A disease of degradation: Farber’s Disease
In October 2015, doctors at Peking University First Hospital in China were presented with an exceptional case.1 A girl, just over the age of two, presented with prolonged joint swelling, developmental regress of both motor movement and intelligence, and intermittent seizures.1 While the presenting symptoms appeared distinct from one another, they are all common to a rare genetic disorder called Farber’s disease, with which the patient was diagnosed.1
““An individual affected by Farber’s disease will commonly experience swollen and painful joints, small lumps of fat in the subcutaneous layer, and a hoarse voice.””
Farber’s disease is described as an autosomal recessive, lysosomal storage disorder that typically affects infants.2 An individual affected by Farber’s disease will commonly experience swollen and painful joints, small lumps of fat in the subcutaneous layer, and a hoarse voice.2 Additionally, exposed individuals may have an enlarged liver or spleen, impaired breathing, and various developmental delays.3 The fatal nature of the disease is due to progressive neurological dysfunction, as well as the common development of various pulmonary diseases, which eventually lead to respiratory failure.2
There are seven different phenotypes of Farber’s disease, which are classified based on various characteristics of the disease, and the expected lifespan of the individual affected.3 The resulting signs and symptoms of Farber’s disease are a result of a mutation to a specific gene, N-acylsphingosine amidohydrolase 1 (ASAH1) found in the lysosomes of cells, which are responsible for digesting and recycling various cellular materials.3 The ASAH1 gene codes for an enzyme called acid ceramidase, which degrades ceramides.3 The enzyme-induced breakdown results in two products: sphingosine (a type of fat) and a fatty acid. Both of the products are recycled by the lysosome to produce new ceramides.3 Ceramides are primarily found in cell membranes, where they regulate cell maturation, growth, and division, as well as cell-induced death or apoptosis.4 Additionally, they are an essential component of the fatty protective covering on neurons, known as the myelin sheath.4
Mutations of the ASAH1 gene result in decreased production of acid ceramidase. As an outcome of this, the degradation of ceramides is impacted, and ceramides build up in the lysosomes of cells throughout the body.3 Furthermore, the products of ceramide breakdown cannot be produced. The combination of both of these effects is hypothesized to be the cause of Farber’s disease, although it is unknown whether the particular levels of acid ceramidase activity play a role in determining the severity of the disorder.3
““Treatment for Farber’s disease is not standardized, but rather case-specific.””
Due to the extremely progressive and severe nature of the disease, current treatments focus on symptom management and enhancing an individual’s quality of life, rather than working towards eliminating symptoms completely. Corticosteroids are commonly used to relieve pain associated with inflammation of the joints.5 Some individuals require surgical procedures to restore proper breathing, which is impaired by abnormal tissue growth in the airway. Additionally, some individuals undergo cosmetic surgery to remove nodules and abnormal growths of the facial area.5 Thus, treatment for Farber’s disease is not standardized, but rather case-specific.
The treatment options for Farber’s disease provide a means by which the comfort of the individual can be improved. However, current treatments do not produce outcomes which significantly extend the patient’s prognosis. Depending on the phenotype, an individual with Farber’s disease can have a very different lifespan, ranging from a few months to a few years, and in rare cases, individuals survive into late childhood.3
““The transplantation of hematopoietic stem cells will generate white blood cells, which contain lysosomes that produce acid ceramidase.””
Recently, significant efforts have been made in developing novel treatments for Farber’s disease, which focus on interrupting the pathogenic pathways that produce the disease. One promising treatment is hematopoietic stem cell transplantation, which involves an intravenous (IV) infusion of stem cells, typically sourced from bone marrow of a histocompatible individual (typically a sibling), into the body of the affected individual.6 Hematopoietic stem cells give rise to the body’s blood cells through a process known as hematopoiesis. Bone marrow is a common source for these cells due to its previous use as a source for hydrolase enzymes in other lysosomal storage disorders.6 The transplantation of hematopoietic stem cells will generate white blood cells, which contain lysosomes that produce acid ceramidase. Production of this enzyme will increase its activity in the body, restoring the proper degradation of ceramides, and thus reducing the severity of Farber’s disease.6
““A case study outlining the details of this treatment concluded that the treatment was effective in reducing inflammation and pain in joints, increasing mobility and range of motion, as well as reducing hoarseness of the voice.””
A case study outlining the details of this treatment concluded that the treatment was effective in reducing inflammation and pain in joints, increasing mobility and range of motion, as well as reducing hoarseness of the voice.6 Additionally, the treatment made small improvements to the overall neurological functioning of the individual, though motor improvements were not seen.6 These results show promise with regards to the efficacy of the treatment halting the progression of Farber’s disease in the future.
Another potential novel treatment for this disease is enzyme-replacement therapy. In this technique, human recombinant acid ceramidase (rhAC) are introduced into affected individuals via IV infusion.7 This recombinant protein increases acid ceramidase levels in the body, which regulate fat metabolism and increase the production of ceramidase within lysosomes.7 While no human models have been used to test the therapy, results produced in mouse models have been promising, showing a reduction of ceramides and an increase in sphingosine storage throughout the body.7 Both of these effects contributed to a small survival advantage in this mouse model.7 The results of this study serve as proof that further research into this technique may increase the likelihood of its use in the future of Farber’s disease treatment.
While it is evident that the fight against Farber’s disease is ongoing, research into novel treatment methods shows great promise in the ability to increase the prognosis of the affected individuals. While cases of Farber’s disease may be rare, the impact of this disease on both the individual and their family is substantial. With research into novel treatments presenting promising results, those affected by Farber’s disease can look forward to life past childhood.
Works Cited:
1. Bao X, Chang X, Ji T, Tian J. A case report of childhood Farber’s disease and literature review. Chinese Journal of Pediatrics. 2017;55(1):54-58. doi:10.3760/cma.j.issn.0578-1310.2017.01.011.
2. Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatric Rheumatology. 2007;5(1):15. doi:10.1186/1546-0096-5-15.
3. Farber lipogranulomatosis. Genetics Home Reference. 2017. Available at: https://ghr.nlm.nih.gov/condition/farber-lipogranulomatosis.
4. ASAH1 gene. Genetics Home Reference. 2017. Available at: https://ghr.nlm.nih.gov/condition/farber-lipogranulomatosis.
Farber’s Disease – NORD (National Organization for Rare Disorders). NORD (National Organization for Rare Disorders). 2017. Available at: https://rarediseases.org/rare-diseases/farbers-disease/.
6. Yeager A, Armfield Uhas K, Coles C, Davis P, Krause W, Moser H. Bone marrow transplantation for infantile ceramidase deficiency (Farber disease). Bone Marrow Transplantation. 2000;26(3):357-363. doi:10.1038/sj.bmt.1702489.
7. He X, Dworski S, Zhu C et al. Enzyme replacement therapy for Farber disease: Proof-of-concept studies in cells and mice. BBA Clinical. 2017;7:85-96. doi:10.1016/j.bbacli.2017.02.001.
Cite This Article:
Dephoure S., Chan G., Palczewski K., Lewis K., Ho J. A disease of degradation: Farber’s Disease. Illustrated by H. Zhang. Rare Disease Review. May 2018. DOI:10.13140/RG.2.2.31142.63042.
