Farber's disease (also known as Farber's lipogranulomatosis) is a one of a group of rare inherited metabolic disorders called lipid storage diseases, in which excess amounts of lipids (oils, fatty acids, and related compounds) build up to harmful levels in the central nervous system, joints, and tissues. The liver, heart, and kidneys also may be affected. Farber's disease is caused by the deficiency of the enzyme called ceramidase.

Both parents need to carry and pass on the defective gene for a child to have Farber's disease. The disease affects both males and females. In the disease's classic form, onset typically begins in early infancy but may occur later in life. Neurological symptoms may include:

• Problems with swallowing
• Increased lethargy and sleepiness
• Chronic shortening of muscles or tendons around the joints
• Moderately impaired mental ability

Other symptoms may include arthritis, swollen lymph nodes and joints, hoarseness, nodules under the skin (and sometimes in the lungs and other parts of the body), and vomiting. Some people may need a breathing tube. Most children with the classic form die by age 2, usually from lung disease.

In one of the most severe forms of the disease, an enlarged liver and spleen can be diagnosed soon after birth. Children born with this form of the disease usually die within 6 months.

Currently there is no specific treatment for Farber's disease. Corticosteroids may be prescribed to relieve pain. Bone marrow transplants may improve granulomas (small masses of inflamed tissue) on people with little or no lung or nervous system complications. Older people may have granulomas surgically reduced or removed.

Farber lipogranulomatosis is a rare inherited condition involving the breakdown and use of fats in the body (a process known as lipid metabolism). In affected individuals, lipids accumulate abnormally in cells and tissues throughout the body, particularly around the joints. Researchers had previously categorized Farber lipogranulomatosis into subtypes based on characteristic features, but the condition is now thought to be a spectrum of overlapping signs of symptoms.

Three classic signs occur in Farber lipogranulomatosis: a hoarse voice or a weak cry, small lumps of fat under the skin and in other tissues (lipogranulomas), and swollen and painful joints. Signs and symptoms typically first develop in infancy.

In addition to the classic signs, Farber lipogranulomatosis often affects multiple body systems. Affected individuals can have developmental delay, behavioral problems, or seizures. In severe cases, people experience progressive decline in brain and spinal cord (central nervous system) function, a buildup of fluid in the brain (hydrocephalus), loss (atrophy) of brain tissue, paralysis of the arms and legs (quadriplegia), loss of speech, or involuntary muscle jerks (myoclonus).

People with Farber lipogranulomatosis often have enlarged liver, spleen, and immune system tissues due to massive lipid deposits. Lipid deposits may also occur in the eyes and lungs, leading to vision problems and breathing difficulty. Affected individuals may develop thinning of the bones (osteoporosis) that worsens over time.

Because of the severity of the signs and symptoms of the condition, individuals with Farber lipogranulomatosis generally do not survive past childhood.

Variants (also known as mutations) in the ASAH1 gene cause Farber lipogranulomatosis. The ASAH1 gene provides instructions for making an enzyme called acid ceramidase. This enzyme is found in cell compartments called lysosomes, which digest and recycle materials. Acid ceramidase breaks down fats called ceramides into a fat called sphingosine and a fatty acid. These two breakdown products are recycled to create new ceramides for the body to use. Ceramides have several roles within cells. For example, they are a component of a fatty substance called myelin that insulates and protects nerve cells. Ceramides are also part of the outer membrane surrounding cells, where they sense stress and other external factors and help the cells react.

Variants in the ASAH1 gene lead to severe reduction in acid ceramidase, typically to below 10 percent of normal. As a result, the enzyme cannot break down ceramides properly and they build up in the lysosomes of various cells, including in the lung, liver, colon, muscles used for movement (skeletal muscles), cartilage, and bone. The buildup of ceramides along with the reduction of its fatty breakdown products in cells likely causes the signs and symptoms of Farber lipogranulomatosis. It is unclear whether the level of acid ceramidase activity is related to the severity of the disorder.

Normal Function

The ASAH1 gene provides instructions for making an enzyme called acid ceramidase. This enzyme is found in lysosomes, which are cell compartments that digest and recycle materials. Within lysosomes, acid ceramidase breaks down fats (lipids) called ceramides. Ceramides are typically found within the membranes that surround cells and play a role in regulating cell maturation (differentiation), growth and division of cells (proliferation), and controlled cell death (apoptosis). Additionally, ceramides are a component of a fatty substance called myelin that insulates and protects nerve cells. Ceramides also serve as building blocks for more complex lipids. When ceramides need to be replaced, they travel to lysosomes where acid ceramidase breaks them down into a fat called sphingosine and a fatty acid. These two breakdown products are recycled to create new ceramides for the body to use.

Health Conditions Related to Genetic Changes

Farber lipogranulomatosis

Variants (also known as mutations) in the ASAH1 gene have been found to cause Farber lipogranulomatosis. This condition is characterized by the buildup of ceramides and other fats in cells throughout the body, particularly around the joints. Most of the variants associated with Farber lipogranulomatosis change a single protein building block (amino acid) in acid ceramidase, which severely reduces the activity of the enzyme, typically to less than one-tenth of normal. As a result, the enzyme cannot break down ceramides properly and they build up in the lysosomes of various cells, including in the lungs, liver, muscles, brain, cartilage, and bone. It is unclear how an accumulation of ceramides impairs the normal functioning of cells, but damage to the affected cells leads to the voice, skin, and joint problems that are characteristic of Farber lipogranulomatosis. Ceramides influence various cell functions, and it is likely that abnormal regulation of these processes also contributes to the features of this condition.

Spinal muscular atrophy with progressive myoclonic epilepsy

Variants in the ASAH1 gene have been found to cause spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). This condition is characterized by muscle weakness and wasting (atrophy) and a combination of seizures and uncontrollable muscle jerks (myoclonic epilepsy) that begin in childhood. The ASAH1 gene variants that cause SMA-PME result in a reduction of acid ceramidase activity to a level less than one-third of normal. The decrease in acid ceramidase activity leads to inefficient breakdown of ceramides and impaired production of its breakdown products sphingosine and fatty acids. The increase in ceramides and reduction in sphingosine and fatty acids likely play a role in the development of the features of SMA-PME, but the exact mechanism is unknown.

The reduction in acid ceramidase activity associated with SMA-PME is less than what occurs in another condition called Farber lipogranulomatosis (described above). Researchers suspect that the small amount of enzyme activity in SMA-PME allows some ceramide breakdown to occur, so the ceramides do not accumulate and damage cells as extensively as seen in Farber lipogranulomatosis. However, because SMA-PME is so rare, the effects of the enzyme changes are still unclear.

Other Names for This Gene

• AC
• ACDase
• acylsphingosine deacylase
• ASAH
• ASAH1_HUMAN
• FLJ21558
• FLJ22079
• N-acylsphingosine amidohydrolase (acid ceramidase) 1
• PHP
• PHP32

Genomic Location

• Joint pain and swelling (arthralgia)
• Failure to thrive
• Enlarged liver (hepatomegaly)
• Hoarse cry due to a soft, floppy voice box (laryngomalacia)
• Lumps of fat under the skin and around the joints (periarticular subcutaneous nodules)
• Short stature
• Developmental delay

• Medical geneticist
• Neurologist
• Rheumatologist
• Pain management specialist
• Otolaryngologist (ENT)