Timing of Fabry enzyme therapy linked to long-term heart stability
Case shows benefit when treatment starts before cardiac involvement
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Despite a delayed start until adulthood, enzyme replacement therapy (ERT) was associated with long-term cardiac stability in a man with Fabry disease who had shown symptoms since early childhood, a case study from Brazil shows.
Because ERT was initiated before any signs of heart involvement appeared, the man maintained normal heart structure and function for more than 15 years. However, starting therapy later was not enough to stop progressive kidney decline, which had already begun by the time treatment started and ultimately required a kidney transplant.
“This case demonstrates severe [kidney] dysfunction that developed because ERT was initiated late, and shows how [heart] dysfunction was avoided because treatment began before [heart] involvement occurred,” the researchers wrote, emphasizing the need for early diagnosis, comprehensive organ screening, and timely treatment intervention.
The study, “Long-Term Cardiac Stability Despite Late Enzyme Replacement Therapy in Fabry Disease With Severe Renal Involvement,” was published in JACC Case Reports.
Understanding the genetic cause of Fabry disease
Fabry is caused by mutations in the GLA gene that lead to a faulty or missing enzyme called alpha-galactosidase A (alpha-Gal A). Without this enzyme, certain fatty molecules — including globotriaosylceramide (Gb3) — build up inside cells, gradually damaging organs, especially the kidneys and heart.
ERT is the standard treatment for Fabry disease. Given through infusions into the bloodstream, it supplies a functional version of the missing enzyme to help reduce this harmful buildup and relieve symptoms.
Previous studies have shown that starting ERT earlier, especially before the heart develops structural damage or the kidneys sustain significant injury, is linked to better outcomes, including improved organ function and a lower risk of long-term complications.
In this report, researchers described a man who began ERT only after kidney disease had already started to progress, but whose heart remained stable because treatment began before any signs of cardiac involvement.
The man, who had a family history of Fabry disease, first developed symptoms at age 5, when small, reddish skin lesions began appearing across his abdomen, knees, fingers, and lips.
A skin biopsy performed four years later, at age 9, supported a diagnosis of Fabry disease, while kidney function at that time remained normal.
Delayed diagnosis and start of enzyme therapy
At 22, genetic testing identified a disease-causing mutation in the GLA gene (c.467C>A). Blood tests also showed high levels of lyso-Gb3, a breakdown product of Gb3, confirming a Fabry disease diagnosis. By that time, his kidney function was already reduced.
He also showed several other hallmark symptoms, including burning and tingling in the hands and feet (acroparesthesia), sweating abnormalities, angiokeratomas — small, dark-red skin lesions caused by fatty buildup — around the lips, numerous skin lesions across the bathing-trunk area, and hearing loss on the left side. Despite these symptoms, there were no signs of heart involvement.
Based on these findings, he began ERT with biweekly infusions of agalsidase alfa (sold as Replagal in Europe and several countries worldwide). Despite the treatment, the disease continued to progress in the kidneys, eventually leading to end-stage kidney disease and the need for a kidney transplant in 2021.
“After kidney transplant, [kidney] function has remained stable to the present day,” the researchers wrote. “Despite the progression to [kidney] dysfunction, no [heart] involvement was detected after 15 years of ERT.”
According to the researchers, the man did not develop signs or symptoms of heart disease, and results from other examinations remained within normal limits.
“This case demonstrates that ERT, even when initiated after irreversible [kidney] damage but before the onset of [heart] involvement, can preserve [heart] structure and function for [more than] 15 years,” the researchers concluded. “The findings underscore the protective [heart] effect of timely intervention and the critical role of [comprehensive] organ screening in [Fabry disease].”
“At the same time, the patient’s progression to end-stage [kidney] disease highlights the limitations of late therapy in preventing [kidney] outcomes, reinforcing the need for diagnosis and treatment before irreversible organ injury occurs,” they added.
