The Genetics of Sphingolipid Hydrolases and Sphingolipid Storage Diseases

  • Edward H. Schuchman
  • Calogera M. Simonaro
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 215)


The relationship of sphingolipids with human disease first arose from the study of sphingolipid storage diseases over 50 years ago. Most of these disorders are due to inherited deficiencies of specific sphingolipid hydrolases, although a small number also result from defects in sphingolipid transport or activator proteins. Due to the primary protein deficiencies sphingolipids and other macromolecules accumulate in cells and tissues of affected patients, leading to a diverse presentation of clinical abnormalities. Over 25 sphingolipid storage diseases have been described to date. Most of the genes have been isolated, disease-causing mutations have been identified, the recombinant proteins have been produced and characterized, and animal models exist for most of the human diseases. Since most sphingolipid hydrolases are enriched within the endosomal/lysosomal system, macromolecules first accumulate within these compartments. However, these abnormalities rapidly spread to other compartments and cause a wide range of cellular dysfunction. This review focuses on the genetics of sphingolipid storage diseases and related hydrolytic enzymes with an emphasis on the relationship between genetic mutations and human disease.


Sphingolipids Hydrolases Lysosomes Genes Mutations 


  1. Abian O, Alfonso P, Velazquez-Campoy A, Giraldo P, Pocovi M, Sancho J (2011) Therapeutic strategies for Gaucher disease: miglustat (NB-DNJ) as a pharmacological chaperone for glucocerebrosidase and the different thermostability of velaglucerase alfa and imiglucerase. Mol Pharm 8(6):2390–2397PubMedCrossRefGoogle Scholar
  2. Aerts JM, Boot RG, van Eijk M, Groener J, Bijl N, Lombardo E, Bietrix FM, Dekker N, Groen AK, Ottenhoff R, van Roomen C, Aten J, Serlie M, Langeveld M, Wennekes T, Overkleeft HS (2011) Glycosphingolipids and insulin resistance. Adv Exp Med Biol 721:99–119PubMedCrossRefGoogle Scholar
  3. Ahmad A, Mazhar AU, Anwar M (2009) Farber disease: a rare neurodegenerative disorder. J Coll Physicians Surg Pak 19(1):67–68PubMedGoogle Scholar
  4. Anheim M, Elbaz A, Lesage S, Durr A, Condroyer C, Viallet F, Pollak P, Bonaïti B, Bonaïti-Pellié C, Brice A (2012) Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology 78(6):417–420PubMedCrossRefGoogle Scholar
  5. Baek RC, Martin DR, Cox NR, Seyfried TN (2009) Comparative analysis of brain lipids in mice, cats, and humans with Sandhoff disease. Lipids 44(3):197–205PubMedCrossRefGoogle Scholar
  6. Baronica KB, Mlinac K, Ozretić D, Vladić A, Bognar SK (2011) Arylsulfatase a gene polymorphisms in relapsing remitting multiple sclerosis: genotype-phenotype correlation and estimation of disease progression. Coll Antropol 35(Suppl 1):11–16PubMedGoogle Scholar
  7. Becker KA, Grassmé H, Zhang Y, Gulbins E (2010) Ceramide in Pseudomonas aeruginosa infections and cystic fibrosis. Cell Physiol Biochem 26(1):57–66PubMedCrossRefGoogle Scholar
  8. Beckham TH, Lu P, Cheng JC, Zhao D, Turner LS, Zhang X, Hoffman S, Armeson KE, Liu A, Marrison T, Hannun YA, Liu X (2012) Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through upregulation of cathepsin B. Int J Cancer 131:2034–2043. doi: 10.1002/ijc.27480 PubMedCrossRefGoogle Scholar
