Farber disease
Farber disease, also known as Farber's lipogranulomatosis or ceramidase deficiency, is a rare, inherited disorder characterized by a progressive buildup of fatty substances in the body’s cells, affecting various organs including the throat, lungs, joints, liver, skin, and brain. It is caused by a mutation in the ASAH1 gene, resulting in a deficiency of the enzyme N-acylsphingosine amidohydrolase (ceramidase) in the lysosomes, leading to the accumulation of chondroitin sulfate B. Symptoms typically present in infancy, starting with a hoarse cry, feeding difficulties, and irritability, and can progress to severe complications such as joint swelling, breathing problems, and organ failure. The disease manifests in several forms, with the most severe cases leading to a significantly reduced lifespan, often by age two, while milder forms may allow individuals to live into their twenties. Diagnosis is primarily based on clinical symptoms, with biochemical and genetic testing available to confirm the condition. Currently, there is no cure for Farber disease, and treatment focuses on managing symptoms. Research is ongoing, including investigational therapies like ACG-801, which aims to replace the deficient enzyme. Genetic counseling and carrier testing can help families understand and manage the risks associated with this condition.
Farber disease
- ALSO KNOWN AS: Farber’s disease; Farber’s lipogranulomatosis; ceramidase deficiency; acid ceramidase deficiency
DEFINITION Farber disease is a severe, progressive inherited disorder that affects the throat, lungs, joints, liver, skin, and brain. The symptoms of Farber disease are caused by the harmful buildup of fatty substances in the body’s cells.
Risk Factors
Farber disease is a very rare genetic disease caused by the inheritance of a nonworking ASAH1 gene from both parents. Although the exact number of individuals affected by Farber disease is unknown, approximately fifty cases have been reported in the literature worldwide. The disease is present in males and females at equal rates. This condition is not caused by infections.
Etiology and Genetics
Farber disease is caused by the lack of an enzyme known as N-acylsphingosine amidohydrolase (ceramidase) in a small cellular organelle called the lysosome. The lysosome is the recycling center of the cell. When the enzyme is missing, a fatty substance called chondoritin sulphate B builds up in the cells of the body.
Farber disease is an autosomal recessive genetic condition. It occurs when a child inherits two copies of the nonworking ASAH1 gene. Individuals with only one copy of a nonworking ASAH1 gene are known as carriers and have no problems related to the condition. In fact, it is believed that all people carry at least eight to ten nonworking genes for harmful, recessive conditions. When two people with the same nonworking recessive ASAH1 gene meet, however, there is a chance, with each pregnancy, for the child to inherit two copies, one from each parent. That child then has no working copies of the ASAH1 gene and therefore has the signs and symptoms associated with Farber disease.
Symptoms
Typically, affected children begin having symptoms of Farber disease in the second or third week after birth. Early symptoms of the disease often include a hoarse cry, problems feeding, irritability, impaired mental and physical abilities, swollen lymph nodes, cherry-red macular spots in the eye, and skin bumps (called erythematous periarticular swellings). These symptoms progressively become worse, with painful joint swelling, shortened muscles around joints, frequent infections, breathing difficulties, and then heart and kidney failure.
Although the most common form of Farber disease is the severe, infant-onset form, Farber disease symptoms can vary from person to person. Accordingly, affected individuals are grouped into at least seven different types of Farber disease. Patients with type 1 disease are very severely affected with symptoms starting in the weeks after birth. Most type 1 patients die during the first years of life. Type 2 and 3 patients do not have liver or lung symptoms, are of normal intelligence, and have a longer life expectancy than do type 1 patients. Type 4 patients have very severe disease with symptoms including an enlarged spleen and liver. These patients rarely live past six months of age. Type 5 patients have classic symptoms beginning at one to two years of age. Types 6 and 7 are severe varieties of Farber disease that result from the lack of ceramidase and one or more other lysosomal enzymes.
Screening and Diagnosis
Screening for Farber disease is not part of routine testing in the prenatal or newborn periods of life. Since the symptoms of Farber disease are present in the first few weeks of life, diagnosis is most often made on the basis of disease signs and symptoms. Biochemical testing is available to confirm the diagnosis through identification of the low or missing enzymes. Molecular genetic testing can help identify the changes in the ASAH1 gene in carriers and affected individuals. This disease can be misdiagnosed as colic, juvenile rheumatoid arthritis, or sarcoidosis.
Treatment and Therapy
At this time, there is no cure or disease specific treatment for Farber disease. Therapy for Farber disease focuses on the treatment of each symptom individually. For example, corticosteroids may be given to reduce painful swelling of the joints and nodes could be surgically removed. In individuals affected by a mild form of Farber disease without brain involvement, bone marrow transplants may help relieve physical symptoms of the disease. Researchers are working on gene therapy to provide individuals affected by Farber disease with a working copy of the altered ASAH1 gene, but this has not yet been proved to be effective in affected humans.
In the early 2020s, an investigational therapy called ACG-801, a recombinant human acid ceramidase enzyme replacement, received special status from the US Food and Drug Administration including classification in the Orphan Drug, Rare Pediatric Disease and Fast Track programs. This allowed ACG-801 to move through the clinical trial phase more quickly and reduced its potential time to market if approved. A similar expedited approval process was initiated in Europe.
Prevention and Outcomes
Carrier testing can be conducted for individuals who are interested in learning if they carry an altered ASAH1 gene. Genetic counseling is available for parents who have an affected child or are concerned about being a carrier for the ASAH1 gene. Although the severity and symptoms of Farber disease varies from individual to individual, death from Farber disease symptoms most often occurs by two years of age as a result of lung disease. Rare individuals affected by a much milder form of the disease may live past their twenties.
Bibliography
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Norris, Marie K, et al. “Adiponectin Overexpression Improves Metabolic Abnormalities Caused by Acid Ceramidase Deficiency but Does Not Prolong Lifespan in a Mouse Model of Farber Disease.” Molecular Genetics and Metabolism Reports, vol. 39, 3 April. 2024, doi:10.1016/j.ymgmr.2024.101077. Accessed 9 Sept. 2024.
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