Fabry disease shares some manifestations with rheumatic diseases, which has raised concerns of wrongful diagnosis and consequent delayed treatment. Still, patients with this rare genetic disease are unlikely to be systematically overlooked in clinical rheumatology practice, results of a genetic analysis of German patients with early undifferentiated arthritis shows.
The study findings were reported in a letter, “Clinical characteristics of patients with alpha- galactosidase A gene variants in a German multicentre cohort of early undifferentiated arthritis,” published in the journal Annals of the Rheumatic Diseases.
Fabry disease is a genetic disorder caused by mutations in the alpha-galactosidase A gene (GLA), resulting in the accumulation of a type of fat — called globotriaosylceramide or Gb3 — in tissues and organs.
Long-term buildup of Gb3 can have a severe impact on organs’ function. But initially, this disease may only manifest by severe musculoskeletal pain, especially affecting the periphery and extremities, medically known as acral pain. This type of manifestation is shared with many other disorders, including more frequent rheumatic diseases such as arthritis, which could lead clinicians to an incorrect diagnosis.
To investigate whether Fabry disease is in fact often mistaken for other diseases, a German research team performed a genetic analysis of 798 patients, 500 of whom were women, who had been diagnosed with early arthritis. In the analysis, the team focused on identifying the presence of mutations specifically on the GLA gene.
In total, they found eight genetic GLA variants, all in female patients, corresponding to a prevalence of 1.6 percent. None of the variants, however, had been previously linked with Fabry disease. Upon analysis of globotriaosylsphingosine (Lyso-Gb3) content, the team concluded that these eight patients did not have active Fabry disease. They were instead confirmed to have rheumatoid arthritis (seven patients) and one patient had systemic sclerosis.
Next, researchers evaluated whether GLA variants were associated with different disease outcomes. They compared patients with rheumatoid arthritis with GLA variants to those who did not carry the variants.
In these patients, GLA variants were associated with a reduced count of swollen joints but not to symptoms linked to Fabry disease, such as heart failure, renal insufficiency, pulmonary disease, gastrointestinal problems, or insufficient blood flow to the brain.
Rheumatoid arthritis patients who had GLA variants responded well to standard-of-care treatment, although this was also seen in patients without GLA variants. Still, improvements in joint function, tender joint count, and duration of morning stiffness were seen only in those with GLA variants.
Overall, these results suggest that it is unlikely that Fabry disease is overlooked in the clinical rheumatology practice. However, “rheumatologists should … be alert to the rare differential diagnosis of Fabry disease as they are often among the first specialists consulted due to acral pain,” researchers said. “Fabry disease should especially be considered in individuals complaining about acral pain without any confirmed joint swelling.”