  9. Benito JM, García Fernández JM, Ortiz Mellet C (2011) Pharmacological chaperone therapy for Gaucher disease: a patent review. Expert Opin Ther Pat 21(6):885–903PubMedCrossRefGoogle Scholar
  10. Bikman BT, Summers SA (2011) Sphingolipids and hepatic steatosis. Adv Exp Med Biol 721: 87–97PubMedCrossRefGoogle Scholar
  11. Bley AE, Giannikopoulos OA, Hayden D, Kubilus K, Tifft CJ, Eichler FS (2011) Natural history of infantile G(M2) gangliosidosis. Pediatrics 128(5):e1233–e1241PubMedCrossRefGoogle Scholar
  12. Bouwman MG, Rombach SM, Schenk E, Sweeb A, Wijburg FA, Hollak CE, Linthorst GE (2012) Prevalence of symptoms in female Fabry disease patients: a case-control survey. J Inherit Metab Dis 35:891–898PubMedCrossRefGoogle Scholar
  13. Bradbury AM, Morrison NE, Hwang M, Cox NR, Baker HJ, Martin DR (2009) Neurodegenerative lysosomal storage disease in European Burmese cats with hexosaminidase beta-subunit deficiency. Mol Genet Metab 97(1):53–59PubMedCrossRefGoogle Scholar
  14. Brown JT, Lahey C, Laosinchai-Wolf W, Hadd AG (2006) Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T > C (L444P). BMC Med Genet 7:69PubMedCrossRefGoogle Scholar
  15. Brunetti-Pierri N, Scaglia F (2008) GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab 94(4):391–396PubMedCrossRefGoogle Scholar
  16. Caciotti A, Garman SC, Rivera-Colón Y, Procopio E, Catarzi S, Ferri L, Guido C, Martelli P, Parini R, Antuzzi D, Battini R, Sibilio M, Simonati A, Fontana E, Salviati A, Akinci G, Cereda C, Dionisi-Vici C, Deodato F, d’Amico A, d’Azzo A, Bertini E, Filocamo M, Scarpa M, di Rocco M, Tifft CJ, Ciani F, Gasperini S, Pasquini E, Guerrini R, Donati MA, Morrone A (2011) GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta 1812(7):782–790PubMedCrossRefGoogle Scholar
  17. Campbell TN, Choy FY (2012) Gaucher disease and the synucleinopathies: refining the relationship. Orphanet J Rare Dis 7:12PubMedCrossRefGoogle Scholar
  18. Chen H, Tran JT, Brush RS, Saadi A, Rahman AK, Yu M, Yasumura D, Matthes MT, Ahern K, Yang H, LaVail MM, Mandal MN (2012) Ceramide signaling in retinal degeneration. Adv Exp Med Biol 723:553–558PubMedCrossRefGoogle Scholar
  19. Choy FY, Campbell TN (2011) Gaucher disease and cancer: concept and controversy. Int J Cell Biol 2011:150450PubMedGoogle Scholar
  20. Clarke CJ, Wu BX, Hannun YA (2011) The neutral sphingomyelinase family: identifying biochemical connections. Adv Enzyme Regul 51(1):51–58PubMedCrossRefGoogle Scholar
  21. Claro E, Wallace MA, Fain JN, Nair BG, Patel TB, Shanker G, Baker HJ (1991) Altered phosphoinositide-specific phospholipase C and adenylyl cyclase in brain cortical membranes of cats with GM1 and GM2 gangliosidosis. Brain Res Mol Brain Res 11(3–4):265–271PubMedCrossRefGoogle Scholar
  22. Cordeiro P, Hechtman P, Kaplan F (2000) The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci. Genet Med 2(6):319–327PubMedCrossRefGoogle Scholar
  23. Cox TM, Cachón-González MB (2012) The cellular pathology of lysosomal diseases. J Pathol 226(2):241–254PubMedCrossRefGoogle Scholar
  24. De Braekeleer M, Hechtman P, Andermann E, Kaplan F (1992) The French Canadian Tay-Sachs disease deletion mutation: identification of probable founders. Hum Genet 89(1):83–87PubMedCrossRefGoogle Scholar
  25. Duffner PK, Barczykowski A, Jalal K, Yan L, Kay DM, Carter RL (2011) Early infantile Krabbe disease: results of the World-Wide Krabbe Registry. Pediatr Neurol 45(3):141–148PubMedCrossRefGoogle Scholar
