Farber disease (ORPHA:333)
A subcutaneous tissue disease characterized by a spectrum of clinical signs ranging from the classical triad of painful and progressively deformed joints, subcutaneous nodules, and progressive hoarseness (due to laryngeal involvement) that presents in infancy, to varying phenotypes with respiratory and neurologic involvement.
Epidemiology
Approximately 200 cases of Farber disease have been reported worldwide in the literature to date.
Clinical description
A high clinical variability is seen between patients. The classic phenotype presents at around 3-6 months of age with painful, swollen and stiff joints of the hands and feet, prominent subcutaneous nodules over pressure points, and progressive hoarseness leading to aphonia due to vocal cord infiltration. Patients can also develop cardiac, pulmonary and neurological defects. Progressive neurological deterioration can be marked in some forms with seizures, paraparesis and developmental delay. The most severe neonatal form presents at birth with hydrops fetalis, lethargy, and failure to thrive, as well as hepatosplenomegaly, rapid neurological deterioration, and granulomatous infiltrations to various other organs (i.e. liver, spleen, lungs). Milder forms have also been described with no neurological defects and a longer life-expectancy. In some patients, the disease manifests in childhood as a spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME) in the absence of subcutaneous nodules.
Etiology
Farber disease is caused by mutations in the N-acylsphingosine amidohydrolase (ASAH1) gene (8p22) which encodes acid ceramidase, a lysosomal enzyme that hydrolyzes ceramide into sphingosine and free fatty acid. A deficient activity of this enzyme leads to an accumulation of ceramide in most tissues.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings by assaying the activity of acid ceramidase in peripheral blood leukocytes, cultured lymphoid cells or cultured skin fibroblasts. Alternatively, diagnosis can be performed by determining ceramide concentration in cultured cells or tissues or by studying lysosomal ceramide catabolism in cultured living cells. Identification of mutations in the ASAH1 gene by molecular genetic testing usually allows for diagnostic confirmation.
Differential diagnosis
Differential diagnoses include juvenile idiopathic arthritis, stiff skin syndrome and lethal restrictive dermopathy. Encephalopathy due to prosaposin deficiency should also be excluded.
Antenatal diagnosis
Prenatal diagnosis by DNA testing is possible in families with a known disease-causing mutation. Alternatively, prenatal diagnosis can be performed by measuring acid ceramidase activity in cultured amniotic fluid cells or chorionic villi.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be proposed to affected families informing them of a 25% risk of transmitting the disease where both parents are unaffected carriers.
Management and treatment
There is currently no effective specific therapy for Farber disease, and symptomatic treatment is based on analgesics, corticotherapy, and plastic surgery. However, allogeneic hematopoietic stem cell transplantation provides a promising approach for patients with limited neurological involvement.
Prognosis
The prognosis varies, with some patients dying within the first few days of life (severe neonatal form) and others living until adolescence or early adulthood (milder forms).

                            Last update: 
                            April 2019


                            - Expert reviewer(s): 
                            Pr Thierry LEVADE