Farber disease

Farber disease

Farber disease also known as Farber’s disease, Farber’s lipogranulomatosis, Farber-Uzman syndrome, acid ceramidase deficiency, acylsphingosine deacylase deficiency or ceramidase deficiency, describes 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 joints, tissues, and central nervous system (brain and spinal cord). The liver, heart, and kidneys may also be affected. There are three classic signs in Farber’s disease: a hoarse voice or a weak cry, small lumps of fat under the skin and in other tissues (lipogranulomas), and swollen and painful joints. Affected individuals may also have difficulty breathing, an enlarged liver and spleen (hepatosplenomegaly), and developmental delay. Farber disease onset typically begins in early infancy but may occur later in life. Symptoms of the classic form may have moderately impaired mental ability and difficulty with swallowing. Other symptoms may include chronic shortening of muscles or tendons around joints. 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. In severe cases, the liver and spleen are enlarged.

Researchers have described seven types of Farber disease or Farber lipogranulomatosis based on their characteristic features.

  • Type 1 Farber disease is the most common also known as the “classical” variant of Farber disease, is associated with the classic signs of subcutaneous nodules, joint contractures, and voice hoarseness that begin a few months after birth. These patients may also develop enlarged liver and spleen along with neurological and respiratory complications 1). Developmental delay and lung disease also commonly occur. Traditionally, Type 1 Farber disease patients exhibit symptoms during infancy and typically do not live past the age of 2–3 years 2).
  • Types 2 and 3 Farber disease have been termed the “intermediate” and “mild” variants of Farber disease, respectively; generally have less severe signs and symptoms than the other types. Affected individuals have the three classic signs and usually do not have developmental delay. Children with these types of Farber lipogranulomatosis typically live into mid- to late childhood due to reduced neurological involvement. However, Types 2 and 3 Farber disease patients suffer from subcutaneous nodules, joint contractures, and aphonia due to inflammation.
  • Types 4 and 5 Farber disease are associated with severe neurological problems. Type 4 is associated with the “Neonatal-Visceral” variant, wherein neonates experience severe organomegaly and visceral histiocytosis 3). Type 4 Farber’s disease
    usually causes life-threatening health problems beginning in infancy due to massive lipid deposits in the liver, spleen, lungs, and immune system tissues. Children with Type 4 Farber’s disease typically do not survive past their first year of life. Type 5 Farber’s disease is the “Neurological Progressive” variant, is characterized by progressive decline in brain and spinal cord (central nervous system) function, which causes paralysis of the arms and legs (quadriplegia), seizures, loss of speech, involuntary muscle jerks (myoclonus), and developmental delay. Nodules and joint involvement are present in Type 5; however, they are less severe. Children with type 5 Farber lipogranulomatosis survive into early childhood.
  • Types 6 and 7 Farber disease are very rare, and affected individuals have other associated disorders in addition to Farber’s disease. Type 6 Farber disease is termed “Combined Farber and Sandhoff Disease variant”, the patient had combined Farber and Sandhoff diseases 4). The patient presented with clinical signs of Farber disease, and demonstrated a deficiency in both acid ceramidase (ACDase) and hexosaminidases A and B 5). Type 7 Farber disease is termed “Prosaposin Deficiency”. This phenotype was identified in one patient and his infant sibling 6); a mutation was identified in the precursor protein of saposins (i.e., prosaposin, encoded by the PSAP gene) 7). A total of 4 saposins have been identified, and these proteins, along with the GM2 ganglioside activator protein, collectively belong to a group of sphingolipid activator proteins (SAPs). Only a handful of patients with Type 7 Farber disease have been reported 8). Similar to Type 6 Farber disease, these patients often have multiple enzyme deficiencies, such as reduced glucocerebrosidase, galactocerebrosidase and ceramidase activities. While patients with prosaposin deficiency may show some biochemical and clinical signs that overlap with Farber disease, it is considered a separate disease. Increasingly, many of the more recently reported cases simply identify Farber disease as either the classic childhood or the mild and attenuated form 9). Since some of these subtypes are rare and represent separate conditions, an updated classification should be considered to incorporate the existing and emerging phenotypes of ceramidase deficiency.

