Farber disease

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
AHM M Huq MD PhD, editor. (Dr. Huq of Wayne State University has no relevant financial relationships to disclose.)
Originally released April 21, 1995; last updated November 27, 2016; expires November 27, 2019

This article includes discussion of Farber disease, ceramidase deficiency, disseminated lipogranulomatosis, Farbers disease, Farber's disease, Farber lipogranulomatosis, and Farber Uzman syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Farber disease is an autosomal recessive progressive devastating disease of lipid metabolism associated with deficiency of lysosomal acid ceramidase caused by ASAH1 gene mutations leading to accumulation of ceramide in cells. The disease presents most commonly during the first few months after birth with painful and progressively deformed joints, subcutaneous nodules, particularly near joints and over pressure points, and progressive hoarseness due to laryngeal involvement. The nervous system is often involved. Other forms may exist, including a form of spinal muscular atrophy associated with progressive myoclonic epilepsy. Hematopoietic stem cell transplantation is effective for the nonneurologic aspects of the disease. Enzyme replacement therapy for this disease is being developed.

Key points

 

• Farber disease is a rare multisystemic autosomal recessive disease.

 

• Farber disease usually presents in infants.

 

• Progressive hoarseness is a clinical hallmark.

 

• A form with high residual acid ceramidase activity associated with spinal muscular atrophy and progressive muscular dystrophy has been described.

 

• Moderate Farber disease is a subset of juvenile idiopathic arthritis.

Historical note and terminology

The first patient with Farber lipogranulomatosis was described by Dr. Sidney Farber in 1957, in the Journal of the Mount Sinai Hospital, as part of a Festschrift for Paul Klemperer (Farber et al 1957). Sidney Farber considered it of special interest because "it (is) a possible bridge between what had appeared to be 2 etiologically unrelated groups of disorders, namely the 'true' (genetically determined) metabolic disorders such as Niemann-Pick disease and the (nongenetic) inflammatory histiocytoses such as Letterer-Siwe disease," or histiocytosis-x.

The "true" genetic component was represented by neuronal storage material that was thought to contain lipids, carbohydrates, and protein, whereas the inflammatory component, resembling histiocytosis-x, was evidenced by granulomatous inflammatory lesions in skin, joints, and larynx. Subsequent studies have shown, however, that a genetically determined abnormality accounts for all of the features of Farber lipogranulomatosis. In 1967, Prensky and associates showed that the tissues of Farber disease patients contained abnormally high levels of ceramide (Prensky et al 1967), and it was shown later that the ceramide accumulation accounted both for the neuronal storage and the inflammatory component (Moser et al 1969). In 1972, Sugita and associates demonstrated that the ceramide accumulation was due to a deficiency of acid ceramidase (Sugita et al 1972), and Farber disease is now classified as 1 of the lysosomal storage disorders. Acid ceramidase was purified in 1995 (Bernardo 1995) and cloned in 1996 (Koch et al 1996). A mutation of this gene was identified in 1 patient with Farber disease (Koch et al 1996).

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