Late-onset Fabry Disease May Start Way Before Typical Signs, Study Shows

In late-onset Fabry disease, the accumulation of a fatty molecule in cells called Gb3 — and potential cellular damage — is present before typical signs of the disease, according to a small Taiwanese study.

These findings suggest that the early detection of Gb3 (globotriaosylceramide) accumulation through an accurate test may be relevant to start early treatment and prevent irreversible damage.

The study, “Identification of lysosomal and extralysosomal globotriaosylceramide (GB3) accumulations in the endomyocardial biopsies before the occurrence of typical pathological changes of the patients with Fabry disease,” was published in the journal Molecular Genetics and Metabolism.

In Fabry disease, the accumulation of two fat molecules — Gb3 and lyso-Gb3 — inside cells can lead to the formation of aggregates and deposits, called inclusion bodies, which cause damage and lead to the dysfunction of several organs, especially the kidney, heart, and brain.

Heart involvement is now the leading cause of reduced life expectancy and Fabry disease-related death.

Late-onset Fabry disease patients lack the classic early symptoms of the disease and frequently develop heart disease or kidney failure in their 40s or 50s. The diagnosis of these patients can be very challenging, and early detection and treatment are crucial to prevent irreversible damage.

A recent study showed that the accumulation of these fat molecules, along with electrical, structural, and functional changes in the heart, may predict heart disease in Fabry patients, before the development of typical signs of the disease.

However, since the threshold of Gb3 levels that precede tissue damage is still unclear, detection of Gb3 inclusion bodies in heart tissue is currently the diagnostic standard test for Fabry-associated heart disease.

Researchers had already discovered that a gene mutation associated with late-onset Fabry disease with heart involvement, called IVS4, is present in high levels in the Taiwanese population, namely in newborns and in undiagnosed people with idiopathic hypertrophic cardiomyopathy — when the heart muscle is abnormally thick due to an unknown cause.

Now, the same team analyzed heart biopsies of five Fabry disease patients carrying the mutation with mild signs of heart disease to determine whether the accumulation of Gb3 could be an early marker of Fabry-associated heart disease.

Patients had either very low or no Gb3 accumulation in their heart tissue as assessed by routine analyses. Three patients had never received enzyme replacement therapy (ERT), while two had received four years or more of ERT.

Using immunofluorescent staining to detect Gb3 accumulation — a method shown to be very specific and sensitive to quantify molecules even at lower levels — the team observed significant buildup of Gb3 inside heart cells of all three ERT-naive patients.

This suggests that Gb3 accumulation precedes the formation of inclusion bodies.

“Before the appearance of Gb3 inclusion bodies, the intracellular Gb3 level might already be considerably higher than the normal level and start inducing tissue damage, although further studies are needed to provide evidence if the occult Gb3 (without inclusion bodies) could induce cellular stress and damages,” the researchers wrote.

Patients on ERT also showed significant Gb3 buildup in their heart cells, suggesting that this quantitative method is more sensitive and provides a more accurate result than the ones routinely used.

“The presence of inclusion bodies by … [routine analysis] should not be the sole criterion for identifying disease-related storage in the heart and probably in other organs,” the team wrote.

The study also highlighted the need to revise common detection methods — which researchers believe should also include analysis of Gb3 through immunofluorescent staining — as well as the time to initiate ERT, which may be beneficial before the presence of inclusion bodies.

Additional studies are needed to clarify this potential benefit.