Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.

Department of Pediatrics Medical College of Wisconsin Milwaukee WI 53226 USA

Department of Pediatrics Medical College of Wisconsin Milwaukee WI 53226 USA; Department of Biochemistry Medical College of Wisconsin Milwaukee WI 53226 USA

Research Unit for Rare Diseases Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Zobrazit více v PubMed

Yu F.P.S., Amintas S., Levade T., Medin J.A. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J. Rare Dis. 2018;13:121. doi: 10.1186/s13023-018-0845-z. PubMed DOI PMC

Antonarakis S.E., Valle D., Moser H.W., Moser A., Qualman S.J., Zinkham W.H. Phenotypic variability in siblings with Farber disease. J. Pediatr. 1984;104:406–409. doi: 10.1016/s0022-3476(84)81106-3. PubMed DOI

Ehlert K., Frosch M., Fehse N., Zander A., Roth J., Vormoor J. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatr. Rheumatol. Online J. 2007;5:15. doi: 10.1186/1546-0096-5-15. PubMed DOI PMC

Najafi A., Tasharrofi B., Zandsalimi F., Rasulinezhad M., Ghahvechi Akbari M., Zamani G., Ashrafi M.R., Heidari M. Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME): three new cases and review of the mutational spectrum. Ital. J. Pediatr. 2023;49:64. doi: 10.1186/s13052-023-01474-z. PubMed DOI PMC

Kleynerman A., Rybova J., Faber M.L., McKillop W.M., Levade T., Medin J.A. Acid Ceramidase Deficiency: Bridging Gaps between Clinical Presentation, Mouse Models, and Future Therapeutic Interventions. Biomolecules. 2023;13:274. doi: 10.3390/biom13020274. PubMed DOI PMC

Dyment D.A., Sell E., Vanstone M.R., Smith A.C., Garandeau D., Garcia V., Carpentier S., Le Trionnaire E., Sabourdy F., Beaulieu C.L., et al. Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy. Clin. Genet. 2014;86:558–563. doi: 10.1111/cge.12307. PubMed DOI

Lee M.M., McDowell G.S.V., De Vivo D.C., Friedman D., Berkovic S.F., Spanou M., Dinopoulos A., Grand K., Sanchez-Lara P.A., Allen-Sharpley M., et al. The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile. Ann. Clin. Transl. Neurol. 2022;9:1941–1952. doi: 10.1002/acn3.51687. PubMed DOI PMC

Zhou H., Wu Z., Wang Y., Wu Q., Hu M., Ma S., Zhou M., Sun Y., Yu B., Ye J., et al. Rare Diseases in Glycosphingolipid Metabolism. Adv. Exp. Med. Biol. 2022;1372:189–213. doi: 10.1007/978-981-19-0394-6_13. PubMed DOI

Rossini L., Durante C., Marzollo A., Biffi A. New Indications for Hematopoietic Stem Cell Gene Therapy in Lysosomal Storage Disorders. Front. Oncol. 2022;12 doi: 10.3389/fonc.2022.885639. PubMed DOI PMC

Thomas E.D., Lochte H.L., Jr., Lu W.C., Ferrebee J.W. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 1957;257:491–496. doi: 10.1056/NEJM195709122571102. PubMed DOI

Lund T.C. Hematopoietic Stem Cell Transplant for Lysosomal Storage Diseases. Pediatr. Endocr. Rev. P. 2013;11:91–98. PubMed

Bigger B.W., Wynn R.F. Novel Approaches and Mechanisms in Hematopoietic Stem Cell Gene Therapy. Discov. Med. 2014;17:207–215. PubMed

Tan E.Y., Boelens J.J., Jones S.A., Wynn R.F. Hematopoietic Stem Cell Transplantation in Inborn Errors of Metabolism. Front. Pediatr. 2019;7:433. doi: 10.3389/fped.2019.00433. PubMed DOI PMC

Tomatsu S., Taylor M., Khan S. Hematopoietic stem cell transplantation for mucopolysaccharidoses past, present, and future. Mol. Genet. Metab. 2019;126:S145. doi: 10.1016/j.ymgme.2018.12.375. PubMed DOI PMC

