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Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Bone Marrow Transplantation volume 26, pages 357–363 (2000)Cite this article

Abstract

Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT improves the peripheral manifestations of infantile ceramidase deficiency, but may not prevent the progressive neurological deterioration, even when carried out in minimally symptomatic patients. Bone Marrow Transplantation (2000) 26, 357–363.

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References

  1. Sugita M, Dulaney J, Moser HW . Ceramidase deficiency in Farber's disease (lipogranulomatosis) Science 1972 178: 1100–1102

    Article  CAS  PubMed  Google Scholar 

  2. Moser HW . Farber disease (lipogranulomatosis). In: Moser HW (ed) Handbook of Clinical Neurology, vol 22 (66): Neurodystrophies and Neurolipidoses Elsevier Science: Amsterdam 1996 pp211–223

    Google Scholar 

  3. Bernardo K, Hurwitz R, Zenk T et al. Purification, characterization, and biosynthesis of human acid ceramidase J Biol Chem 1995 270: 11098–11102

    Article  CAS  PubMed  Google Scholar 

  4. Koch J, Gartner S, Li CM et al. Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification of the first molecular lesion causing Farber disease J Biol Chem 1996 271: 33110–33115

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. Farber S . A lipid metabolic disorder – disseminated ‘lipogranulomatosis’. A syndrome with similarity to and important differences from Niemann–Pick and Hand–Schüller-Christian disease Am J Dis Child 1952 84: 499–500 (Abstr.)

    CAS  Google Scholar 

  7. Farber S, Cohen J, Uzman LL . Lipogranulomatosis. A new lipoglycoprotein storage disease J Mt Sinai Hosp 1957 24: 816–837

    CAS  Google Scholar 

  8. Yeager AM . Hematopoietic cell transplantation in storage diseases. In: Blume K, Forman SJ, Thomas ED (eds) Hematopoietic Cell Transplantation, edn2 Blackwell Science: Malden, MA 1999 pp1182–1191

    Google Scholar 

  9. Souillet G, Guiband P, Fensom AH et al. Outcome of displacement bone marrow transplantation in Farber's disease: a report of a case. In: Hobbs JR (ed) Correction of Certain Genetic Diseases by Transplantation COGENT: London 1989 pp137–141

    Google Scholar 

  10. Yeager AM, Wagner JE Jr, Graham ML et al. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation Blood 1992 80: 2425–2428

    CAS  PubMed  Google Scholar 

  11. Scharf SJ, Smith AG, Hansen JA et al. Quantitative determination of bone marrow transplant engraftment using fluorescent polymerase chain reaction primers for human identity markers Blood 1995 85: 1954–1963

    CAS  PubMed  Google Scholar 

  12. Chen TL, Grochow LB, Hurowitz LA, Brundrett RB . Determination of busulfan in human plasma by gas chromatography with electron-capture detection J Chromatogr Biomed Appl 1988 425: 303–309

    Article  CAS  Google Scholar 

  13. Grochow LB, Krivit W, Whitley CB, Blazar B . Busulfan disposition in children Blood 1990 75: 1723–1727

    CAS  PubMed  Google Scholar 

  14. Momoi T, Ben-Yoseph Y, Nadler HL . Substrate-specificities of acid and alkaline ceramidases in fibroblasts from patients with Farber disease and controls Biochem J 1982 205: 419–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bayley N . Bayley Scales of Infant Development, edn1 Psychological Corporation: New York 1969

    Google Scholar 

  16. Bayley N . Bayley Scales of Infant Development, edn2 Psychological Corporation Harcourt Brace and Company: San Antonio, TX 1993

    Google Scholar 

  17. Sparrow SS, Balla DA, Cicchetti DV . Vineland Adaptive Behavior Scales, Interview Edition (A Revision of the Vineland Social Maturity Scale by Edgar A. Doll) American Guidance Service: Circle Pines, MN 1984

    Google Scholar 

  18. Hamill PVV, Drizd TA, Johnson CL et al. Physical growth: National Center for Health Statistics percentiles Am J Clin Nutr 1979 32: 607–629

    Article  CAS  PubMed  Google Scholar 

  19. Blazar BR, Ramsay NK, Kersey JH et al. Pretransplant conditioning with busulfan (Myleran) and cyclophosphamide for nonmalignant diseases. Assessment of engraftment following histocompatible allogeneic bone marrow transplantation Transplantation 1985 39: 597–603

    Article  CAS  PubMed  Google Scholar 

  20. Hobbs JR, Hugh-Jones K, Shaw PJ et al. Engraftment rates related to busulfan and cyclophosphamide dosages for displacement bone marrow transplants in fifty children Bone Marrow Transplant 1986 1: 201–208

    CAS  PubMed  Google Scholar 

  21. Martin PJ . Overview of marrow transplantation immunology. In: Thomas ED, Blume KG, Forman SJ (eds) Hematopoietic Cell Transplantation, 2nd edn Blackwell Science: Malden, MA 1999 pp19–27