  26. Duffner PK, Granger C, Lyon N, Niewczyk P, Barczykowski A, Bauer S (2012) Msall ME (2012) developmental and functional outcomes in children with a positive newborn screen for Krabbe disease: a pilot study of a phone-based interview surveillance technique. J Pediatr 161:258–263PubMedCrossRefGoogle Scholar
  27. Eliyahu E, Shtraizent N, Martinuzzi K, Barritt J, He X, Wei H, Chaubal S, Copperman AB, Schuchman EH (2010) Acid ceramidase improves the quality of oocytes and embryos and the outcome of in vitro fertilization. FASEB J 24(4):1229–1238PubMedCrossRefGoogle Scholar
  28. Farber S, Cohen J, Uzman LL (1957) Lipogranulomatosis; a new lipo-glycoprotein storage disease. J Mt Sinai Hosp NY 24(6):816–837Google Scholar
  29. Farfel-Becker T, Vitner EB, Futerman AH (2011) Animal models for Gaucher disease research. Dis Model Mech 4(6):746–752PubMedCrossRefGoogle Scholar
  30. Flowers M, Fabriás G, Delgado A, Casas J, Abad JL, Cabot MC (2012) C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth. Breast Cancer Res Treat 133:447–458PubMedCrossRefGoogle Scholar
  31. Frisch A, Colombo R, Michaelovsky E, Karpati M, Goldman B, Peleg L (2004) Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis. Hum Genet 114(4):366–376PubMedCrossRefGoogle Scholar
  32. Furuya H, Shimizu Y, Kawamori T (2011) Sphingolipids in cancer. Cancer Metastasis Rev 30(3–4):567–576PubMedCrossRefGoogle Scholar
  33. Gassas A, Raiman J, White L, Schechter T, Clarke J, Doyle J (2011) Long-term adaptive functioning outcomes of children with inherited metabolic and genetic diseases treated with hematopoietic stem cell transplantation in a single large pediatric center: parents’ perspective. J Pediatr Hematol Oncol 33(3):216–220PubMedCrossRefGoogle Scholar
  34. Geiselmann V, Matzner, U, Hess B, Lullmann-Rauch R, Coenen R, Hartmann D, D’Hooge R, DeDeyn P, Nagels G (1998) Metachromatic leukodystrophy: molecular genetics and an animal model. J. Inherit Metab Dis:564–574Google Scholar
  35. Gieselmann V, Zlotogora J, Harris A, Wenger DA, Morris CP (1994) Molecular genetics of metachromatic leukodystrophy. Hum Mutat 4(4):233–242PubMedCrossRefGoogle Scholar
  36. Goker-Alpan O (2011) Therapeutic approaches to bone pathology in Gaucher disease: past, present and future. Mol Genet Metab 104(4):438–447PubMedCrossRefGoogle Scholar
  37. Grossi S, Regis S, Rosano C, Corsolini F, Uziel G, Sessa M, Di Rocco M, Parenti G, Deodato F, Leuzzi V, Biancheri R, Filocamo M (2008) Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles. Hum Mutat 29(11):E220–E230PubMedCrossRefGoogle Scholar
  38. Gulinello M, Chen F, Dobrenis K (1994) Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease. Proc Natl Acad Sci U S A 91(21):9975–9979CrossRefGoogle Scholar
  39. Hofer D, Paul K, Fantur K, Beck M, Bürger F, Caillaud C, Fumic K, Ledvinova J, Lugowska A, Michelakakis H, Radeva B, Ramaswami U, Plecko B, Paschke E (2009) GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid beta-galactosidase. Hum Mutat 30(8):1214–1221PubMedCrossRefGoogle Scholar
  40. Horinouchi K, Erlich S, Perl DP, Ferlinz K, Bisgaier CL, Sandhoff K, Desnick RJ, Stewart CL, Schuchman EH (1995) Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat Genet 10(3):288–293PubMedCrossRefGoogle Scholar
  41. Hruska KS, LaMarca ME, Scott CR, Sidransky E (2008) Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 29(5):567–583PubMedCrossRefGoogle Scholar
