Gene mutation, kidney health linked to lower stroke risk in Fabry: UK Study
Having a coexisting autoimmune disease more than triples the threat
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Nearly one in five adults with Fabry disease experienced a stroke over roughly a decade of follow-up, with risk shaped by genetic factors, kidney function, and coexisting autoimmune disease, a large U.K. study found.
Preserved kidney function and carrying the disease-causing N215S mutation — which is often linked to a late-onset and generally milder form of Fabry — were both associated with a lower risk of stroke, by up to 60%. In contrast, having a coexisting autoimmune disease raised stroke risk more than threefold.
Researchers said these findings “suggest multiple pathways” may contribute to stroke in people with Fabry disease and “might help stratify patients” based on their individual risk, potentially informing clinicians and guiding future preventive and therapeutic strategies.
The study, “Stroke in Fabry Disease: Identification of Risk Factors for Stroke in a Large Single-Centre Cohort,” was published in the European Journal of Neurology.
Fabry patients have increased risk of stroke
Fabry disease, a metabolic storage disorder, is caused by mutations in the GLA gene, which provides instructions for producing an enzyme necessary for breaking down certain fatty molecules. When this enzyme is missing or not functioning properly, these molecules accumulate inside cells and gradually damage organs — especially the kidneys, heart, and nervous system — ultimately driving disease symptoms.
People with Fabry are known to have an increased risk of stroke across all age groups, with studies reporting rates ranging from about 4% to nearly 50%. Although several potential risk factors — including genetic variants, smoking, and kidney or heart involvement — have been suggested, studies have produced conflicting results.
As a result, the precise reasons why some people with Fabry go on to experience a stroke while others do not remain unclear, the researchers wrote.
To learn more, a team of researchers in the U.K. analyzed long-term clinical and MRI data from 368 adults with Fabry disease who were followed at a national reference center, using records collected from each patient’s first visit through March 2019. Participants were followed for a median of 10.4 years.
More than half of the participants were women (61.7%). The median age at the study’s start was 42.7 years for men and 39.9 years for women, while age at Fabry diagnosis was 35.1 and 34 years, respectively.
Most participants carried a missense mutation, a change in the GLA gene that alters the structure of the enzyme it produces. The missense N215S variant was found in 56 men (39.7%) and 64 women (28.2%).
Stroke risk rose steadily with age, study finds
By the end of follow-up, 69 people (18.8%) had experienced a stroke, up from 41 at their first clinic visit. Nearly half of these strokes (42%) were silent, meaning they caused no clear symptoms and were detected only on routine brain MRI scans.
Lacunar strokes, caused by blockages in the small blood vessels deep within the brain, were the most common type, accounting for about two-thirds (66.7%) of all stroke events. Less frequently, strokes involved larger arteries supplying the front (18.9%) or the back of the brain (13%). One additional case (1.4%) was caused by a clot in a vein that drains blood from the brain.
People who experienced a stroke were generally older at their first clinic visit than those who did not (44 years vs. 36.9 years). The age at first stroke was similar between men and women — 50.6 and 51.4 years, respectively.
In the survival analysis, no strokes were observed before age 26. After that, the risk increased steadily with age, with median stroke-free survival — the age by which half of patients were expected to have experienced a first stroke — estimated at 43 years for men and 58 years for women.
Findings suggest multiple pathways may contribute to stroke in [Fabry disease]. These results might help stratify patients and are of interest not only to metabolic physicians, but to general stroke physicians too.
When the researchers compared adults who had a stroke with those who did not, several differences were seen between the groups. However, after accounting for multiple factors simultaneously, only a few remained independently associated with stroke risk.
Carrying the N215S genetic variant was associated with a 60% lower risk of stroke compared with other variants. Kidney function was also a significant predictor, as adults with preserved kidney function had about 50% lower risk of stroke than those with reduced kidney function. In contrast, having a concomitant autoimmune disease increased the likelihood of stroke by more than threefold.
The team also developed a tool that combines these and other clinical features to estimate a patient’s likelihood of remaining stroke-free with age. Because accurate predictions required considering multiple variables together, the researchers noted that “stroke in [Fabry disease] arises from complex, multifactorial mechanisms.”
They added that these “findings suggest multiple pathways may contribute to stroke in [Fabry disease]. These results might help stratify patients and are of interest not only to metabolic physicians, but to general stroke physicians too.” Further studies exploring these pathways are warranted, according to the researchers.