    Google Scholar 

  22. Gale RP, Sparkes RS, Golde DW . Bone marrow origin of hepatic macrophages (Kupffer cells) in humans Science 1978 201: 937–938

    Article  CAS  PubMed  Google Scholar 

  23. Thomas ED, Ramberg RE, Sale GE et al. Direct evidence for a bone marrow origin of the alveolar macrophage in man Science 1976 192: 1016–1018

    Article  CAS  PubMed  Google Scholar 

  24. Bou-Gharios G, Abraham D, Olsen I . Lysosomal storage diseases: mechanisms of enzyme replacement therapy Histochem J 1993 25: 593–605

    Article  CAS  PubMed  Google Scholar 

  25. Perry VH, Gordon S . Macrophages and the nervous system Int Rev Cytol 1991 125: 203–244

    Article  CAS  PubMed  Google Scholar 

  26. Krivit W, Sung JH, Shapiro EG, Lockman LA . Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases Cell Transplant 1995 4: 385–392

    Article  CAS  PubMed  Google Scholar 

  27. Hickey WF, Kimura H . Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo Science 1988 239: 290–292

    Article  CAS  PubMed  Google Scholar 

  28. Kennedy DW, Abkowitz JL . Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model Blood 1997 90: 986–993

    CAS  PubMed  Google Scholar 

  29. Krall WJ, Challita PM, Perlmutter LS et al. Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation Blood 1994 83: 2737–2748

    CAS  PubMed  Google Scholar 

  30. Yeager AM, Shinn C, Hart C, Pardoll DM . Repopulation by donor-derived macrophages in the murine central nervous system (CNS) after congenic bone marrow transplantation (BMT): a quantitative study Blood 1992 80: (Suppl.1) 269a (Abstr.)

    Google Scholar 

  31. Walkley SU, Thrall MA, Dobrenis K et al. Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease Proc Natl Acad Sci USA 1994 91: 2970–2974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Krivit W, Shapiro EG, Lockman LA et al. Bone marrow transplantation treatment for globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, and Hurler's syndrome. In: Moser HW (ed) Handbook of Clinical Neurology, Vol22 (66): Neurodystrophies and Neurolipidoses Elsevier Science: Amsterdam 1996 pp87–106

    Google Scholar 

  33. Krivit W, Shapiro EG, Peters C et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy New Engl J Med 1998 338: 1119–1126

    Article  CAS  PubMed  Google Scholar 

  34. Pridjian G, Humbert J, Willis J, Shapira E . Presymptomatic late-infantile metachromatic leukodystrophy treated with bone marrow transplantation J Pediatr 1994 125: 755–758

    Article  CAS  PubMed  Google Scholar 

  35. Zetterström R . Disseminated lipogranulomatosis (Farber's disease) Acta Paediatrica (Scand) 1958 47: 501–510

    Article  Google Scholar 

  36. Samuelsson K, Zetterström R . Ceramides in a patient with lipogranulomatosis (Farber's disease) with chronic course Scand J Clin Lab Invest 1971 27: 393–400

    Article  CAS  PubMed  Google Scholar 

  37. Fiumara A, Nigro F, Pavone L, Moser HW . Farber disease with prolonged survival J Inher Metab Dis 1993 16: 915–916

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Donald Hutcherson for assistance with determination of busulfan pharmacokinetics, and the nurses at the AFLAC Cancer Center of Children's Healthcare of Atlanta at Egleston and at Scottish Rite for their expert and compassionate care of the patient. This work was supported in part by grant Nos R01 NS24097 and U10 CA20549 from the National Institutes of Health, Bethesda, Maryland, and by the Phil Niekro Beat Leukemia Celebrity Classic/Jill Andrews Leukemia Research Fund, the Andrew McLeroy Memorial Research Fund, the Stott Research Fund, and the Emory-Egleston Children's Research Center.

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Authors and Affiliations

  1. Departments of Medicine and Pediatrics and Winship Cancer Institute, Stem Cell Transplant Program, Emory University School of Medicine, Atlanta, GA, USA

    AM Yeager

  2. Department of Genetics, Children's Healthcare of Atlanta at Scottish Rite, Atlanta, GA, USA

    K Armfield Uhas & WL Krause

  3. Department of Psychiatry and Behavioral Sciences, and Marcus Institute (a Division of the Kennedy Krieger Institute), Emory University School of Medicine, Atlanta, GA, USA

    CD Coles

  4. Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA

    PC Davis

  5. Kennedy Krieger Institute, Baltimore, MD, USA

    HW Moser

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Yeager, A., Armfield Uhas, K., Coles, C. et al. Bone marrow transplantation for infantile ceramidase deficiency (Farber disease). Bone Marrow Transplant 26, 357–363 (2000). https://doi.org/10.1038/sj.bmt.1702489

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