  42. Hughes DA, Pastores GM (2010) The pathophysiology of GD - current understanding and rationale for existing and emerging therapeutic approaches. Wien Med Wochenschr 160(23–24):594–599PubMedCrossRefGoogle Scholar
  43. Itoh M, Matsuda J, Suzuki O, Ogura A, Oshima A, Tai T, Suzuki Y, Takashima S (2001) Development of lysosomal storage in mice with targeted disruption of the beta-galactosidase gene: a model of human G(M1)-gangliosidosis. Brain Dev 23(6):379–384PubMedCrossRefGoogle Scholar
  44. Jain A, Kohli A, Sachan D (2010) Infantile Sandhoff’s disease with peripheral neuropathy. Pediatr Neurol 42(6):459–461PubMedCrossRefGoogle Scholar
  45. Kehrer C, Blumenstock G, Gieselmann V, Krägeloh-Mann I, Leukonet G (2011) The natural course of gross motor deterioration in metachromatic leukodystrophy. Dev Med Child Neurol 53(9):850–855PubMedCrossRefGoogle Scholar
  46. Kinghorn KJ (2011) Pathological looping in the synucleinopathies: investigating the link between Parkinson’s disease and Gaucher disease. Dis Model Mech 4(6):713–715PubMedCrossRefGoogle Scholar
  47. Kohlschütter A, Eichler F (2011) Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother 11(10):1485–1496PubMedCrossRefGoogle Scholar
  48. Kolter T, Sandhoff K (2010) Lysosomal degradation of membrane lipids. FEBS Lett 584(9): 1700–1712PubMedCrossRefGoogle Scholar
  49. Kölzer M, Ferlinz K, Bartelsen O, Hoops SL, Lang F, Sandhoff K (2004) Functional characterization of the postulated intramolecular sphingolipid activator protein domain of human acid sphingomyelinase. Biol Chem 385(12):1193–1195PubMedCrossRefGoogle Scholar
  50. Kosanke SD, Pierce KR, Read WK (1979) Morphogenesis of light and electron microscopic lesions in porcine GM2-gangliosidosis. Vet Pathol 16(1):6–17PubMedGoogle Scholar
  51. Kumperscak HG, Dolzan V, Videtic A, Plesnicar BK (2008) Polymorphisms in genes encoding the serotonin and dopamine pathways in two sisters with metachromatic leukodystrophy. J Int Med Res 36(5):1123–1128PubMedGoogle Scholar
  52. Lachmann RH (2011) Enzyme replacement therapy for lysosomal storage diseases. Curr Opin Pediatr 23(6):588–593PubMedCrossRefGoogle Scholar
  53. Lee JY, Lee BH, Kim GH, Jung CW, Lee J, Choi JH, Yoo HW (2012) Clinical and genetic characteristics of Gaucher disease according to phenotypic subgroups. Korean J Pediatr 55(2): 48–53PubMedCrossRefGoogle Scholar
  54. Li CM, Park JH, Simonaro CM, He X, Gordon RE, Friedman AH, Ehleiter D, Paris F, Manova K, Hepbildikler S, Fuks Z, Sandhoff K, Kolesnick R, Schuchman EH (2002) Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Genomics 79(2):218–224PubMedCrossRefGoogle Scholar
  55. Lin DS, Hsiao CD, Liau I, Lin SP, Chiang MF, Chuang CK, Wang TJ, Wu TY, Jian YR, Huang SF, Liu HL (2011) CNS-targeted AAV5 gene transfer results in global dispersal of vector and prevention of morphological and function deterioration in CNS of globoid cell leukodystrophy mouse model. Mol Genet Metab 103(4):367–377PubMedCrossRefGoogle Scholar
  56. Linke T, Wilkening G, Sadeghlar F, Mozcall H, Bernardo K, Schuchman E, Sandhoff K (2001) Interfacial regulation of acid ceramidase activity. Stimulation of ceramide degradation by lysosomal lipids and sphingolipid activator proteins. J Biol Chem 276(8):5760–5768PubMedCrossRefGoogle Scholar
  57. Linthorst GE, Hollak CE, Donker-Koopman WE, Strigland A, Aerts JM (2004) Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase slpha and beta. Kidney Int 66: 1589–95PubMedCrossRefGoogle Scholar
