Higher rate of rheumatic manifestations and delay in diagnosis in Brazilian Fabry disease patients
Authors: Rosa Neto Nilton Salles , Bento Judith Campos de Barros , Pereira Rosa Maria Rodrigues 
Published: January 2020

Background

Fabry disease (FD) is an X-linked lysosomal disorder due to mutations in theGLAgene resulting in defective enzyme alpha-galactosidase A. FD patients are frequently misdiagnosed, commonly for rheumatic diseases. Determining pathogenicity of a mutation depends of in silico predictions but mostly on available clinical information and interpretation may change in light of evolving knowledge. Similar signs and symptoms in carriers ofGLAgene genetic variants of unknown significance or of benign variants may hamper diagnosis. This study reviews rheumatic and immune-mediated manifestations in a cohort of Brazilian FD patients with classic mutations and also in subjects withGLAgene A143T and R118C mutations. Misdiagnoses, time to correct diagnosis or determination of GLA gene status, time to treatment initiation and reasons for treatment prescription in A143T and R118C subjects are reviewed.

Methods

Genotype confirmed classic FD patients (n = 37) and subjects with GLA gene mutations A143T and R118C (n = 19) were referred for assessment. Subjects with R118C and A143T mutations had been previously identified during screening procedures at hemodialysis units. All patients were interviewed and examined by a rheumatologist with previous knowledge of disease and/or mutation status. A structured tool developed by the authors was used to cover all aspects of FD and of common rheumatic conditions. All available laboratory and imaging data were reviewed.

Results

Thirty-seven consecutive FD patients were interviewed – 16 male / 21 female (mean age: 43.1 years) and 19 consecutive subjects withGLAgene mutations R118C and A143T were evaluated – 8 male / 11 female (mean age: 39.6 years); 15 [R118C] / 4 [A143T]. Misdiagnosis in FD patients occurred in 11 males (68.8%) and 13 females (61.9%) of which 10 males and 9 females were previously diagnosed with one or more rheumatic conditions, most frequently rheumatic fever or “rheumatism” (unspecified rheumatic disorder). Median time for diagnosis after symptom onset was 16 years (range, 0–52 years). Twenty-two patients were treated with enzyme replacement therapy (ERT) – 13 male and 9 female. Median time to ERT initiation after FD diagnosis was 0.5 years (range, 0–15 years). Rheumatic manifestations occurred in 68.4% of R118C and A143T subjects. Two subjects had been prescribed ERT because of renal disease [R118C] and neuropsychiatric symptoms [A143T].

Conclusion

Misdiagnoses occurred in 64.8% of FD patients, most frequently for rheumatic conditions. Median time for correct diagnosis was 16 years. Rheumatic manifestations are also frequent in subjects withGLAgene R118C and A143T mutations. These results reinforce the need to raise awareness and increase knowledge about Fabry disease among physicians, notably rheumatologists, who definitely have a role in identifying patients and determining disease burden. Decision to start treatment should consider expert opinion and follow local guidelines.