The study, “Recurrent fever of unknown origin: An overlooked symptom of Fabry disease,” was published in the journal Molecular Genetics & Genomic Medicine.
Fabry is a rare genetic disorder caused by mutations in the GLA gene that typically lower the activity of the enzyme alpha-galactosidase A, which is responsible for breaking down a fatty molecule called globotriaosylceramide (Gb3) in cells.
In the absence of the alpha-galactosidase A enzyme, Gb3 starts accumulating in several tissues and organs, slowly impairing their function and triggering the classic disease symptoms, including kidney failure, proteinuria (proteins in the urine), angiokeratomas (skin lesions), nerve pain, and heart enlargement.
“Recurrent fever represents a rare manifestation of FD [Fabry disease], yet is easily overlooked,” the researchers wrote.
They describe the case of three Chinese patients who experienced episodes of recurrent fever without an apparent cause, and were later diagnosed with Fabry disease.
All had been referred to Peking Union Medical College Hospital, a tertiary medical center in China. Investigators gathered and analyzed detailed clinical data from their medical records.
Next-generation sequencing to examine the sequence of all protein-coding genes, and an enzyme activity assay to measure the activity of the alpha-galactosidase A were used to confirm a Fabry diagnosis.
The boy’s lab tests, including blood cell counts, liver and kidney measures, and urine analysis were all within a normal range. But the enzyme activity assay showed severely low alpha-galactosidase A activity (1.8 nanomoles per milligram per hour; normal range: 24.5–86.1 nmol/mg/h).
Genetic analyses revealed the boy had a novel mutation in the GLA gene (c.440G>A), which was also found in his mother. He also carried two other mutations, in the NLRC4 and NOD2 genes, which have been associated with autoinflammatory diseases.
Although his lab tests came out all normal, the enzyme activity test showed very low alpha-galactosidase A activity (1.1 nmol/mg/h). Genetic analyses also revealed he had a mutation in the GLA gene (c.1176_1179delGAAG), which was also found in his mother. The man was also found to have a mutation in MEFV, a gene that is involved in the control of the body’s immune and inflammatory response.
The last patient, a 17-year-old boy, was referred to the hospital due to complaints of progressive pain affecting his hands and feet, along with recurrent fevers over the past 10 years. His sister had also been experiencing symptoms of intermittent pain in her fingers and toes since age 13.
As with the other two patients, standard lab tests were all within a normal range. However, the activity levels of alpha-galactosidase A were close to zero (0.2 nmol/mg/h). Genetic analyses revealed the boy also had a mutation in the GLA gene (c.782G>A), confirming a diagnosis of Fabry.
“In conclusion, RFUO [recurrent fever of unknown origin] can be one of the initial manifestations of FD, and FD should be considered as a rare cause of RFUO,” the researchers wrote.
“The coexistence of gene variants related to systemic autoinflammatory diseases may make the clinical phenotypes [evident symptoms] of FD more complex and prone to recurrent fever,” they added.
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