some months after surgery, the woman began treatment with Fabrazyme every other week. She saw no infusion reactions or treatment-related side effects, and she remained stable without new Fabry-related events during follow-up.

The case underscores “the importance of considering FD [Fabry disease] in women presenting with unexplained hypertrophic cardiomyopathy,” particularly when heart MRI shows extensive or unusual patterns of fibrosis, the researchers wrote.