Background/Purpose: Farber disease is frequently misdiagnosed as polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis which leads to a delay in diagnosis for many patients. Farber disease is an ultra-rare lysosomal storage disease caused by mutations in the ASAH1 gene. The resulting deficiency of the acid ceramidase enzyme leads to accumulation of the pro-inflammatory and pro-apoptotic sphingolipid ceramide.  Accumulation of ceramide throughout the body causes the cardinal symptoms of Farber disease including joint disease (polyarticular arthritis and contractures), subcutaneous nodules, and dysphonia due to laryngeal nodules. The purpose of the first natural history study of Farber disease was to further define the clinical presentation and broad phenotypic spectrum to aid in clinical diagnosis and reduce diagnostic delay.   

Methods: The Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NCT03233841) was the first systematic clinical study of the natural history of Farber disease. The study collected retrospective and prospective data on living and deceased patients, including demographics, clinical presentation, diagnostic history, and patient reported outcomes.  

Results: 45 patients with Farber disease (27 living, 18 deceased) who had or had not undergone hematopoietic stem cell transplant (HSCT) were enrolled from 16 centers in 9 countries. The patients represented the broad phenotypic spectrum of Farber disease, from rapidly progressive (severe) to slowly progressive (attenuated). The average age of living patients at enrollment was 7.2 years (range 1 to 28 years). For deceased patients, most with rapidly progressive disease, the average age of death was 3.4 years (range 0.3 to 18.3 years). The average age of onset of joint disease (arthritis and/or contractures) was 15 months (range 3 months to 7 years), of subcutaneous nodules was 13 months (range 3 months to 5 years), and of dysphonia was 13 months (range birth to 8 years). The average time from onset of symptoms to Farber disease diagnosis was 2 years (range < 1 to 12 years). At baseline, the mean number of joints affected with active arthritis was 11.3 (range 0-36) and the mean number affected with contractures was 18 (range 0-38). Bone disease, including osteoporosis and osteolysis, was common. The Child Health Assessment Questionnaire Disability Index (CHAQ) ranging from 0 (no impairment) to 3 (unable to do) was high, with mean scores of 2.62-3.00 across visits.   

Conclusion: Data from the Farber disease natural history study further defined the cardinal symptoms, phenotypic spectrum, and high disease-related burden in patients with Farber disease. The large number of joints affected with arthritis or contractures causes individuals with Farber disease to be referred to rheumatology and frequently misdiagnosed with polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis. ASAH1 genetic testing for adult and pediatric patients with symptoms including polyarticular arthritis, subcutaneous nodules, dysphonia, or osteolysis, may shorten the time to diagnosis in patients with Farber disease. 

« Back to ACR Convergence 2022

ACR Meeting Abstracts - https://acrabstracts.org/abstract/polyarticular-arthritis-and-osteolysis-caused-by-mutations-in-the-asah1-gene-farber-disease-clinical-presentations-in-the-first-ever-natural-history-study/