Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology

» This represents a truly significant advancement in the study of this disorder. « Farber disease (Lipogranulomatosis) is a rare, invariably fatal, inherited metabolic disorder first described by Sidney Farber in 1957 (Farber et al, 1957). Farber disease is inherited in an autosomal recessive fashion and is caused by mutations in the lysosomal acid ceramidase (ASAH1) gene. Therefore, Farber disease is classified as one of the >50 distinct lysosomal storage disorders (LSDs). Acid ceramidase (ACDase) is a soluble lysosomal enzyme responsible for the degradation of ceramide. Low levels ( 10% normal) of ACDase activity result in the progressive accumulation of ceramide in most tissues. Affected children initially present with joint stiffness and deformation, prominent subcutaneous nodules and progressive hoarseness due to laryngeal involvement. As the disease progresses affected children can also develop cardiac, pulmonary and central nervous system defects. Like most LSDs, there is a spectrum of severities associated with Farber disease. The most severe neonatal form results in death within the first few days of life. Children with the most common, ‘classical’ form of Farber dis-