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Farber disease: clinical presentation, pathogenesis and a new approach to treatment
Karoline Ehlert1, Michael Frosch, Natalja Fehse
1University Children's Hospital Muenster, Department of Pediatric Hematology and Oncology, Albert-Schweitzer-Strasse 33, D-48149 Muenster, Germany. ehlertk@mednet.uni-muenster.de
Insights
Allogeneic hematopoietic stem cell transplantation (HSCT) offers a promising curative option for Farber Disease patients lacking neurological involvement, effectively resolving granulomas and improving joint mobility.
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Farber Disease is a rare, inherited lysosomal storage disorder caused by acid ceramidase deficiency.
- It presents with diverse clinical phenotypes, including joint deformities and respiratory issues, with neurological involvement often leading to early mortality.
- The inflammatory aspect suggests leukocyte dysregulation, making immune system restoration a potential therapeutic avenue.
Purpose of the Study:
- To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) in Farber Disease patients without neurological involvement.
- To assess the impact of HSCT on physical manifestations and overall well-being in affected individuals.
Main Methods:
- Four Farber Disease patients without neurological symptoms underwent myeloablative, busulfan-based conditioning followed by HSCT.
- Stem cell sources included bone marrow (BM) in three and peripheral blood stem cells (PBSC) in one patient.
- Graft-versus-host disease (GvHD) prophylaxis involved cyclosporine (CsA) and a short course of methotrexate (MTX).
Main Results:
- HSCT led to near-complete resolution of granulomas and joint contractures in all patients.
- Significant improvements in mobility and joint motility were observed.
- Patients are alive and well, exhibiting stable donor cell chimerism without chronic GvHD or transplantation-related late sequelae.
Conclusions:
- Allogeneic HSCT is a viable and effective treatment for Farber Disease in patients without neurological compromise.
- The procedure demonstrates significant therapeutic benefits, including symptom resolution and improved quality of life.
- HSCT offers a potentially curative approach, restoring immune function and mitigating disease progression.
Background:
Farber Disease is an autosomal-recessively inherited, lysosomal storage disorder caused by acid ceramidase deficiency and associated with distinct clinical phenotypes. 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 live. As the inflammatory component of this disorder is caused by some kind of leukocyte dysregulation, allogeneic hematopoietic stem cell transplantation can restore a healthy immune system and thus may provide a curative option in Farber Disease patients without neurological involvement. Previous stem cell transplantations in two children with severe neurological involvement had resulted in a disappointing outcome, as both patients died of progressive deterioration of their neurological status. As a consequence, stem cell transplantation does not appear to be able to abolish or even reduce the neurotoxic effects of the abundant ceramide storage in the brain.
Methods:
After myeloablative, busulfan-based preparative regimens, four Farber Disease patients without neurological involvement received an allogeneic hematopoietic stem cell transplantation from related and unrelated donors. Stem cell source was BM in three patients and PBSC in one patient; GvHD-prophylaxis consisted of CsA and short course MTX.
Results And Discussion:
In all patients, HSCT resulted in almost complete resolution of granulomas and joint contractures, considerable improvement of mobility and joint motility without relevant therapy-related morbidities. All patients are alive and well at this point with stabile donor cell chimerism and without evidence of chronic GvHD or other late sequelae of stem cell transplantation.
Conclusion:
Allogeneic hematopoietic stem cell transplantation provides a promising approach for Farber Disease patients without neurological involvement.
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