Morbus Farber: eine Ursache der Arthritis im Kindesalter

Zusammenfassung

Morbus Farber ist eine Erkrankung des Sphingolipid-Metabolismus, der seine Ursache in einem Mangel des lysosomalen Enzyms saure Ceramidase hat, woraus eine Unfähigkeit der Zellen entsteht, Ceramide zu zerlegen. Die Erkrankung tritt als Folge der Vererbung von Mutationen auf beiden Allelen des ASAH1-Gens auf, und zeigt sich hauptsächlich mit einem für lysosomale Speichererkrankungen untypischen, entzündlichen Phänotyp. Betroffen sind Gelenke und Bindegewebe. Eine typische Fazies, Dysostose oder wesentliche Organomegalie fehlen. Dies begründet sich in der Tatsache, dass Ceramid ein pro-inflammatorisches und pro-apoptotisches Sphingolipid ist. Diese Eigenschaften sind offensichtlich hauptsächlich verantwortlich für das klinische Erscheinungsbild der Erkrankung, d. h.: Gelenkbeteiligung in Form von Kontrakturen und/oder Arthritis, subkutane Noduli und eine laryngeale Mitbeteiligung in Form einer heiseren oder schwachen Stimme. In den letzten Jahren hat sich jedoch gezeigt, dass Manifestation, Phänotyp und Verlauf des M. Farber eine starke Variabilität aufweisen: von Tod innerhalb weniger Monate nach der Geburt bis zu einem abgeschwächten Verlauf mit Diagnosestellung im jungen Erwachsenenalter. Es ist bemerkenswert, dass manche Patienten mit Morbus Farber auf eine Behandlung mit anti-entzündlichen Medikamenten – insbesondere mit Biologika – gegen TNF-alpha oder Interleukin-6-Rezeptoren, mit einer Schmerzreduktion und einer Verbesserung der Schwere der Arthritis reagiert haben. Es ist daher angebracht, einen Test auf Morbus Farber bei Patienten in Betracht zu ziehen, deren Arthritis nicht adäquat auf eine Behandlung anspricht.

Abstract

Farber disease is a disorder of sphingolipid metabolism, resulting from deficiency in the lysosomal enzyme acid ceramidase and the inability of cells to break down ceramide. The disease occurs when deleterious mutations are inherited in both alleles of the ASAH1 gene. What is unusual for a lysosomal storage disease is that it principally presents with an inflammatory phenotype affecting joints and connective tissue, without typical facies, dysostosis or significant organomegaly. This is because ceramide is a pro-inflammatory and pro-apoptotic sphingolipid, and these properties appear to be primarily responsible for the major clinical features of the disease, which are: joint disease in the form of contractures and/or arthritis with synovitis, subcutaneous nodules, and laryngeal involvement presenting as a hoarse or weak voice. In recent years, it has become clear that the presentation, phenotype, and outcome of the disease is widely variable, ranging from death within months of birth to an attenuated course with normal achievement of physical and intellectual developmental milestones but with progressive arthritis and joint deformation, along with a hoarse voice and subcutaneous nodules. In this context, the current view of the Farber phenotype of acid ceramidase deficiency is rather that of a spectrum reaching from severe disease leading to death in early childhood, to mild disease with patients living well into adulthood. It is important to note that some Farber patients have shown a response to treatment with anti-inflammatory medications, particularly with biologicals, including a reduction in pain and limited decrease in the severity of arthritis. Therefore, it is justified to consider testing for Farber disease in certain patients with arthritis in childhood who have not responded adequately to standard of care treatment.

