Farber disease, also known as Farber’s lipogranulomatosis, is an autosomal recessive lysosomal storage disease marked by a deficiency in enzyme ceramidase which cause a progressive accumulation of fatty material lipids leading to abnormalities in the joints, liver, throat, tissues and central nervous system.
EPIDEMIOLOGY
Farber disease is an extremely rare disorder, with a prevalence of less than 1/1000000. Currently only about 80 cases are reported worldwide. Disease onset is typically in early infancy but may occur later in life.
It is inherited with a autosomal recessive pattern.
epidemiology of FD
HISTORICAL NOTES
This disorder was first described in 1957 by Dr. Sidney Farber, an American pediatric pathologist, in the Journal of the Mount Sinai Hospital, as “a possible bridge between what had appeared to be 2 etiologically unrelated groups of disorders, namely the 'true' (genetically determined) metabolic disorders such as Niemann-Pick disease and the (nongenetic) inflammatory histiocytoses such as Letterer-Siwe disease”.
The "true" genetic component was represented by neuronal storage material that was thought to contain lipids, carbohydrates, and protein, whereas the inflammatory component, resembling histiocytosis-x, was evidenced by granulomatous inflammatory lesions in skin, joints, and larynx. Subsequent studies have shown, however, that a genetically determined abnormality accounts for all of the features of Farber lipogranulomatosis.
historical notes on FD
SYMPTOMS
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. Also, a characteristic sign of FD is the development of a progressive hoarseness due to laryngeal involvement.
Beside these major manifestations seven phenotypes have been described which differ in severity and additional organ involvement, like 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 mainly die within the first years of life, but prolonged courses in patients without severe CNS disease may also be observed.
First description of Farber Disease
Phenotypes of Farber Disease
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.
PATHOGENESIS
Faber 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.
ASAH1 mutations causing Farber lipogranulomatosis
acid ceramidase deficiency in a neonatal form of Farber disease
In Farber's Disease, the mutation in ASAH1 gene lead to a reduction in acid ceramidase's activity of over 90%. Consequently the ceramide istn’t properly broken down and it gather 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.
Systemic ceramide accumulation leads to severe and varied pathological consequences
Ceramides is mostly found within the cell membrane, taking part in the composition of sphingomyelin, one of the major lipids in the lipid bilayer. In addiction of being a structural element of the bilayer, ceramide also have a signalling function and can participate in the regulation of the differentiantion, proliferation and programmed cell death of the cells (apoptosis). Ceramides are generated within rafts by the action of acid sphingomyelinase, causing small rafts to merge into larger units and modifying the membrane structure in a manner that is believed to permit oligomerization of specific proteins. Through the medium of these modified rafts, they are able to function in signal transduction. Specific receptor molecules and signalling proteins cluster within such domains, thereby excluding potential inhibitory signals, while initiating and greatly amplifying primary signals. It is believed that ceramide-rich platforms amplify both receptor- and stress-mediated signalling events and thence may influence various disease states. They may also provide an entry route into cells for viral and bacterial pathogens.
Due to his role in the regulation of apoptosis, ceramides have been implicated in the actions of tumor necrosis factor-α and in the cytotoxic responses to amyloid Aβ peptide, which are involved in Alzheimer’s disease and neuro-degeneration. addition, ceramides appear to be involved in many aspects of the biology of aging and of male and female fertility. These effects may hold implications for diseases associated with obesity, including diabetes and cardiovascular disease.
dissecting ceramide biology
DIAGNOSIS
The diagnosis is possible thanks to test to determine acid ceramidase activity, usually less than 6% of control values, measured in cultured skin fibroblasts, white blood cells or amniocytes. And as a major symptom FD patients exhibit chronic destructive joint inflammation resembling rheumatoid arthritis.
Children who have the classic form of Farber's disease develop symptoms within the first few weeks of life. It is characterized by a clinical triad including painful joint deformity, subcutaneous nodules, and hoarseness. Subcutaneous nodules appear especially near the joints and on pressure points. Rarely, these nodules are reported in other sites including the conjunctivae, nostrils, ears, and oral cavity. Most infants have problems about feeding and respiratory system. The central nervous system is variably affected, leading to a severe progressive impairment of psychomotor development and neurologic deterioration with epilepsy. Children with significant neurological involvement usually die early in infancy, whereas patients without or only mild neurological findings suffer from progressive joint deformation and contractures, subcutaneous nodules, inflammatory, periarticular granulomas, a hoarse voice, and finally respiratory insufficiency caused by granuloma formation in the respiratory tract and interstitial pneumonitis leading to death in the third or fourth decade of the life.
clinical diagnosis
THERAPY
Currently there is no specific therapy, and symptomatic treatment is based on antalgics, corticotherapy, and plastic surgery.
Since the symptoms of metabolic disorders are usually caused by the lack of enzymatic activity it is largely thought that the trasplantation of hematopoetic stem cells from a healthy donor can be a source of a sufficient amount of enzyme and thus abolish or at least decrease or stabilize symptoms of disease in some patients. The data is still lacking, but HSCT may be a good therapeutic approach for patients whose central nervous system is not involved.
new approach to treatment
FD therapy
