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Abstract

Abstract 

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

  2. 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 owing 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 are the most prominent clinical manifestation, and somewhat milder forms with later onset and longer survival. Some patients have survived to adulthood with mild or absent neurologic involvement.

  3. Acid ceramidase (EC 3.5.1.23) has been purified and cloned. The full-length cDNA contains an 1185-bp open-reading frame. To date, at least 20 different disease-linked mutations have been described in the acid ceramidase ASAH1 gene. Point mutations have been found in Farber patients, as have complete deletions of exons. In addition, three polymorphisms have been identified that have no effect on enzyme activity.

  4. 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 and derivatives in other subcellular compartments. Apoptosis, for example, is apparently not increased in cultured fibroblasts of Farber disease patients.

  5. 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 microscopic studies of biopsy samples. Prenatal diagnosis is possible.

  6. The disease is rare. Data on almost 80 patients in a variety of ethnic groups have been assembled. The mode of inheritance is autosomal recessive.

  7. Bone marrow transplantations with unmodified allogeneic grafts have been performed for Farber disease. In the first two patients transplanted, while there was regression of joint manifestations and reductions of subcutaneous nodules along with improvements in the level of hoarseness, the overall outcomes were unfavorable because of continued neurologic deterioration. More recently, four patients with type 2/3 Farber disease (presenting with minimal central nervous system involvement) have been transplanted with allogeneic cells derived from bone marrow or cord blood. Stable hematopoietic chimerism was established in each patient, and resolution of granulomas and joint contractures with a gradual improvement in mobility occurred.

  8. Some efforts have been initiated to develop gene therapy for Farber disease. Given the bone marrow transplantation results mentioned earlier and the fact that leukocyte dysregulation occurs in Farber disease, the hematopoietic system has been the initial target for development and implementation of gene therapy. This schema is also buoyed by the observations that hematopoietic cells can traverse into the brain and that metabolic cooperativity or “cross-correction” also occurs in this context. Here, gene-modified cells diffuse acid ceramidase activity, which can be taken up and used functionally by unmodified bystander cells. Recombinant oncoretrovirus- and lentivirus-based vectors have been generated that engineer overexpression of acid ceramidase in transduced Farber patient cells with concomitant reductions in ceramide levels. Small- and large-animal studies to accumulate additional preclinical efficacy and safety data have been published or are currently under way.

  9. Acid ceramidase, β-galactocerebrosidase and β-glucocerebrosidase activities are diminished in patients with sphingolipid activator prosaposin deficiency and in a mouse model of this disorder. This fatal disease is dominated by severe neurovisceral manifestations.

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