Mutations in the ASAH1 gene (N-acylsphingosine amidohydrolase 1 gene) cause Farber disease. At least 20 mutations in the ASAH1 gene have been found to cause Farber’s disease. The ASAH1 gene provides instructions for making an enzyme called acid ceramidase (ACDase). Farber’s disease is caused by a deficiency of the enzyme acid ceramidase (ACDase). Farber disease or 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 these damaged cells lead to the voice, skin, and joint problems that are characteristic of Farber disease. Ceramides influence various cell functions, and it is likely that abnormal regulation of these processes also contributes to the features of Farber disease.

Farber disease is inherited in an autosomal recessive pattern 10). All individuals inherit two copies of each gene. Autosomal means the gene is found on one of the numbered chromosomes found in both sexes. Recessive means that both copies of the responsible gene must be altered to have the condition. Farber’s disease occurs when both parents carry and pass on the defective gene that regulates the protein sphingomyelin. Children born to these parents have a 25 percent chance of inheriting the disorder and a 50 percent chance of carrying the faulty gene. Farber disease affects both males and females.

Farber disease is a ultra-rare disorder. Less than 200 people with Farber disease have been described in the medical literature. The exact number of people with Farber’s disease is unknown 11). While no formal comprehensive international epidemiological study has been performed for Farber disease, one recent quantitative analysis of 96 case studies found that India and the USA had more than 10 reported cases, followed by Saudi Arabia, Germany, France, and Italy all of which had between 6 to 10 cases 12).

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

Figure 1. Farber disease

Farber's disease

Footnote: a) swelling in the knee of a child with Farber disease at the age of 2 years. b) Multiple nodules on extensor surface of hands at the age of 2 years. c) Nodular masses within lumbar regions on the spine at 4 years.

[Source 13) ]

Farber disease causes

Mutations in the ASAH1 gene (N-acylsphingosine amidohydrolase 1 gene) cause Farber disease. At least 20 mutations in the ASAH1 gene have been found to cause Farber’s disease. The ASAH1 gene provides instructions for making an enzyme called acid ceramidase (ACDase). 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.

Mutations 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 disease. It is unclear whether the level of acid ceramidase activity is related to the severity of Farber’s disease.

Farber disease inheritance pattern

Farber disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

  • If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
  • Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
  • This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
  • There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
  • Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 2 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 2. Farber disease autosomal recessive inheritance pattern

Farber disease autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Farber’s disease symptoms

The following list includes the most common signs and symptoms in people with Farber disease. These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition

Signs and symptoms of Farber disease may include 14):

  • 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

Symptoms typically appear in the first few weeks of life. In severe cases, both the liver and spleen are enlarged. Seven types of Farber disease have been described, each with slightly different characteristics. Types 4 and 5 are generally associated with severe neurological problems 15).

Figure 3. Farber’s disease symptoms

Farber's disease symptoms

Footnote: The typical clinical manifestations by organ type that have been reported in cases of Farber’s disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) in the published literature. Farber’s disease symptoms organized by neurological symptoms, ophthalmic symptoms, cardinal triad symptoms, respiratory symptoms, hematopoietic symptoms, gastrointestinal involvement, dermatological manifestations, liver disease, motor neuron and muscle weakness, and bone disease phenotypes

Abbreviations: FD = Farber’s disease; SMA-PME = spinal muscular atrophy with progressive myoclonic epilepsy

[Source 16) ]

Farber disease diagnosis

Farber disease is diagnosed through a clinical history and exam and specialized tests looking for abnormalities in white blood cells. Genetic testing may also be used to confirm the diagnosis 17).

