Late-onset Fabry Disease May Be More Common Than Estimated
Researchers hailed the analysis as one of the largest Fabry screening efforts
Mutations likely to cause Fabry disease, particularly those associated with late-onset disease, were found to be more common in an adult population of U.K. residents than the estimated prevalence of the disease itself, a genetic analysis showed.
The findings suggest late-onset Fabry disease prevalence may be higher than estimates, according to researchers.
The study, “Prevalence of Fabry disease-causing variants in the UK Biobank,” was published in the Journal of Medical Genetics.
Fabry disease is a genetic disease caused by mutations in the GLA gene, which provides instructions for making an enzyme responsible for degrading a fatty substance called globotriaosylceramide (Gb3). This results in Gb3 building up to toxic levels in several organs, causing disease symptoms.
To date, more than 950 disease-causing mutations in GLA have been identified. Fabry disease is classified into two forms, depending on how severely these mutations affect alpha-galactosidase A (Gal A) enzyme activity.
Mutations that lead to less than 3% of normal enzyme activity cause the classic, more severe type of Fabry disease, which usually develops in childhood or adolescence. Mutations generating an enzyme with some residual activity (3%–15% of normal) lead to a later, somewhat less severe form of the disease.
Current estimates for the global prevalence of Fabry disease range from one in 40,000 people to one in 170,000. Newborn screening studies suggest the number is higher.
Scientists used samples from the UK Biobank to determine the prevalence of known Fabry disease-causing variants and the symptoms associated with them.
The biobank contains demographic, lifestyle, and clinical information as well as biological samples from more than 500,000 people, ages 37–73, recruited throughout the U.K. between 2006 and 2010.
The researchers created two groups based on age and health conditions that suggested Fabry. The first included men younger than 60 with chronic kidney disease, heart disease, and hearing loss. The second had men under 60 with chronic kidney disease, heart disease, and cerebrovascular disease.
A genetic analysis was carried out in 200,643 people from the UK Biobank.
“This is one of the largest Fabry screening efforts ever undertaken and to our knowledge the largest … in an unselected adult population including men and women,” the researchers wrote.
Results showed 36 people carried 81 genetic variants of GLA, including eight rare variants. Almost all the variants were associated with late-onset Fabry. The most common — c.644A>G — was associated with later-onset heart symptoms.
The prevalence of disease-causing variants in this population was one in every 5,573. As only one variant, called c.718_719del, was associated with the classic form of disease, the prevalence of classic Fabry disease was estimated at one in 200,643.
Only three people with disease-causing variants had medical records suggesting Fabry disease. All patients with evidence of an existing Fabry diagnosis had a disease-causing variant.
Researchers noted that although the c.1067G>A variant has been associated with classic Fabry disease in some reports, none of the four participants with this variant had a diagnosis of Fabry disease or symptoms suggestive of the disease. This suggests genetic variants of GLA have variable penetrance, meaning not all patients with a given variant will have disease symptoms.
“Fabry disease-causing GLA variants are more prevalent in an unselected population sample than the reported prevalence of Fabry disease,” the researchers concluded. “As genetic screening becomes more widely used, it will be essential to understand the penetrance of these variants to inform clinical monitoring strategies and identify those who will benefit from treatment.”