  58. Liu Y, Gibson J, Wheeler J, Kwee LC, Santiago-Turla CM, Akafo SK, Lichter PR, Gaasterland DE, Moroi SE, Challa P, Herndon LW, Girkin CA, Budenz DL, Richards JE, Allingham RR, Hauser MA (2011) GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. PLoS One 6(11):e27134PubMedCrossRefGoogle Scholar
  59. Lo SM, Choi M, Liu J, Jain D, Boot RG, Kallemeijn WW, Aerts JM, Pashankar F, Kupfer GM, Mane S, Lifton RP, Mistry PK (2012) Phenotypic diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematological malignancy phenotype by individual genome analysis. Blood 119:4731–4740PubMedCrossRefGoogle Scholar
  60. Ługowska A, Ponińska J, Krajewski P, Broda G, Płoski R (2011) Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed? PLoS One 6(6):e20218PubMedCrossRefGoogle Scholar
  61. Luzi P, Rafi MA, Zaka M, Curtis M, Vanier MT, Wenger DA (2001) Generation of a mouse with low galactocerebrosidase activity by gene targeting: a new model of globoid cell leukodystrophy (Krabbe disease). Mol Genet Metab 73(3):211–223PubMedCrossRefGoogle Scholar
  62. Maegawa G (2012) GM2 gangliosidosis: the prototype of lysosomal storage disorders. Dev Med Child Neurol 54(2):104–105PubMedCrossRefGoogle Scholar
  63. Malandrini A, D’Eramo C, Palmeri S, Gaudiano C, Gambelli S, Sicurelli F, Berti G, Formichi P, Kuqo A, Dotti MT, Federico A (2013) Peripheral neuropathy in late-onset Krabbe disease: report of three cases.Neurol Sci 34:79–83PubMedCrossRefGoogle Scholar
  64. Mao C, Obeid L (2008) Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine and sphingosine-1-phosphate. Biochim Biophys Acta 1781(9):424–434PubMedCrossRefGoogle Scholar
  65. Martin DC, Mark BL, Triggs-Raine BL, Natowicz MR (2007) Evaluation of the risk for Tay-Sachs disease in individuals of French Canadian ancestry living in new England. Clin Chem 53(3): 392–398PubMedCrossRefGoogle Scholar
  66. Matsuda J, Yoneshige A, Suzuki K (2007) The function of sphingolipids in the nervous system: lessons learnt from mouse models of specific sphingolipid activator protein deficiencies. J Neurochem 103(Suppl 1):32–38PubMedCrossRefGoogle Scholar
  67. Matthes F, Stroobants S, Gerlach D, Wohlenberg C, Wessig C, Fogh J, Gieselmann V, Eckhardt M, D’Hooge R, Matzner U (2012) Efficacy of enzyme replacement therapy in an aggravated mouse model of metachromatic leukodystrophy declines with age. Hum Mol Genet 21:2599–2609PubMedCrossRefGoogle Scholar
  68. McGovern MM, Schuchman EH (2009) Acid sphingomyelinase defieciency. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds) Gene Reviews™ [Internet]. University of Washington, Seattle, WAGoogle Scholar
  69. Mikosch P, Hughes D (2010) An overview on bone manifestations in Gaucher disease. Wien Med Wochenschr 160(23–24):609–624PubMedCrossRefGoogle Scholar
  70. Miranda SR, He X, Simonaro CM, Gatt S, Dagan A, Desnick RJ, Schuchman EH (2000) Infusion of recombinant human acid sphingomyelinase into niemann-pick disease mice leads to visceral, but not neurological, correction of the pathophysiology. FASEB J 14(13):1988–1995PubMedCrossRefGoogle Scholar
  71. Misasi R, Hozumi I, Inuzuka T, Capozzi A, Mattei V, Kuramoto Y, Shimeno H, Soeda S, Azuma N, Yamauchi T, Hiraiwa M (2009) Biochemistry and neurobiology of prosaposin: a potential therapeutic neuro-effector. Cent Nerv Syst Agents Med Chem 9(2):119–131PubMedCrossRefGoogle Scholar
  72. Miyatake T, Suzuki K (1972) Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. Biochem Biophys Res Commun 48(3):539–543PubMedCrossRefGoogle Scholar
