Farber Disease

Dr. Sidney Farber. Source: National Library of Medicine".

Farber disease (FD) describes a group of inherited metabolic disorders also called lipid storage diseases, in which excess amounts of lipids (oils, fatty acids, and related compounds) build up to harmful levels in the joints, tissues, and central nervous system. The liver, heart, and kidneys may also be affected.

Other Names

• Farber's lipogranulomatosis
• Ceramidase deficiency

Types

Several Types of Farber disease have been identified: ^[1]

Type 1

Type 1 FD is characterized by subcutaneous nodules, arthritis, and laryngeal involvement. Increasing lung and neurological involvement are common.

Type 2 and Type 3

These types of FD also present with subcutaneous nodules, hoarseness and lung involvement. These types are also characterized by joint pain, contractures, and failure to thrive. The central nervous system is often not involved in these types and patients may live longer than in other types.

Type 4

Patients with type 4 FD present early in infancy with an enlarged liver and spleen and histiocytic (immune cell) infiltration of the spleen, thymus, liver and lungs. Death generally occurs in the first six months of life.

Type 5

Type 5 FD presents with significant central nervous system disease involvement beginning in or shortly after the first year of life. Patients may have limb paralysis, mental retardation, speech difficulty, seizures and myoclonus (muscle twitching).

Signs and Symptoms

Symptoms of Farber disease may include:

• Impaired motor and mental ability
• Difficulty with swallowing
• Arthritis
• Swollen lymph nodes and joints
• Hoarseness
• Nodules under the skin (and sometimes in the lungs and other parts of the body)
• Chronic shortening of muscles or tendons around joints
• Vomiting
• Liver and/or spleen enlargement
• Lung disease caused by granulomas (inflammatory nodules) in the lung and interstitial pneumonitis.

Causes

Patients with Farber disease are lacking the enzyme ceramidase, which is used to break down ceramide in the cell's lysosomes. Ceramidase converts ceramide to sphingosine and fatty acid. When ceramidase is deficient, ceramide accumulates and causes cell damage with an inflammatory response. This leads to the formation of granules and nodules in the tissue around the joints, in the vocal cords, in the lungs, and in the airway. The central nervous system may or may not be involved in this disease process.

Farber disease is inherited in an autosomal recessive manner. Both parents must carry and pass on the defective gene. Children born to these parents have a 25% chance of inheriting the disorder and a 50% chance of carrying the faulty gene. The disorder affects both males and females equally. Six new mutations in the ceramidase gene were identified in a 2001 study from Germany. ^[2]

Diagnosis

The diagnosis of Farber disease can be suggested clinically, especially in Type 1 disease if the classic triad of symptoms is present. Other ways the diagnosis can be made include:

• By observing a deficiency of ceramide in white blood cells or fibroblasts (connective tissue cells that produce material to provide structure).
• By demonstrating a ceramide deficiency in amniotic cells or chorionic villus cells in the fetus
• By identifying Farber bodies (seen in fibroblasts and endothelial cells).
• If elevated levels of ceramide are seen in the urine
• On tissue biopsy, if intracellular lipid inclusions are seen in subcutaneous (under the skin) nodules or other tissue
• Ceramide accumulation may be seen in tissue by chromatography or mass spectrometry.

Treatment

Currently there is no specific treatment for Farber’s disease. Some potentially helpful therapies:

Medications

Corticosteroids may be helpful to reduce inflammation and decrease pain. Pain medication may involve narcotic and non-narcotic types as well as non-steroidal anti-inflammatory medicines.

Therapies

Nodules, granulomas and possibly enlarged lymph nodes may be candidates for surgical removal.

Physical therapy and surgery may be required for relief of contractures.

Bone marrow transplantation, especially in patients without significant neurological involvement, may be a therapeutic option. ^{[3] [4]}

Clinical Trials

A list of ongoing Clinical Trials: Farber disease trials.

Research

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), conducts research about lipid storage diseases such as Farber’s disease in laboratories at the NIH and also supports additional research through grants to major medical institutions across the country.

Expected Outcome

Most children with the classic form of Farber’s disease die by age two, usually from lung disease. Individuals having a milder form of the disease may live into their teenage years. Death typically results from granuloma formation in the respiratory tract, pneumonia, and respiratory insufficiency caused by immobility.

History

Farber Disease was named for Dr. Sidney Farber (1903-1973), a Harvard pathologist attributed with many remarkable discoveries, including the use of amphotericin as the first chemotherapeutic agent for the treatment of acute leukemia. Dr. Farber is also recognized as the founder of pediatric pathology ^[5] Dr. Farber studied the pathology of the cardiovascular and respiratory systems and conducted research on histocytosis X and lipid disorders, including Farber disease. He also recognized cystic fibrosis as a generalized disease and described hyaline membrane disease in newborns. Finally, Dr. Farber started the Children's Cancer Research Foundation in Boston, the first institution created solely for the treatment of cancer in children. This facility, initially known as the Sidney Farber Cancer Institute, is now known as the Dana-Farber Cancer Institute.

References

1. ↑ Moser, H. W.; Moser, A. B.; Chen, W. W.; Schram, A. W. Ceramidase deficiency: Farber lipogranulomatosis. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. : The Metabolic Basis of Inherited Disease. Vol. II (6th ed.) New York: McGraw-Hill (pub.) 1989. Pp. 1645-1654.
2. ↑ Bär J, Linke T, Ferlinz K, Neumann U, Schuchman EH, Sandhoff K. Molecular analysis of acid ceramidase deficiency in patients with Farber disease. Hum Mutat. 2001 Mar;17(3):199-209. Abstract
3. ↑ Yeager AM, Uhas KA, Coles CD, Davis PC, Krause WL, Moser HW. Bone marrow transplantation for infantile ceramidase deficiency (Farber disease). Bone Marrow Transplant. 2000 Aug;26(3):357-63. Abstract | Full Text
4. ↑ Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatr Rheumatol Online J. 2007 Jun 29;5:15. Abstract | Full Text
5. ↑ Sidney Farber (1903-1973). CA Cancer J Clin. 1974 Sep-Oct;24(5):294-6. PDF

External Links

Children Living with Metabolic Disease (CLIMB) (UK)

Vaincre Les Maladies Lysosomales (France}

Hide and Seek Foundation for Lysosomal Disease Research