Ehlert K., Roth J., Frosch M., Fehse N., Zander N., Vormoor J. Farber's disease without central nervous system involvement: bone-marrow transplantation provides a promising new approach. Ann. Rheum. Dis. 2006;65:1665–1666. doi: 10.1136/ard.2005.048322. PubMed DOI PMC

Broomfield A.A., Chakrapani A., Wraith J.E. The effects of early and late bone marrow transplantation in siblings with alpha-mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option? J. Inherit. Metab. Dis. 2010;33:S123–S127. doi: 10.1007/s10545-009-9035-4. PubMed DOI

Escolar M.L., Poe M.D., Provenzale J.M., Richards K.C., Allison J., Wood S., Wenger D.A., Pietryga D., Wall D., Champagne M., et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N. Engl. J. Med. 2005;352:2069–2081. doi: 10.1056/NEJMoa042604. PubMed DOI

Goudie C., Alayoubi A.M., Tibout P., Duval M., Maranda B., Mitchell D., Mitchell J.J. Hematopoietic stem cell transplant does not prevent neurological deterioration in infants with Farber disease: Case report and literature review. JIMD Rep. 2019;46:46–51. doi: 10.1002/jmd2.12008. PubMed DOI PMC

Sikora J., Dworski S., Jones E.E., Kamani M.A., Micsenyi M.C., Sawada T., Le Faouder P., Bertrand-Michel J., Dupuy A., Dunn C.K., et al. Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities. Am. J. Pathol. 2017;187:864–883. doi: 10.1016/j.ajpath.2016.12.005. PubMed DOI PMC

Yu F.P.S., Sajdak B.S., Sikora J., Salmon A.E., Nagree M.S., Gurka J., Kassem I.S., Lipinski D.M., Carroll J., Medin J.A. Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment. Am. J. Pathol. 2019;189:320–338. doi: 10.1016/j.ajpath.2018.10.018. PubMed DOI PMC

Yu F.P.S., Islam D., Sikora J., Dworski S., Gurka J., López-Vásquez L., Liu M., Kuebler W.M., Levade T., Zhang H., Medin J.A. Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency. Am. J. Physiol. Lung Cell. Mol. Physiol. 2018;314:L406–L420. doi: 10.1152/ajplung.00223.2017. PubMed DOI PMC

Dworski S., Berger A., Furlonger C., Moreau J.M., Yoshimitsu M., Trentadue J., Au B.C.Y., Paige C.J., Medin J.A. Markedly perturbed hematopoiesis in acid ceramidase deficient mice. Haematologica. 2015;100:e162–e165. doi: 10.3324/haematol.2014.108530. PubMed DOI PMC

Rybova J., Kuchar L., Sikora J., McKillop W.M., Medin J.A. Skin inflammation and impaired adipogenesis in a mouse model of acid ceramidase deficiency. J. Inherit. Metab. Dis. 2022;45:1175–1190. doi: 10.1002/jimd.12552. PubMed DOI PMC

Yu F.P.S., Molino S., Sikora J., Rasmussen S., Rybova J., Tate E., Geurts A.M., Turner P.V., McKillop W.M., Medin J.A. Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency. Lab. Invest. 2019;99:1572–1592. doi: 10.1038/s41374-019-0271-4. PubMed DOI

Alayoubi A.M., Wang J.C.M., Au B.C.Y., Carpentier S., Garcia V., Dworski S., El-Ghamrasni S., Kirouac K.N., Exertier M.J., Xiong Z.J., et al. Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol. Med. 2013;5:827–842. doi: 10.1002/emmm.201202301. PubMed DOI PMC

Nagree M.S., Rybova J., Kleynerman A., Ahrenhoerster C.J., Saville J.T., Xu T., Bachochin M., McKillop W.M., Lawlor M.W., Pshezhetsky A.V., et al. Spinal muscular atrophy-like phenotype in a mouse model of acid ceramidase deficiency. Commun. Biol. 2023;6:560. doi: 10.1038/s42003-023-04932-w. PubMed DOI PMC

Dworski S., Lu P., Khan A., Maranda B., Mitchell J.J., Parini R., Di Rocco M., Hugle B., Yoshimitsu M., Magnusson B., et al. Acid Ceramidase Deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy. BBA - Mol. Basis Dis. 2017;1863:386–394. doi: 10.1016/j.bbadis.2016.11.031. PubMed DOI PMC

