Same mutation caused late-onset and classic Fabry in same family

Case report findings show importance of individualized treatment, researchers say

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The same mutation caused both late-onset and classic forms of Fabry disease among different members of the same family, according to a new report.

“To our knowledge, there are no previous reports showing that the same missense mutation causes both late-onset and classic form of [Fabry disease] in male carriers of the same family,” the researchers wrote.

The team said these findings highlight the importance of individualized treatment — even for Fabry patients from the same family with the same disease-causing mutation.

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The study, “Late-onset and classic phenotypes of Fabry disease in males with the GLA-Thr410Ala mutation,” was published in the journal Open Heart.

Fabry disease is caused by mutations in the GLA gene, which is located on the sex-determining X chromosome and provides instructions for making the alpha-galactosidase A enzyme. As a result of these mutations, fatty molecules build up to toxic levels in the body’s tissues, causing damage to the heart and other organs.

Fabry is broadly divided into two types based on when symptoms appear. In classic Fabry, symptoms are present in the first decades of life and generally are more severe, whereas in late-onset Fabry, symptoms usually develop after age 30.

In this report, scientists described the case of a Finnish woman who, as part of her participation in a separate study, was found to harbor a mutation in the GLA gene. The specific mutation, referred to as T410A, had been documented only twice before in scientific literature, having been found previously in families in China and Taiwan.

T410A is known as a missense mutation, meaning it causes a change in a single amino acid (the building blocks of proteins) when the GLA gene is read to produce protein. Structural analyses suggested this mutation would disrupt the structure of the GLA protein, likely reducing its function, which supports the idea that this mutation can cause Fabry disease.

“The molecular structure analysis of the T410A mutated GLA protein suggested disturbed folding, further supporting pathogenicity [disease-causing property] of T410A,” the researchers wrote.

Genetic testing for the mutation

After the mutation was identified in the woman, many of her biological relatives also underwent genetic testing to see if they carried the mutation. Four of her siblings who were available for testing did not have the mutation, which suggests it probably developed de novo — meaning the mutation occurred for the first time in this patient, rather than being inherited from her biological parents.

The same mutation also was found in the woman’s son, as well as his daughter (the original patient’s granddaughter) and her two sons (the original patient’s great-grandsons).

The woman, her son, and granddaughter all presented with symptoms consistent with late-onset Fabry. None of these individuals had substantial symptoms in early life, though all of them had cardiomyopathy (heart disease) in latter decades.

The two great-grandsons, however, had manifestations of classic Fabry disease. Both boys began to experience symptoms including abnormal fatigue and pain due to nerve damage when they were preschool age. One of the boys also had digestive symptoms.

“In the present family study, we showed that [the T410A mutation] causes classic FD [Fabry disease] in two young males and late-onset FD with cardiomyopathy in a middle-aged male, which, to our knowledge, is a novel finding,” the researchers concluded.

Molecular analyses suggested that the two boys had essentially no alpha-galactosidase A enzyme activity, whereas their grandfather had some residual activity of the enzyme. This difference likely contributed to the more severe symptoms in the boys, the researchers said.

“The two young males with no active [alpha-galactosidase A] had classic FD symptoms starting from age under 10. In contrast, their grandfather with residual [alpha-galactosidase A] activity had typical late-onset [Fabry-related heart disease] characterised by cardiomyopathy without history of any symptoms of FD in childhood or adolescence,” the researchers wrote.

Treatment with enzyme replacement therapy was effective for easing the symptoms of the two young boys, the scientists reported. Their grandfather also was treated with enzyme replacement, though he ultimately died from heart complications. This case highlights a need for future studies to better determine risk of heart-related death in Fabry disease, the researchers said.