Morbidity and mortality associated with Farber disease and prospects for therapy

ABSTRACT

Introduction: Farber disease is the lysosomal storage disorder due to the deficiency of acid ceramidase activity. Although it was described over six decades ago, it remains poorly described due to its unusual clinical presentation and rarity. No targeted therapies currently exist.

Areas covered: The history of Farber disease, acid ceramidase and research leading to the development of therapy will be summarized, along with current knowledge regarding the clinical presentation and patient management.

Expert opinion: Farber disease is often misdiagnosed as idiopathic juvenile arthritis. The clinical presentation is broad, with onset and survival ranging from early childhood to adults. Multiple organ systems, including the central nervous system, may be involved, but the most consistent finding in all patients is subcutaneous nodules that form mostly around joints. The nodules consist of lipid-filled macrophages, and inflammation is a major driver of the pathobiology. Pain, dysphonia and limitation of movement are common associated findings in patients. Current management is symptomatic aiming to reduce pain and inflammation. Hematopoietic stem cell transplantation has been undertaken in several patients, and may have positive effects on the non-neurological findings. Studies in Farber disease mice have also revealed the potential of enzyme replacement therapy, and first-in-man clinical trials are currently being planned.

KEYWORDS:

• Ceramide
• arthritis
• inflammation

Article highlights

• Farber disease is frequently misdiagnosed and likely to be under-diagnosed due to its unusual presentation resembling juvenile idiopathic arthritis.

• Age at onset of particular symptoms, and lifespan, range from early childhood through later adulthood.

• Subcutaneous joint nodules (lipogranulomas) are the most consistent findings in all patients, though their number, clinical impact and overall severity may vary greatly.

• Pathobiology is principally due to inflammation secondary to ceramide storage.

• Current patient management focuses on symptom control, including that of pain and inflammation.

• Hematopoietic stem cell transplantation has been undertaken in some patients and improves non-neurological features when the transplant itself has been successful.

• Enzyme replacement therapy using recombinant acid ceramidase is currently being developed

This box summarizes key points contained in the article.

Declaration of interest

EH Schuchman is an employee of the Icahn School of Medicine at Mount Sinai. He is also consultant for Enzyvant Sciences, a company developing ERT for Farber Disease. He is also an inventor on patents licenced to Enzyvant, and is a minority shareholder in the company. He also receives a research grant from them. A Solyom is an employee of Enzyvant Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by U.S. Department of Health and Human Services, National Institutes of Health, R01 DK54830