  73. Morita M, Saito S, Ikeda K, Ohno K, Sugawara K, Suzuki T, Togawa T, Sakuraba H (2009) Structural bases of GM1 gangliosidosis and Morquio B disease. J Hum Genet 54(9):510–515PubMedCrossRefGoogle Scholar
  74. Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441(3):789–802PubMedCrossRefGoogle Scholar
  75. Nada R, Gupta K, Lal SB, Vasishta RK (2011) An autopsy case of infantile GM1 gangliosidosis with adrenal calcification. Metab Brain Dis 26(4):307–310PubMedCrossRefGoogle Scholar
  76. Neri M, Ricca A, di Girolamo I, Alcala’-Franco B, Cavazzin C, Orlacchio A, Martino S, Naldini L, Gritti A (2011) Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy. Stem Cells 29(10):1559–1571PubMedCrossRefGoogle Scholar
  77. Ohto U, Usui K, Ochi T, Yuki K, Satow Y, Shimizu T (2012) Crystal structure of human β-galactosidase: structural basis of Gm1 gangliosidosis and morquio B diseases. J Biol Chem 287(3):1801–1812PubMedCrossRefGoogle Scholar
  78. Okino N, He X, Gatt S, Sandhoff K, Schuchman EH (2003) The reverse activity of human acid ceramidase. J Biol Chem 278(32):29948–29953PubMedCrossRefGoogle Scholar
  79. Osher E, Fattal-Valevski A, Sagie L, Urshanski N, Amir-Levi Y, Katzburg S, Peleg L, Lerman-Sagie T, Zimran A, Elstein D, Navon R, Stern N, Valevski A (2011) Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs. Mol Genet Metab 102(3):356–633PubMedCrossRefGoogle Scholar
  80. Oya Y, Nakayasu H, Fujita N, Suzuki K, Suzuki K (1998) Pathological study of mice with total deficiency of sphingolipid activator proteins (SAP knockout mice). Acta Neuropathol 96(1): 29–40PubMedCrossRefGoogle Scholar
  81. Park JH, Eliyahu E, Narla G, DiFeo A, Martignetti JA, Schuchman EH (2005) KLF6 is one transcription factor involved in regulating acid ceramidase gene expression. Biochim Biophys Acta 1732(1–3):82–87PubMedGoogle Scholar
  82. Park JH, Schuchman EH (2006) Acid ceramidase and human disease. Biochim Biophys Acta 1758(12):2133–2138PubMedCrossRefGoogle Scholar
  83. Pastores GM (2010) Neuropathic Gaucher disease. Wien Med Wochenschr 160(23–24):605–608PubMedCrossRefGoogle Scholar
  84. Perlman SJ, Mar S (2012) Leukodystrophies. Adv Exp Med Biol 724:154–171PubMedCrossRefGoogle Scholar
  85. Peleg L, Meltzer F, Karpati M, Goldman B (1995) GM2 gangliosidosis B1 variant: biochemical and molecular characterization of hexosaminidase A. Biochem Mol Med 54(2):126–132PubMedCrossRefGoogle Scholar
  86. Petrache I, Petrusca DN, Bowler RP, Kamocki K (2011) Involvement of ceramide in cell death responses in the pulmonary circulation. Proc Am Thorac Soc 8(6):492–496PubMedCrossRefGoogle Scholar
  87. Phaneuf D, Wakamatsu N, Huang JQ, Borowski A, Peterson AC, Fortunato SR, Ritter G, Igdoura SA, Morales CR, Benoit G, Akerman BR, Leclerc D, Hanai N, Marth JD, Trasler JM, Gravel RA (1996) Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. Hum Mol Genet 5(1):1–14PubMedCrossRefGoogle Scholar
  88. Podbielska M, Krotkiewski H, Hogan EL (2012) Signaling and regulatory functions of bioactive sphingolipids as therapeutic targets in multiple sclerosis. Neurochem Res 37:1154–1169PubMedCrossRefGoogle Scholar
  89. Reddy AS, Kim JH, Hawkins-Salsbury JA, Macauley SL, Tracy ET, Vogler CA, Han X, Song SK, Wozniak DF, Fowler SC, Klein RS, Sands MS (2011) Bone marrow transplantation augments the effect of brain- and spinal cord-directed adeno-associated virus 2/5 gene therapy by altering inflammation in the murine model of globoid-cell leukodystrophy. J Neurosci 31(27):9945–9957PubMedCrossRefGoogle Scholar