The most common biochemical method in use for a definitive diagnosis of Farber disease is an enzyme activity assay using cultured patient fibroblasts. Enzyme activity in Farber disease cells is typically < 10% of normal controls 18). In addition to fibroblasts, the enzyme activity assay has been tested using leukocytes, plasma, post-mortem tissue, and cultured amniocytes from prenatal testing 19). Conventionally, acid ceramidase (ACDase) activity is determined by the use of either radiolabeled ceramides or fluorescent ceramide analogues. Many of these compounds are not water-soluble and require the use of detergents in addition to specialized technical equipment for analyses 20). This drawback means that diagnosis is available in only a very limited number of laboratories. Currently, acid ceramidase (ACDase) activity can be detected with the use of the fluorogenic substrate Rbm14–12 in a 96-well plate in a high-throughput manner 21).

Another method that has been adopted to assist in the diagnosis of Farber disease is a lipid loading test on cultured living cells. In this technique, exogenously labeled sphingolipids are added to patient cells and ceramide turnover is assessed. A variety of precursors have been used, including [14C] stearic acid–labeled cerebroside sulfate in skin fibroblasts, [3H] sphingomyelin in both patient cultured fibroblasts and transformed lymphocytes, and [14C] serine, a precursor substrate in the de novo ceramide synthesis pathway, to demonstrate impaired ceramide degradation in Farber disease 22).

Quantitation of excess ceramides is another method to assist in the diagnosis. The diacylglycerol kinase assay was commonly used in early studies to measure total ceramides, but it was limited because it did not provide information about individual ceramide species 23). Later, chromatographic methods such as thin-layer chromatography and high-performance liquid chromatography, were also employed to quantify ceramides 24). The major drawbacks to these methods were the requirement for radiolabeling or fluorophore incorporation. These methods were found to be difficult to perform and provided limited information on individual ceramide species. Mass spectrometry, in particular electrospray ionization mass spectrometry, is currently the most sensitive method for the discrimination and detection of sphingolipids 25). These methods have been implemented to demonstrate excess ceramide in biopsy samples of subcutaneous nodules, post-mortem liver samples, urine samples, and cultured cells 26).

Genetic testing

The first few mutations in ASAH1 were identified in patient cultured fibroblasts and required amplification of genomic sequences of ASAH1 and a combination of polymerase chain reaction (PCR) and Sanger sequencing 27). Exome sequencing is now commonly performed and, in conjunction with biochemical assays, provides a conclusive diagnosis of ceramidase deficiency 28).

Farber disease treatment

There is currently no cure for Farber disease. Treatment for Farber disease is focused on managing the symptoms. Anti-inflammatory medications, corticosteroids and physical therapy can help address pain and mobility issues 29). Surgical intervention may occasionally be applied for the removal of nodules in the hands and oral cavity 30). Individuals with difficulty breathing due to swelling and abnormal fat build-up in the upper airway may require a breathing tube (tracheostomy). In some cases, surgery or a bone marrow transplant may be helpful 31). Bone marrow transplant is another therapeutic option and has been demonstrated to substantially improve mobility and pain in a number of Farber disease patients lacking central nervous system involvement 32). Early studies in which bone marrow transplant was performed in two patients with classical Farber disease with central nervous system complications were promising because they showed an elevation in acid ceramidase activity and resolution of voice hoarseness, subcutaneous nodules, and painful joints 33). However, in both cases, bone marrow transplant did not reverse the neurological phenotypes, and the patients deteriorated over time. A recent article has provided long-term follow-up data on 10 Farber disease patients who underwent bone marrow transplant within the last 15 years 34). Eight of the 10 transplanted Farber disease patients in that study are still alive with a mean survival time to date of 10.4 years 35). Inflammatory joint disease was resolved in all the surviving patients, respiratory findings were variable, and the neurological deficits persisted (and even progressed in some of the patients) 36). Despite the scarcity of patient data, bone marrow transplant appears to be a promising treatment for mild and attenuated Farber disease.

Specialists involved in the care of someone with Farber disease may include:

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

Farber disease prognosis

Most children with the classic form of Farber disease die by age 2, usually from lung disease. Children born with the most severe form of the disease usually die within 6 months, while individuals having a milder form of the disease may live into their teenage years or young adulthood.

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