Biomarker for Farber disease - An international, multicenter, epidemiological protocol


Farber disease, also known as Farber’s lipogranulomatosis, is an autosomal recessive lysosomal storage disease marked by a deficiency in enzyme ceramidase which causes a progressive accumulation of fatty material lipids leading to abnormalities in the joints, liver, throat, tissues, and central nervous system.

Farber disease is an extremely rare disorder, with a prevalence of less than 1/1,000,000. Currently only about 80 cases have been reported worldwide. Disease onset is typically in early infancy but may also
occur later in life.

It is inherited with an autosomal recessive pattern.

New methods, such as mass-spectrometry, provide a good chance for characterizing specific metabolic
alterations in the blood (plasma) of affected patients that in the future will allow us to diagnose the disease earlier, with higher sensitivity and specificity.

Therefore, it is the goal of this study to identify and validate a new biochemical marker from the plasma of affected patients helping to benefit other patients by an early diagnosis and thereby with earlier treatment. Examining saliva samples will allow us to determine whether measurement is
feasible in saliva samples and will further promote early detection of Farber disease.

Study population:

Patients with Farber disease or high-grade suspicion for Farber disease

For more information please find the whole BioFarber outline here.


Partner in this collaborative project is the Albrecht-Kossel-Institute at the Universitaetsmedizin Rostock.


Susanne Zielke
Clinical Research Associate

Phone: +49 (0) 381 494 4739
Mobile: +49 (0) 151 161 439 24
Fax:     +49 (0) 381 494 4798

Background of information

The clinical presentation of Farber disease (FD) is characterized by the appearance of subcutaneous skin nodules, ordinarily near the joints, most often interphalangeal, wrist, elbow and ankle joints, or over points of mechanical pressure. These manifestations are very painful and lead to progressive joint stiffness,
limitation of motion by contractures, and finally to immobilization and deformation of joints. Another
characteristic sign of FD is the development of a progressive hoarseness due to laryngeal involvement.

In addition to these major manifestations, seven phenotypes have been described which differ in severity and additional organ involvement, such as the lungs, nervous system, heart, and lymph nodes. Dependent on residual lysosomal ceramidase turnover, patients have a variable degree of central nervous system
disease, leading to progressive neurologic deterioration. In most cases the neuronal dysfunction rather than the general physical dystrophy seems to limit the duration of FD. As well, patients with FD may die due to pulmonary disease with interstitial pneumonia.

First symptoms usually appear between the newborn period and the first birthday. Milder forms of type 3 were described with onset at 20 months of age. Clinical manifestation in type 5 of FD, dominated by
neurologic deterioration, begins at 1 to 2 1/2 years of life. Patients usually die within the first years of life, but prolonged courses in patients without severe CNS disease may also be observed.

Type 1 is the most common or classical, form of this condition and is associated with the classic signs of voice, skin, and joint problems that begin a few months after birth. Developmental delay and lung disease also commonly occur. Infants born with type 1 Farber lipogranulomatosis usually survive only into early childhood.

Types 2 and 3 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.

Types 4 and 5 are associated with severe neurological problems. Type 4 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 this type typically do not survive past their first year of life. Type 5 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. Children with type 5 Farber lipogranulomatosis survive into early childhood.

Types 6 and 7 are very rare, and affected individuals have other associated disorders in addition to Farber lipogranulomatosis.

Farber lipogranulomatosis is caused by a mutation in the ASAH1 gene, situated on the short arm of
chromosome 8. This gene codes for acid ceramidase, a lysosomal heterodimeric enzyme that hydrolyzes ceramide into sphingosine and fatty acid. To date, less than 25 distinct mutations have been identified in Farber patients, but no large deletions have yet been reported. A total of 13 different mutations were
identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven
mutations were exclusive to the Indian population.

In Farber disease, the mutation in the ASAH1 gene leads to a reduction in acid ceramidase's activity of over 90%. Consequently the ceramide isn’t broken down properly and it gathers in the lysosomes of cell of various tissues, such as lung, liver, colon, skeletal muscles, cartilage, and bone. Certain studies on the
inflammatory symptoms in FD indicates that the granulomatous inflammation is not a consequence of mere ceramide storage but reflects a dysregulation of leukocyte functions, probably due to the intracellular role of ceramide in intracellular signal transduction. However, the sequence of molecular mechanisms leading from a defect in ceramide metabolism to chronic granulomatous inflammation still needs elucidation. Alterations of receptor-mediated apoptosis by ceramide accumulation in inflammatory cells may be one of the
mechanisms underlying abnormal granuloma formation.

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