Genetic Screenings Can Help Diagnose Fabry Early Among People with Kidney Disease, Study Suggests

Genetic screenings for people at high risk for Fabry disease — particularly those with kidney disease requiring dialysis — can help physicians diagnose the rare genetic disorder early, according to a recent review study.

Such early diagnosis allows patients to start treatment promptly, preventing unnecessary organ damage, the researchers said.

The review, “Identifying Fabry patients in dialysis population: prevalence of GLA mutations by renal clinic screening, 1995–2019,” was published in the Journal of Nephrology.

Fabry disease is caused by mutations in the GLA gene, which provides instructions to produce an enzyme called alpha-galactosidase that breaks down certain fat molecules.

So far, scientists have identified and reported several different types of mutations in the GLA gene. Some of these mutations are benign, meaning that the alpha-galactosidase is still functional, and people carrying them have none of the typical signs or symptoms of Fabry. In contrast, others are pathogenic, or disease-causing, meaning that the alpha-galactosidase enzymes are no longer functional. In such cases, individuals may start showing clear signs of the disease.

Mutations also can be deemed of uncertain significance, when the symptoms associated with them are still unknown.

Because Fabry affects different types of cells, and is associated with several symptoms, patients may initially be misdiagnosed, or remain undiagnosed for a long period of time. The lack of a prompt identification of Fabry also makes it difficult for scientists and physicians to calculate the real prevalence of the disease.

Genetic screenings among populations at high risk of developing Fabry, such as those with kidney disease, can help identify the disease early and provide the best possible treatment and clinical outcomes for those who are diagnosed.

A team of Italian researchers now performed a systematic review to estimate the true prevalence of Fabry disease. Their goal was to evaluate the effectiveness of diagnoses among those with kidney damage who were undergoing dialysis.

The review included data from 25 screening studies published between 1995 and 2019, involving a total of 39,621 adult dialysis patients (66.8% males) who had tests to assess the activity of alpha-galactosidase and which type of GLA mutations they carried. All of the studies reported if the mutations were pathogenic, benign, or of uncertain significance.

The results revealed that 116 people — 91 men and 25 women — had GLA mutations, which corresponded to a general prevalence of 0.24%. Investigators noted these findings provide a “more realistic estimate of the prevalence of [Fabry] in hemodialysis patients” than previous studies.

“Nevertheless, the true prevalence of [Fabry disease] remains not known,” the researchers said.

“Our results give an indirect estimate of prevalence in a particular subpopulation at risk for renal pathology, and only systematic screening for … [Fabry disease] in the general population in the future will help determine it,” they added.

Regarding the type of mutations identified, 56 (48.2%) were benign, eight (6.9%) were of uncertain significance, and 52 (44.8%) were pathogenic.

Among the 52 that were considered pathogenic, 39 were associated with classic Fabry disease (type 1) and 13 with late-onset Fabry (type 2). Classic Fabry is the most common type of the disease, in which symptoms appear during childhood or adolescence. In late-onset Fabry, conversely, symptoms appear later during adulthood.

The general prevalence of pathogenic mutations among those requiring dialysis was 0.14%.

“The majority of patients diagnosed in dialysis screening programs had a classic phenotype [disease manifestations] and they had not a correct diagnosis even though they presented all the renal and extrarenal signs typical of the disease from childhood,” the researchers said.

These findings highlight the importance of genetic screenings to ensure an early and accurate diagnosis, they noted.

“Although the real prevalence of classic [Fabry disease] is low, the screening in the high-risk renal population remains of primary interest as early diagnosis is fundamental for a timely specific therapy; moreover, the identification of index cases could allow patients’ relatives to be investigated and promptly treated,” the researchers concluded.