With More Than 1,000 Variants, Classifying Fabry Can Be Challenging

Fabry disease (FD) is a genetic condition caused by variants in the GLA gene. This gene instructs the body to produce the alpha-galactosidase A (alpha-Gal A) enzyme, which is necessary for the body to function properly. Low or absent alpha-Gal A enzyme activity can cause a toxic buildup of fatty molecules, leading to tissue or organ damage.

In the largest Facebook group for people with FD, where I serve as a moderator, members often discuss the classification of GLA variants. Over 1,000 unique GLA variants have been documented thus far. Some families have the same variant, while others may be the only family in the world with a documented variant. In addition to sharing information and providing mutual support, group members often look for others with the same GLA variant so that they can compare symptoms, disease progression, and disease management methods.

A representation of the X chromosome, with the GLA gene highlighted in red. (Courtesy of Jerry Walter)

Historically, medical literature has sometimes used the terms variant and mutation interchangeably, but variant seems to be emerging as the preferred term for genetic differences. I think both terms will continue to be used, though one may be more applicable than the other, depending on the context.

Some genetic variants have no adverse effects, while others can cause disease or other problems. Variations in the genes that determine hair color, eye color, and other physical characteristics are what make us unique individuals.

Disease-causing GLA variants are referred to as pathogenic, while GLA variants that are not believed to cause FD symptoms are referred to as nonpathogenic or benign. When it’s unclear how a GLA variant affects the body, it may be classified as a variant of unknown significance (VUS). The majority of people with pathogenic variants exhibit a variety of common disease manifestations.

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Because FD is an inherited disorder, all affected family members will have the same GLA variant. The GLA gene is on the X chromosome. Females have two X chromosomes, whereas males have one X and one Y chromosome. In females, the process of X-chromosome inactivation causes one of the two X chromosomes to become inactive, meaning each cell in a female’s body will randomly activate either the GLA variant or a normal GLA gene. This causes females to experience greater variability in Fabry symptoms. With only one X chromosome, affected males have the GLA variant in every cell.

Pathogenic GLA variants are further classified as classic or late-onset. Symptoms, age of onset, and severity can vary greatly among people with both types.

Determining one’s variant can be difficult sometimes. A review published last month in the journal Clinical Genetics noted several challenges physicians face in interpreting GLA variants. Fortunately, my diagnosis of a classic variant was straightforward, although my Fabry journey has been anything but ordinary.

GLA variants are typically classified based on many factors, including alpha-Gal A activity levels (more reliable in males), clinical presentation, biomarker levels, and other cases reported in medical literature.

For people whose GLA variant has been classified as likely benign, benign, or VUS because they don’t exhibit Fabry-specific symptoms, their classification may leave them searching for other reasons for their health issues. Their physician also may not prescribe an approved Fabry treatment until they confirm the cause of the patient’s symptoms. It can be difficult for people who have long searched for the cause of their illness to learn their GLA variant is nonpathogenic.

However, if a person with a presumably benign variant has Fabry-specific symptoms, such as angiokeratoma, cornea verticillata, or neuropathic pain, particularly in childhood, it is critical to be evaluated by a physician with Fabry expertise. There are also molecular biomarkers that may help determine the correct classification.

To make correct classification even more challenging, there are cases where a variant was reported benign in one person, but causes symptoms in another person with the same variant. This is possibly the result of other genetic or environmental factors, which vary greatly between individuals.

When in doubt, try to be evaluated by a geneticist with Fabry expertise. Geneticists and genetic counselors are trained to interpret gene variant information.

Note: Fabry Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Fabry Disease News or its parent company, Bionews, and are intended to spark discussion about issues pertaining to Fabry disease.