New Mutation That Causes Fabry Found in GLA Gene, Case Study Reports

Investigators have identified a new mutation in the GLA gene that caused Fabry disease in a 25-year-old man with end-stage kidney failure.

His case was described in the study “Rare Etiology of Renal Failure in a 25-Year-Old Caucasian Man: Fabry Disease With a Novel Mutation of GLA Gene,” published in the journal Cureus.

Fabry is a rare genetic disorder caused by mutations in the GLA gene that provides instructions for the production of an enzyme called alpha-galactosidase A.

These mutations typically reduce the activity of alpha-galactosidase A, leading to the accumulation of globotriaosylceramide (Gb3), a fatty molecule, in several tissues and organs. When Gb3 accumulates in the kidneys, it starts to slowly impair their function. This results in kidney disease, and eventually in kidney failure requiring hemodialysis.

“Although nearly a thousand mutations of the GLA gene have been identified, the majority of them are of unknown significance [ability to cause disease],” the researchers wrote.

Now, a team at the LewisGale Medical Center in Virginia have described the case of a young man with end-stage kidney failure who was found to carry a new mutation in the GLA gene. This mutation was determined to cause Fabry disease.

The patient, a Caucasian man, had no history of past illnesses, but had a family history of Fabry (his aunt). He was admitted from the hospital’s emergency department after complaining of tingling and burning sensations in his hands and feet (neuropathy) that had been lasting for several days. He also noticed a reduction in the volume of urine while urinating, which was not accompanied by pain or blood loss.

Lab tests revealed the man was anemic and had high levels of creatinine — a waste product produced by muscles — suggesting his kidney function was impaired. His liver function was normal.

A subsequent urinalysis revealed that the patient had small amounts of protein and blood in the urine, again indicating that his kidneys were not working properly. This was reinforced by a computerized tomography (CT) scan of the abdomen, which showed that both of his kidneys had shrunk.

His doctors found that the man had developed uremic neuropathy, or nerve damage caused by the accumulation of urine toxins, as well as encephalopathy (brain disease) associated with kidney failure. The patient was started on hemodialysis.

“Due to the patient’s family history of FD [Fabry disease], severe neuropathy, and … proteinuria [proteins in urine], the genetic testing, alpha-Gal A activity test, and renal biopsy were performed,” the researchers wrote.

Alterations in the man’s kidney tissue were observed in the biopsy, and the tests indicated that the activity of alpha-galactosidase A was abnormally low (less than 0.4 nanomole per hour per milligram (nmol/hour/mg) protein; normal range: 42.1-112.9 nmol/hour/mg protein). These findings confirmed the diagnosis of Fabry disease.

Genetic tests performed afterward showed the patient had a new mutation — c.281G>T — in the GLA gene.

His symptoms of encephalopathy and neuropathy lessened gradually over the course of hemodialysis, and the patient was eventually discharged with a referral to visit a kidney transplant center. He also was referred for genetic counseling.

“Patients with ESRD [end-stage renal disease] secondary to FD should be referred to renal transplant centers, as renal transplantation improves their prognosis,” the researchers wrote.