A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features

Purpose Farber disease (OMIM 22800) is an ultrarare progressive multisystemic neurodevelopmental storage disorder caused by a deficiency of the lysosomal enzyme acid ceramidase (AC). Hard clinical end points for future clinical trials remain to be defined. Methods We quantitatively analyzed published cases with Farber disease ( N = 96). The main outcome variables were survival and diagnostic delay. As a potential predictor of survival, the influence of residual AC enzyme activity was investigated. The analysis was performed in compliance with STROBE criteria. Results The median survival period of the study population was 3 years. The median age at disease onset was 3 months, and the median age at diagnosis was 17 months. The median diagnostic delay was 13.75 months. Patients with residual AC activity in fibroblasts at more than 5.1% of the normal level survived significantly longer than patients with residual AC activity below this threshold. In addition, higher residual AC activity was associated with a later onset of symptoms. Conclusion Farber disease onset is in infancy. Diagnostic delay is typically substantial. Our data suggest a phenotype-biomarker association with implications for future clinical and therapeutic trials. In the absence of a prospective multicenter natural-history study protocol, we believe that our modeling approach, based on published case descriptions, is the best and most timely approximation for generalizability.