Comprehensive New Urine Test May Help Doctors Monitor Fabry Disease Progression

A newly developed urine test that measures the levels of different proteins may help doctors to more quickly and accurately monitor the progression of Fabry disease, a study finds.

The study, “Rapid, proteomic urine assay for monitoring progressive organ disease in Fabry disease,” was published in the Journal of Medical Genetics.

Fabry disease is caused by a mutation in the GLA gene, which provides instructions to produce the enzyme alpha-galactosidase A. As a result of that mutation, the molecule globotriaosylceramide (Gb3) — a type of fat — is not efficiently broken down. That leads to Gb3 accumulation in cells, which can cause a wide range of symptoms, including heart and kidney damage.

One problem in treating Fabry, however, is that the severity of symptoms can vary from patient to patient, depending partially on age and sex. Treatment options therefore can range from managing symptoms to starting enzyme replacement therapy (ERT) — a lifelong treatment plan in which patients are given injections of alpha-galactosidase A to compensate for its deficiency.

The decision to begin ERT can be a difficult one. The process is expensive, and there are varying opinions as to when treatment should begin, especially in asymptomatic patients, in order to achieve the best results.

There also are conflicting views as to which biomarkers should be measured to evaluate an individual’s response to treatments.

Assessing Fabry progression is typically accomplished by measuring the levels of Gb3 through either a blood test or a urine test. However, recent studies have provided evidence that measuring the level of lyso-Gb3, another type of fat molecule that builds up due to alpha-galactosidase A deficiency, may be a more effective indicator.

Now, researchers have developed an alternative approach that concurrently measures the levels of numerous proteins that may be affected by Fabry disease. Testing for multiple molecules at the same time is called a multiplex assay. One advantage of this multiplex approach is that it can produce results within a few minutes.

In this study, the researchers collected urine samples from 66 people (27 males) with Fabry disease and 66 age-matched healthy adults (controls). To determine the severity of Fabry disease and the specific organs affected, all of the patients were given medical examinations that included kidney, heart, and brain function tests.

Of the 41 proteins analyzed in the study, 20 showed potential to be used as Fabry disease biomarkers.

“The biomarkers could be divided into two groups, those that had potential for aiding the diagnosis of FD and those that could be used potentially for monitoring treatment or studying disease progression,” the researchers wrote.

Compared with the levels found in the healthy controls, six proteins were determined to be significantly elevated in Fabry patients who were not yet showing symptoms — known as early-stage/asymptomatic. These were albumin, uromodulin, alpha1-antitrypsin, glycogen phosphorylase brain form, endothelial protein receptor C, and intracellular adhesion molecule 1.

From all these proteins, only the levels of glycogen phosphorylase brain form continued to increase throughout disease progression.

The researchers hypothesized that differences in this specific patient subgroup may have helped with monitoring treatments and understanding subtle aspects of the disease.

Three proteins increased proportionally to Fabry progression, but were not detectable in those showing few to no symptoms.

Further, urinary levels of six proteins associated with kidney disease significantly changed with the progression of clinical symptoms associated with Fabry. Specifically, four of these proteins — podocalyxin, fibroblast growth factor 23, cubulin, and Alpha-1-Microglobulin/Bikunin Precursor (AMBP) — were elevated only among groups that showed kidney disease.

Five proteins were associated with heart damage in people with Fabry disease. Two of these proteins, glycogen phosphorylase B and troponin T, showed a significant elevation only in patients with cardiac symptoms.

“We believe this rapid multiplex urine assay has much potential and indicates some proteins may be specific disease biomarkers that could have promise for monitoring treatment or disease progression,” the researchers wrote.

One drawback to the study was that all of the symptomatic patients were already undergoing ERT, which may influence protein levels. The researchers believe that a follow-up study, evaluating patients before and after ERT treatment, would provide more meaningful insights.

The researchers noted that other tests — including one that measures lyso-Gb3 levels — may be more sensitive. However, they suggest that multiplex protein assay could be used in conjunction with other tests to quickly provide doctors with important information about the progression of Fabry disease.