  90. Renaud DL (2012) Lysosomal disorders associated with leukoencephalopathy. Semin Neurol 32(1):51–54PubMedCrossRefGoogle Scholar
  91. Rozenfeld P, Neumann PM (2011) Treatment of Fabry disease: current and emerging strategies. Curr Pharm Biotechnol 12:916–22PubMedCrossRefGoogle Scholar
  92. Sakai N (2009) Pathogenesis of leukodystrophy for Krabbe disease: molecular mechanism and clinical treatment. Brain Dev 31(7):485–487PubMedCrossRefGoogle Scholar
  93. Sandhoff K, Kolter T (1998) Processing of sphingolipid activator proteins and the topology of lysosomal digestion. Acta Biochim Pol 45(2):373–384PubMedGoogle Scholar
  94. Sardi SP, Singh P, Cheng SH, Shihabuddin LS, Schlossmacher MG (2012) Mutant GBA1 expression and synucleinopathy risk: first insights from cellular and mouse models. Neurodegener Dis 10:195–202PubMedCrossRefGoogle Scholar
  95. Schaefer E, Mehta A, Gal A (2005) Genotype and phenotype in Fabry disease; analysis of the Fabry outcome survey. Acta Paediatr Suppl 94:87–92PubMedCrossRefGoogle Scholar
  96. Schissel SL, Keesler GA, Schuchman EH, Williams KJ, Tabas I (1998) The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J Biol Chem 273(29):18250–18259PubMedCrossRefGoogle Scholar
  97. Schuchman EH (2009) The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. Int J Clin Pharmacol Ther 47(Suppl 1):S48–S57PubMedGoogle Scholar
  98. Schulze H, Sandhoff K (2011) Lysosomal lipid storage diseases. Cold Spring Harb Perspect Biol 3(6):pii: a0084804. doi: 10.1101/cschperspect.a004804 CrossRefGoogle Scholar
  99. Scott SA, Edelmann L, Liu L, Luo M, Desnick RJ, Kornreich R (2010) Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases. Hum Mutat 31(11):1240–1250PubMedCrossRefGoogle Scholar
  100. Simonaro CM, Park JH, Eliyahu E, Shtraizent N, McGovern MM, Schuchman EH (2006) Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease. Am J Hum Genet 78(5):865–870PubMedCrossRefGoogle Scholar
  101. Smith NJ, Winstone AM, Stellitano L, Cox TM, Verity CM (2012) GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed. Dev Med Child Neurol 54(2):176–182PubMedCrossRefGoogle Scholar
  102. Solders G, Celsing G, Hagenfeldt L, Ljungman P, Isberg B, Ringdén O (1998) Improved peripheral nerve conduction, EEG and verbal IQ after bone marrow transplantation for adult metachromatic leukodystrophy. Bone Marrow Transplant 22(11):1119–1122PubMedCrossRefGoogle Scholar
  103. Spáčil Z, Elliott S, Reeber SL, Gelb MH, Scott CR, Tureček F (2011) Comparative triplex tandem mass spectrometry assays of lysosomal enzyme activities in dried blood spots using fast liquid chromatography: application to newborn screening of Pompe, Fabry, and Hurler diseases. Anal Chem 83(12):4822–4828PubMedCrossRefGoogle Scholar
  104. Steenweg ME, Vanderver A, Blaser S, Bizzi A, de Koning TJ, Mancini GM, van Wieringen WN, Barkhof F, Wolf NI, van der Knaap MS (2010) Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain 133(10):2971–2982PubMedCrossRefGoogle Scholar
  105. Stroobants S, Gerlach D, Matthes F, Hartmann D, Fogh J, Gieselmann V, D’Hooge R, Matzner U (2011) Intracerebroventricular enzyme infusion corrects central nervous system pathology and dysfunction in a mouse model of metachromatic leukodystrophy. Hum Mol Genet 20(14): 2760–2769PubMedCrossRefGoogle Scholar