Beckmann N., Kadow S., Schumacher F., Göthert J.R., Kesper S., Draeger A., Schulz-Schaeffer W.J., Wang J., Becker J.U., Kramer M., et al. Pathological manifestations of Farber disease in a new mouse model. Biol. Chem. 2018;399:1183–1202. doi: 10.1515/hsz-2018-0170. PubMed DOI

Cappellari A.M., Torcoletti M., Triulzi F., Corona F. Nervous system involvement in Farber disease. J. Inherit. Metab. Dis. 2016;39:149–150. doi: 10.1007/s10545-015-9890-0. PubMed DOI

Zielonka M., Garbade S.F., Kölker S., Hoffmann G.F., Ries M. A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features. Genet. Med. 2018;20:524–530. doi: 10.1038/gim.2017.133. PubMed DOI

Wu N.L., Hingorani S., Cushing-Haugen K.L., Lee S.J., Chow E.J. Late Kidney Morbidity and Mortality in Hematopoietic Cell Transplant Survivors. Transpl. Cell. Ther. 2021;27:434.e1–434.e6. doi: 10.1016/j.jtct.2021.02.013. PubMed DOI PMC

Hingorani S., Guthrie K.A., Schoch G., Weiss N.S., McDonald G.B. Chronic kidney disease in long-term survivors of hematopoietic cell transplant. Bone Marrow Transpl. 2007;39:223–229. doi: 10.1038/sj.bmt.1705573. PubMed DOI

Wynn R.F., Wraith J.E., Mercer J., O'Meara A., Tylee K., Thornley M., Church H.J., Bigger B.W. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J. Pediatr. 2009;154:609–611. doi: 10.1016/j.jpeds.2008.11.005. PubMed DOI

Torcoletti M., Petaccia A., Pinto R.M., Hladnik U., Locatelli F., Agostoni C., Corona F. 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. doi: 10.1093/rheumatology/keu010. PubMed DOI

Zappatini-Tommasi L., Dumontel C., Guibaud P., Girod C. Farber disease: an ultrastructural study. Report of a case and review of the literature. Virchows Arch. A. Pathol. Anat. Histopathol. 1992;420:281–290. doi: 10.1007/BF01600282. PubMed DOI

Singh S., Anshita D., Ravichandiran V. MCP-1: Function, regulation, and involvement in disease. Int. Immunopharmacol. 2021;101 doi: 10.1016/j.intimp.2021.107598. PubMed DOI PMC

Solomon M., Muro S. Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives. Adv. Drug Deliv. Rev. 2017;118:109–134. doi: 10.1016/j.addr.2017.05.004. PubMed DOI PMC

Fratantoni J.C., Neufeld E.F., Uhlendorf B.W., Jacobson C.B. Intrauterine diagnosis of the hurler and hunter syndromes. N. Engl. J. Med. 1969;280:686–688. doi: 10.1056/NEJM196903272801303. PubMed DOI

Edelmann M.J., Maegawa G.H.B. CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges. Front. Mol. Biosci. 2020;7 doi: 10.3389/fmolb.2020.559804. PubMed DOI PMC

Schuchman E.H., He X., Dworski S., Zhu C., DeAngelis V., Solyom A., Levade T., Medin J.A., Simonaro C.M. Proof-of-concept studies underlying enzyme replacement therapy for acid ceramidase deficiency. Mol. Genet. Metab. 2017;120:S120. doi: 10.1016/j.ymgme.2016.11.310. DOI

Mitchell J., Solyom A., Makay B., Arslan N., Batu E.D., Ozen S., Hügle B., Schuchman E., Magnusson B. Farber disease: Implications of anti-inflammatory treatment. Mol. Genet. Metab. 2016;117:S81–S82. doi: 10.1016/j.ymgme.2015.12.364. DOI

Vormoor J., Ehlert K., Groll A.H., Koch H.G., Frosch M., Roth J. Successful hematopoietic stem cell transplantation in Farber disease. J. Pediatr. 2004;144:132–134. doi: 10.1016/j.jpeds.2003.09.051. PubMed DOI

Lee M.M., McDowell G.S.V., De Vivo D.C., Friedman D., Berkovic S.F., Spanou M., Dinopoulos A., Grand K., Sanchez-Lara P.A., Allen-Sharpley M., et al. The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile. Ann. Clin. Transl. Neurol. 2022;9:1941–1952. doi: 10.1002/acn3.51687. PubMed DOI PMC

