Abstract Background Fabry disease (FD) is caused by pathogenic variants in the GLA gene. A143T and R118C variants are considered not disease causing. Patient-reported outcomes provide information concerning the effects of their disease but should be carefully analyzed in rare diseases. Objectives To evaluate pain, depression, sleep disturbances, disability and quality of life in A143T or R118C Brazilian subjects and compare to data published for classic FD patients. Methods Nineteen subjects - 8:11 male:female - were evaluated and answered the questionnaires: Brief Pain Inventory (BPI), Hamilton Depression Rating Scale, Pittsburgh Sleep Quality Index, Health Assessment Questionnaire Disability Index (HAQ-DI), Short-Form Health Survey 36 (SF-36). Lyso-Gb3 and residual enzyme activity were obtained. Results Alpha-galactosidase A activity was low in males. Lyso-Gb3 levels were normal in all subjects. Comparing A143T/R118C subjects and FD patients, BPI severity, BPI interference, HAQ-DI values were not different (p>0.05) whereas raw scores for physical functioning (p=0.01) and general health perception (p<0.01) favored A143T/R118C. Depression and sleep disturbances were similar between groups. Conclusions A143T/R188C subjects had normal lyso-Gb3 levels. Depression, sleep disturbances and disability were frequent and under-recognized. However, findings depicted in this study are nonspecific and should not be considered as ground for diagnosing Fabry disease.

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal disease caused by variants of the GLA gene; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs. Chronic inflammation is thought to contribute to organ damage in FD patients. METHODS: In total, 36 classic FD patients (15 men/21 women) and 25 healthy controls (20 men/8 women) were assessed. The Mainz Severity Score Index (MSSI) was established after conducting interviews with the patients and chart review. Serum IL-6, IL-1β, and TNF-α levels were evaluated in both groups. RESULTS: The mean age (years) for FD patients was 43.1±15.4 and that for the controls was 47.4±12.2 (p>0.05). Twenty-two patients (59.5%) were treated with enzyme replacement therapy (ERT). Serum IL-6 and TNF-α levels were significantly higher in FD patients than in the controls. Patients treated with ERT had higher serum IL-6 and TNF-α levels than those not treated with ERT. There was no difference in the serum IL-1β levels between patients treated with ERT and those who were not. The MSSI scores in the patients were correlated with serum levels of IL-6 (r=0.60, p<0.001) and TNF-α (r=0.45, p<0.001). CONCLUSION: FD was associated with elevated serum levels of IL-6 and TNF-α in this cohort. The FD patients treated with ERT, particularly, women, exhibited higher levels of serum IL-6 and TNF-α than those not treated with ERT; the serum IL-6 and TNF-α levels were correlated with the MSSI scores reflecting greater disease burden.

Abstract Background: Fabry disease (FD) is an X-linked lysosomal disorder due to mutations in the GLA gene 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 of GLA gene 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 with GLA gene 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 with GLA gene 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 with GLA gene 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.