Background/Purpose: Mutations in the ASAH1 gene cause acid ceramidase deficiency, accumulation of the pro-inflammatory and pro-apoptotic lipid ceramide, and a distinct set of clinical features, which can vary greatly in severity (Farber disease). Typically, Farber disease presents in childhood with polyarticular arthritis or joint contractures, subcutaneous nodules and a hoarse or weak voice due to nodule formation in the larynx. A recent report of patients diagnosed at over 40 years of age indicates that peripheral osteolysis can also be caused by ASAH1 mutations, and reinforces the fact that mild forms of the disease may only be diagnosed in adulthood. The prevalence of Farber disease is currently unknown, but it is likely underdiagnosed due to lack of awareness of the clinical presentation and of the availability of diagnostic testing. All known phenotypes are associated with autosomal recessive inheritance. Acid ceramidase enzyme replacement therapy is currently under development.

Methods: Using physician reporting and retrospective chart review, data from 22 recently diagnosed Farber disease patients has been collected to explore the spectrum of symptoms and disease severity associated with acid ceramidase deficiency. When available, data on previous diagnosis, presence of specific symptoms, age at presentation of first symptom, and time between presentation of each additional symptom was compared between patients with severe, moderate and attenuated phenotypes.

Results: Data indicates that Farber disease represents a broad clinical spectrum, with first symptoms presenting most often from infancy through late childhood, with a mean age at onset of 1.2 months for the most severe form in this group of patients, and reinforces the validity of the characteristic features of Farber disease: polyarticular arthritis, subcutaneous nodules and a hoarse or weak voice. However, there are patients who present with only one or two of these symptoms, and the spectrum of disease includes remarkably attenuated forms (mean age at onset of 4.5 years). 10 of 14 patients (71%) with moderate or attenuated disease were initially misdiagnosed with JIA. Treatment with anti-inflammatory therapies or disease modifying anti-rheumatic drugs (including biologics) may have some effect on the severity of pain and inflammation in Farber disease patients, and this can initially reinforce a misdiagnosis. Such treatments cannot resolve the major symptoms of Farber disease, or prevent disease progression.

Conclusion: The broad spectrum of phenotypes associated with ASAH1 mutations indicate that Farber disease should be considered in the differential diagnosis of therapy resistant arthritis in childhood and adulthood, as well as in cases of peripheral osteolysis. A better understanding of the clinical symptoms associated with ASAH1 mutations, and the availability of biochemical and genetic diagnostic testing, means that screening programs can be initiated to identify patients with Farber disease from among those currently treated by adult and pediatric rheumatologists around the world.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/asah1-gene-mutations-cause-acid-ceramidase-deficiency-farber-disease-with-symptoms-including-arthritis-and-subcutaneous-nodules-patients-are-often-misdiagnosed-with-jia-and-slowly-progressiv/