Roughly half of the patients diagnosed with Fabry disease experience white matter lesions, which tend to develop earlier in males and are more prevalent as patients get older, a review study shows.
The study, “Development and clinical consequences of white matter lesions in Fabry disease: a systematic review,” was published in Molecular Genetics and Metabolism.
Fabry disease is a rare genetic disorder caused by mutations in the GLA gene — located on the X chromosome — that provides instructions for the production of an enzyme called alpha-galactosidase A (GLA). These mutations typically affect the function of GLA, leading to the accumulation of a type of fat called globotriaosylceramide (Gb3) in several organs, including the brain, heart and kidneys.
As a result, Fabry patients are prone to develop medical complications linked to organ damage, including white matter lesions (WMLs) and stroke. White matter refers to areas of the brain made up of myelinated nerve segments (axons) responsible for the transmission of nerve signals and for communication between different brain areas.
Detection of WMLs can also have diagnostic implications: in some diseases other than Fabry, the specific location and distribution of WMLs suggest a specific underlying disease. However, not much is known regarding the impact of WMLs on Fabry disease symptoms and its prognosis. “Moreover, despite the status of WMLs as an early marker of cerebral involvement in [Fabry], their clinical consequences and response to enzyme replacement therapy (ERT) have been rarely addressed in follow-up studies,” the authors wrote.
This systematic review analyzed the incidence, severity, location and development of WMLs in Fabry disease patients. It drew on data collected from 46 research articles documenting Fabry disease and WMLs outcomes based on magnetic resonance imaging (MRI). Disease prevalence and severity were analyzed by gender and evaluated in a total of 1,276 patients.
WMLs were found in about 46% of all patients and their prevalence seemed to increase with patients’ age. Although the severity and incidence of WMLs in female and male patients was similar, the onset of WMLs occurred much earlier in men than in women.
“As FD [Fabry disease] is an X-linked [linked to the X chromosome] disorder, men are generally more severely affected and develop disease complications earlier in life than women,” the researchers explained. This is due to the fact that men only have one copy of the X chromosome, while women have two.
In addition, 16.4% of Fabry patients showed extensive confluent WMLs — a lesion type characterized by the presence of large portions of severely damaged brain tissue.
Although most patients (75.4%) had stable WMLs, in 24.6% of the cases WMLs worsened during 38.1 months of follow-up. WMLs progression affected both female and male patients, but men were significantly younger at time of WML assessment.
Altogether, these findings indicate that Fabry disease patients are at risk of developing WMLs, especially men. Researchers are now convinced that WMLs should be used in future clinical trials to evaluate the effects on the brain of potential Fabry treatments.
“Future studies should focus on longitudinal follow-up using modern imaging techniques, with emphasis on the clinical consequences of WMLs and use of WMLs in treatment trials,” the authors concluded.