Genetic testing uncovers 10 new GLA mutations in Fabry disease

Direct genetic testing in Spanish adults at high risk for Fabry disease uncovered 10 previously unreported mutations in the GLA gene, a new study has found.

“These findings highlight the value of direct genetic analysis in high-risk populations for identifying both known and previously unreported GLA variants,” noted researchers, who caution that genetic results alone are not enough to confirm a diagnosis or guide treatment.

The study, “Genotype analysis of Fabry disease in a Spanish at-risk population reveals 10 novel GLA variants,” was published in the journal Scientific Reports.

Fabry disease is a rare inherited disorder caused by mutations in the GLA gene, which provides instructions for making alpha-galactosidase A (alpha-Gal A). This enzyme helps break down certain fatty molecules inside lysosomes, the cell compartments that act as recycling centers.

When alpha-Gal A’s activity is deficient or absent, fatty molecules such as globotriaosylceramide can build up in organs and tissues. This buildup can cause symptoms that affect the kidneys, heart, brain, blood vessels, skin, and eyes.

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The disease can be difficult to diagnose because symptoms vary widely. Some people develop classic Fabry, with early symptoms such as burning pain in the hands and feet, clusters of small dark-red skin spots called angiokeratomas, and cornea verticillata, a whorl-like pattern in the eye. Others have late-onset Fabry, in which symptoms may mainly affect one organ, such as the heart or kidneys.

Screening people with a family history of Fabry, or those with features that raise suspicion for the disease, is one of the main ways to identify patients before more serious symptoms develop. To better understand Fabry-related genetic variation, researchers in Spain analyzed the GLA gene in people considered at high risk for the disease.

In total, the analysis included 260 people (125 women) from multiple centers across Spain who underwent molecular testing between 2002 and 2020. Participants were considered at risk of Fabry because they had a family history of the disease or symptoms suggestive of Fabry. These included chronic kidney disease, heart disease, skin or eye findings, stroke, neuropathic pain — pain caused by damage to the nervous system — or biopsy findings compatible with Fabry.

Genetic testing was performed directly, regardless of enzyme or biomarker results to evaluate how effectively targeted molecular screening detects GLA mutations.

The researchers identified 35 distinct GLA mutations among 127 participants (48.8%). Among the 35 mutations, 10 were novel and not previously associated with Fabry disease. These were present in 34 participants, representing 26.7% of those with GLA alterations.

Using established classification criteria, seven of the novel mutations were considered disease-causing, two were likely disease-causing, and one was classified as a mutation of uncertain significance.

Clinical information was available for 64 of the 127 people who carried GLA mutations. Among those with documented clinical manifestations, kidney involvement was the most common finding, reported in 33 participants (51.5%). This included chronic kidney disease, dialysis, or a kidney transplant.

Cardiac manifestations, including arrhythmias and hypertrophic cardiomyopathy (thickening of the heart muscle), were observed in 20 participants (31.3%). Neurological events, including neuropathic pain or stroke-related complications, were reported in 11 participants (17.2%).

Skin symptoms were present in nine participants (14.1%). Eye involvement and digestive symptoms were each reported in five participants (7.8%).

Three participants had clinical features consistent with classic Fabry disease. Two carried previously reported mutations, while one carried a novel complex rearrangement and had kidney biopsy-confirmed Fabry nephropathy, which is kidney damage caused by the buildup of fatty molecules in Fabry disease. Several other novel mutations were seen in participants with kidney involvement.

Overall, the results underscore how targeted screening can expand the known profile of GLA mutations, though the team noted that tracking long-term patient outcomes will be crucial to fully understand how these new variants affect disease severity.

The development of genotype-phenotype registries — which link specific genetic variants to real-world clinical symptoms — alongside long-term patient follow-up will be essential for defining the true clinical impact of newly identified mutations, the researchers concluded.