Farber disease (FD) (MIM 228000) is a genetically determined disorder of lipid metabolism associated with deficiency of lysosomal acid ceramidase and accumulation of ceramide in the lysosome.

The disease presents most commonly during the first few months after birth with a unique triad of clinical manifestations: (a) painful and progressively deformed joints; (b) subcutaneous nodules, particularly near joints and over pressure points; and (c) progressive hoarseness due to laryngeal involvement. These tissues show granulomas and lipid-laden macrophages. The liver, spleen, lung, and heart are often involved, and the nervous system may show accumulation of ceramides and gangliosides in the neurons of brain and spinal cord. The illness is progressive, and often leads to death during the first few years. Other, less frequent, phenotypes also occur, including a rapidly fatal neonatal form associated with massive hepatosplenomegaly; a form in which progressive neurologic disability associated with retinal cherry-red spots is the most prominent clinical manifestations; and somewhat milder forms with later onset and longer survival. Some patients have survived to adulthood with mild or absent neurologic involvement.

Acid ceramidase (EC 3.5.1.23) has been purified and cloned. The full-length cDNA contains a 1185-bp open-reading frame. To date, 11 different mutations have been reported in the acid ceramidase gene. The point mutations M72V and V93I were identified as polymorphisms and had no effect on the enzymatic activity. The point mutations Y36C, E138V, T222K, R254G, N320D, D331N, and P362R all significantly reduced or abolished enzymatic activity. In addition, two splice-site mutations leading to the deletion of either exon 6 or exon 13 were demonstrated in two Farber disease patients.

The ceramide that accumulates in Farber disease is confined to the lysosomal compartment, and does not appear to contribute to the multiple biomodulatory roles attributed to ceramides in other subcellular compartments. Apoptosis is apparently not increased in cultured fibroblasts of Farber disease patients.

Laboratory diagnosis is achieved by demonstration of reduced acid ceramidase activity in white blood cells, cultured skin fibroblasts, and amniocytes, or by loading studies with labeled precursors in cultured cells. Other diagnostic procedures include the demonstration of abnormally high ceramide levels in cultured cells, biopsy samples or urine, or of characteristic “Farber bodies” by electron microscope studies in biopsy samples. Prenatal diagnosis is possible.

The disease is rare. Data on 78 patients in a variety of ethnic groups have been assembled. The mode of inheritance is autosomal recessive.

There is no effective therapy. Bone marrow transplants have been performed in two patients. While there was regression of joint manifestations and subcutaneous nodules and the hoarseness improved, the overall outcome was unfavorable because of continued neurologic deterioration which led to death in both patients. Transfection with acid ceramidase cDNA corrects the biochemical defect in cultured skin fibroblasts.

Acid ceramidase activity and glucocerebrosidase activities are diminished in patients with sphingolipid activator deficiency and in a mouse model of this disorder. Clinical manifestations of this disorder resemble those of Gaucher disease.