Schlüsselwörter

Farber - KontrakurenArthritisNoduli - Kindesalter

Key words

Farbercontracture - arthritis - - nodule - children

• Literatur

• 1 Sugita M, Dulaney JT, Moser HW. Ceramidase Deficiency in Farber’s Disease (Lipogranulomatosis). Science 1972; 178: 1100-1102
• 2 Li CM, Park JH, He X et al. The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis and expression. Genomics 1999; 62: 223-231
• 3 Hügle B, Mueller L, Levade T. Why Farber disease may be misdiagnosed as juvenile idiopathic arthritis. The Rheumatologist 2014; 8: 1-35
• 4 Torcoletti M, Petaccia A, Pinto RM et al. Farber disease in infancy resembling juvenile idiopathic arthritis: identification of two new mutations and a good early response to allogeneic haematopoietic stem cell transplantation. Rheumatology (Oxford) 2014; 53: 1533-1534
• 5 Kostik M, Chikova I, Avramenko V et al. Farber lipogranulomatosis with predominant joint involvement mimicking juvenile idiopathic arthritis. J Inherit Metab Dis 2013; 36: 1079-1080
• 6 Sólyom A, Ehlert K, Hügle B et al. Farber disease: First natural history cohort demonstrates a broad clinical spectrum with implications for juvenile idiopathic arthritis patients. Ann Rheum Dis 2015; 74 (Suppl2) 838-839
• 7 Levade T, Sandhoff K, Schultze H et al. Acid ceramidase deficiency: Farber lipogranulomatosis. In: Valle D. (ed.). Scriver’s Online Metabolic and Molecular Basis of Inherited Disease. McGraw Hill; 2009. Im Internet: www.ommbid.com/OMMBID/the_online_metabolic_and_molecular_bases_of_inherited_disease/b/abstract/part16/ch143 (10.10.2015)
• 8 Zeidan YH, Hannun YA. The acid sphingomyelinase/ceramide pathway: biomedical significance and mechanisms of regulation. Curr Mol Med 2010; 10: 454-466
• 9 Schuchman EH, Simonaro CM. The genetics of sphingolipid hydrolases and sphingolipid storage diseases. Handb Exp Pharmacol 2013; 215: 3-32
• 10 Alayoubi AM, Wang JC, Au BC et al. Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol Med 2013; 5: 827-842
• 11 Sana C, Larbi E, Samir A et al. Farber disease in a newborn. Pediatr Dermatol 2009; 26: 44-46
• 12 Fusch C, Huenges R, Moser HW et al. A case combined Farber’s and Sandhoff’s disease. Eur J Pediatr 1989; 148: 558-562
• 13 Schnabel D, Schröder M, Furst W et al. Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. J Biol Chem 1992; 267: 3312-3315
• 14 Beck M, Moser H, Sandhoff K. Acid ceramidase deficiency: Farber lipogranulomatosis and spinal muscular atrophy associated with progressive myoclonic epilepsy. In: Rosenberg R, Pascual J. (ed.). Rosenberg’s Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 5^th ed. London: Elsevier; 2015: 395-400
• 15 Ehlert K, Frosch M, Fehse N et al. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatr Rheumatol Online J 2007; 5: 15
• 16 Mitchell J, Solyom A, Makay B et al. Farber disease: implications of anti-inflammatory treatment. Mol Gen Metab 2016; 117: S81-S82
• 17 Sands M. Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology. EMBO Mol Med 2013; 5: 799-801
• 18 Bonafé L, Kariminejad A, Royer-Bertrand B et al. Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber’s Disease. Arthritis Rheumatol 2016; [in press]
• 19 Beukelmann T, Patkar NM, Saag KG et al. 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features. Arthritis Care Res (Hoboken) 2011; 63: 465-482
• 20 Klingowski U, Beck M, Zepp F. An 18-month-old girl with hoarseness, stiff joints and subcutaneous nodules. Eur J Pediatr 1998; 157: 515-516
• 21 Jarisch A, Steward CG, Sörensen J et al. Odontoid infiltration and spinal compression in Farber disease: reversal by haematopoietic stem cell transplantation. Eur J Pediatr 2014; 173: 1399-1403
• 22 Simonaro CM, Ge Y, Eliyahu E et al. Involvement of the Toll-like receptor 4 pathway and use of TNF-alpha antagonists for treatment of the mucopolysaccharidoses. Proc Natl Acad Sci U S A 2010; 107: 222-227