Fabry disease still underdiagnosed, especially among women: Study  

Results show 1 undiagnosed case per every 3,225 people

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Fabry disease remains widely underdiagnosed, especially among women, according to a new population-based study that identified one undiagnosed case per every 3,225 people.

The study found that the genetic mutations that cause Fabry, a rare disorder primarily affecting the heart, nervous system, and kidneys, are more common than previously reported.

Still, the scientists noted that their estimate itself is likely an underestimation, given the strict criteria they used to consider a mutation as disease-causing. In addition, already-diagnosed patients were excluded from their analysis, and some mutation types were not part of the database they used.

“This study confirms that Fabry disease is more common than previously recognized and still underdiagnosed especially in women,” the researchers wrote, adding that their findings “reflect that many women with Fabry disease are undiagnosed but still have the risks of kidney failure, heart disease, and stroke.”

The study, “Population frequency of undiagnosed Fabry disease in the general population,” was published in the journal Kidney International Reports.

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Fabry disease occurs due to mutations in the GLA gene, which provides instructions for making an enzyme called alpha-galactosidase A (Gal A). Gal A absence or deficiency leads to the buildup of certain fatty molecules — particularly Gb3 and lyso-Gb3 — that damage organs.

Determining how frequent Fabry disease is in the population may help inform clinicians on the likelihood of a patient being affected — and in confirmed cases, aid in diagnosing any other affected family members.

Further, identifying Fabry cases can be key to predicting organ involvement and accessing earlier treatment for patients.

A definite diagnosis of Fabry disease is made with genetic testing and the confirmation of a disease-causing GLA mutation. However, reaching a conclusive diagnosis remains challenging, as it is difficult to determine whether many mutations are truly disease-causing and because mutations are typically different in each family.

Now, a team of researchers at the University of Melbourne, in Australia, sought to assess the frequency of Fabry in the general population. They used genetic information available from the Genome Aggregation database, known as gnomAD, a publicly available database developed by an international coalition of investigators that includes data from various genome sequencing projects.

Overall,  the researchers found 100 GLA genetic variants among 119,329 individuals, with 99 classified as missense mutations. These lead to a switch of an amino acid — the building blocks of proteins — in the resulting protein. One variant was classified as null, meaning there was loss of gene function.

A total of 20 variants, present in 37 individuals, were predicted to be pathogenic or disease-causing, according to pre-established criteria. This resulted in a Fabry population frequency of 37 cases per 119,329 people, or 1 case per 3,225 individuals.

Of the variants identified, 13 (65%) had been previously reported as disease-causing. They were more than three times more frequent in women than men. The median age for both males and females with such variants was 50.

The predicted disease-causing mutations were seen across different ethnic backgrounds, but were absent in people from Ashkenazi Jewish, Finnish, or South Asian ancestries. According to the scientists, this could be due to underrepresentation of these populations in the queried database, as well as the geographic and cultural isolation of Ashkenazim and Finns.

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Next, the researchers analyzed data from gnomAD’s control group, which includes 48,688 individuals recruited as controls from studies of heart disease, diabetes, and neuropsychiatric disease.

A total of 11 predicted disease-causing variants were found in 14 individuals, corresponding to a frequency of 1 in 3,478 cases. Such variants were six times more common among females than males.

The investigators concluded that “genetic testing is the most sensitive method for the detection of GLA variants and hence for the diagnosis of Fabry disease.” Further, they said their “criteria for pathogenicity may be useful in further assessment of variants from [a] Fabry database.”

Knowing the true population frequency of Fabry disease indicates to clinicians how often it is likely to affect their patients.

Using those criteria may help to improve the diagnosis of Fabry, especially in women, who particularly remain underdiagnosed.

“Recognition of Fabry disease is important to predict organ involvement, to identify and treat other affected family members, and because of the availability of treatment. Knowing the true population frequency of Fabry disease indicates to clinicians how often it is likely to affect their patients,” the team wrote.

The researchers also noted that more treatments for Fabry are now available, including enzyme replacement and other therapies that may slow or prevent kidney and heart problems.

“Early treatment prevents irreversible organ damage,” the team wrote.