Late-onset Fabry disease may be more common than expected |  Fabry...

Late-onset Fabry disease may be more common than expected | Fabry…

Mutations likely to cause Fabry disease, particularly those associated with late-onset disease, were found to be more common in an adult population of UK residents than the estimated prevalence of the disease itself, genetic analysis has shown. .

The results suggest that the late prevalence of Fabry disease may be higher than estimates, the researchers said.

The study, “Prevalence of variants causing Fabry disease in the UK Biobank”, was published in the Journal of Medical Genetics.

Fabry disease is a genetic disorder caused by mutations in GLA gene, which provides instructions for making an enzyme responsible for breaking down a fatty substance called globotriaosylceramide (Gb3). This results in an accumulation of Gb3 to toxic levels in several organs, causing symptoms of disease.

To date, more than 950 pathogenic mutations in GLA was identified. Fabry disease is classified into two forms, depending on the severity of the impact of these mutations on the enzyme activity of alpha-galactosidase A (Gal A).

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Mutations that lead to less than 3% of normal enzyme activity cause the classic, more severe type of Fabry disease, which typically develops during childhood or adolescence. Mutations generating an enzyme with some residual activity (3% to 15% of normal) lead to a later, somewhat less severe form of the disease.

Current estimates of the worldwide prevalence of Fabry disease range from one in 40,000 people to one in 170,000 people. Newborn screening studies suggest the number is higher.

The scientists used samples from the UK Biobank to determine the prevalence of variants known to cause Fabry disease and the symptoms associated with them.

The biobank contains demographic, lifestyle and clinical information and biological samples from over 500,000 people, aged 37 to 73, recruited across the UK between 2006 and 2010.

Researchers created two groups based on age and health conditions that Fabry suggested. The first included men under 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 on 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 comprising both males and females,” the researchers wrote.

The results showed that 36 people carried 81 genetic variants of GLA, including eight rare variants. Almost all variants were associated with a late-onset Fabry. The most common – c.644A>G — was associated with late onset cardiac symptoms.

The prevalence of pathogenic variants in this population was one in 5,573. As a single variant, called c.718_719delwas associated with the classic form of the disease, the prevalence of classic Fabry disease was estimated at one in 200,643.

Only three people with pathogenic variants had medical records suggesting Fabry disease. All patients with evidence of an existing Fabry diagnosis had a pathogenic variant.

The 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, which means that not all patients with a given variant will show symptoms of the disease.

“GLA variants responsible for Fabry disease 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, understanding the penetrance of these variants will be critical to inform clinical surveillance strategies and identify those who will benefit from treatment.”

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