Mohseni R., Hamidieh A.A., Shoae-Hassani A., Ghahvechi-Akbari M., Majma A., Mohammadi M., Nikougoftar M., Shervin-Badv R., Ai J., Montazerlotfelahi H., Ashrafi M.R. An open-label phase 1 clinical trial of the allogeneic side population adipose-derived mesenchymal stem cells in SMA type 1 patients. Neurol. Sci. 2022;43:399–410. doi: 10.1007/s10072-021-05291-2. PubMed DOI

Cabanes C., Bonilla S., Tabares L., Martínez S. Neuroprotective effect of adult hematopoietic stem cells in a mouse model of motoneuron degeneration. Neurobiol. Dis. 2007;26:408–418. doi: 10.1016/j.nbd.2007.01.008. PubMed DOI

Li G., Kidd J., Kaspar C., Dempsey S., Bhat O.M., Camus S., Ritter J.K., Gehr T.W.B., Gulbins E., Li P.L. Podocytopathy and Nephrotic Syndrome in Mice with Podocyte-Specific Deletion of the Asah1 Gene: Role of Ceramide Accumulation in Glomeruli. Am. J. Pathol. 2020;190:1211–1223. doi: 10.1016/j.ajpath.2020.02.008. PubMed DOI PMC

Renaghan A.D., Jaimes E.A., Malyszko J., Perazella M.A., Sprangers B., Rosner M.H. Acute Kidney Injury and CKD Associated with Hematopoietic Stem Cell Transplantation. Clin. J. Am. Soc. Nephrol. 2020;15:289–297. doi: 10.2215/CJN.08580719. PubMed DOI PMC

Rodrigues N., Fragao-Marques M., Costa C., Branco C., Marques F., Vasconcelos P., Martins C., Leite-Moreira A., Lopes J.A. Predictive Risk Score for Acute Kidney Injury in Hematopoietic Stem Cell Transplant. Cancers (Basel) 2023;15:3720. doi: 10.3390/cancers15143720. PubMed DOI PMC

Kong S.G., Jeong S., Lee S., Jeong J.Y., Kim D.J., Lee H.S. Early transplantation-related mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia. BMC Cancer. 2021;21:177. doi: 10.1186/s12885-021-07897-3. PubMed DOI PMC

Savas B., Astarita G., Aureli M., Sahali D., Ollero M. Gangliosides in Podocyte Biology and Disease. Int. J. Mol. Sci. 2020;21:9645. doi: 10.3390/ijms21249645. PubMed DOI PMC

Masson E., Wiernsperger N., Lagarde M., El Bawab S. Glucosamine induces cell-cycle arrest and hypertrophy of mesangial cells: implication of gangliosides. Biochem. J. 2005;388:537–544. doi: 10.1042/BJ20041506. PubMed DOI PMC

Liu X., Quan N. Immune Cell Isolation from Mouse Femur Bone Marrow. Bio. Protoc. 2015;5 doi: 10.21769/bioprotoc.1631. PubMed DOI PMC

Schneider C.A., Rasband W.S., Eliceiri K.W. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Hartree E.F. Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal. Biochem. 1972;48:422–427. doi: 10.1016/0003-2697(72)90094-2. PubMed DOI

Bugajev V., Paulenda T., Utekal P., Mrkacek M., Halova I., Kuchar L., Kuda O., Vavrova P., Schuster B., Fuentes-Liso S., et al. Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways. J. Lipid Res. 2021;62 doi: 10.1016/j.jlr.2021.100121. PubMed DOI PMC

Kuchar L., Ledvinová J., Hrebícek M., Mysková H., Dvoráková L., Berná L., Chrastina P., Asfaw B., Elleder M., Petermöller M., et al. Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am. J. Med. Genet. A. 2009;149A:613–621. doi: 10.1002/ajmg.a.32712. PubMed DOI PMC

Hulkova H., Ledvinova J., Kuchar L., Smid F., Honzikova J., Elleder M. Glycosphingolipid profile of the apical pole of human placental capillaries: the relevancy of the observed data to Fabry disease. Glycobiology. 2012;22:725–732. doi: 10.1093/glycob/cws050. PubMed DOI