  106. Sugita M, Dulaney JT, Moser HW (1972) Ceramidase deficiency in Farber’s disease (lipogranulomatosis). Science 178(4065):1100–1102PubMedCrossRefGoogle Scholar
  107. Sun Y, Ran H, Zamzow M, Kitatani K, Skelton MR, Williams MT, Vorhees CV, Witte DP, Hannun YA, Grabowski GA (2010) Specific saposin C deficiency: CNS impairment and acid beta-glucosidase effects in the mouse. Hum Mol Genet 19(4):634–647PubMedCrossRefGoogle Scholar
  108. Sun Y, Witte DP, Ran H, Zamzow M, Barnes S, Cheng H, Han X, Williams MT, Skelton MR, Vorhees CV, Grabowski GA (2008) Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice. Hum Mol Genet 17(15):2345–2356PubMedCrossRefGoogle Scholar
  109. Tanaka A, Hoang LT, Nishi Y, Maniwa S, Oka M, Yamano T (2003) Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form. J Hum Genet 48(11):571–574PubMedCrossRefGoogle Scholar
  110. Tarabuso AL (2011) Fabry disease. Skinmed 9(3):173–177PubMedGoogle Scholar
  111. Tatano Y, Takeuchi N, Kuwahara J, Sakuraba H, Takahashi T, Takada G, Itoh K (2006) Elastogenesis in cultured dermal fibroblasts from patients with lysosomal beta-galactosidase, protective protein/cathepsin A and neuraminidase-1 deficiencies. J Med Invest 53(1–2):103–112PubMedCrossRefGoogle Scholar
  112. Tinsa F, Caillaud C, Vanier MT, Bousnina D, Boussetta K, Bousnina S (2010) An unusual homozygous arylsulfatase: a pseudodeficiency in a metachromatic leukodystrophy Tunisian patient. J Child Neurol 25(1):82–86PubMedCrossRefGoogle Scholar
  113. Tohyama J, Oya Y, Ezoe T, Vanier MT, Nakayasu H, Fujita N, Suzuki K (1999) Ceramide accumulation is associated with increased apoptotic cell death in cultured fibroblasts of sphingolipid activator protein-deficient mouse but not in fibroblasts of patients with Farber disease. J Inherit Metab Dis 22(5):649–662PubMedCrossRefGoogle Scholar
  114. Tomasic IB, Metcalf MC, Guce AI, Clark NE, Garman SC (2010) Interconversion of the specificities of human lysosomal enzymes associated with Fabry and Schindler diseases. J Biol Chem 285(28):21560–21566PubMedCrossRefGoogle Scholar
  115. Toyooka K (2011) Fabry disease. Curr Opin Neurol 24(5):463–468PubMedCrossRefGoogle Scholar
  116. Truman JP, Al Gadban MM, Smith KJ, Hammad SM (2011) Acid sphingomyelinase in macrophage biology. Cell Mol Life Sci 68(20):3293–3305PubMedCrossRefGoogle Scholar
  117. Vaccaro AM, Motta M, Tatti M, Scarpa S, Masuelli L, Bhat M, Vanier MT, Tylki-Szymanska A, Salvioli R (2010) Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting. Hum Mol Genet 19(15):2987–2997PubMedCrossRefGoogle Scholar
  118. van der Voorn JP, Kamphorst W, van der Knaap MS, Powers JM (2004) The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction. Acta Neuropathol 107(6):539–545PubMedCrossRefGoogle Scholar
  119. Wähe A, Kasmapour B, Schmaderer C, Liebl D, Sandhoff K, Nykjaer A, Griffiths G, Gutierrez MG (2010) Golgi-to-phagosome transport of acid sphingomyelinase and prosaposin is mediated by sortilin. J Cell Sci 23(Pt 14):2502–2511CrossRefGoogle Scholar
  120. Wendeler M, Lemm T, Weisgerber J, Hoernschemeyer J, Bartelsen O, Schepers U, Sandhoff K (2003) Expression of recombinant human GM2-activator protein in insect cells: purification and characterization by mass spectrometry. Protein Expr Purif 27(2):259–266PubMedCrossRefGoogle Scholar
  121. Wennekes T, van den Berg RJ, Boot RG, van der Marel GA, Overkleeft HS, Aerts JM (2009) Glycosphingolipids–nature, function, and pharmacological modulation. Angew Chem Int Ed Engl 48(47):8848–8869PubMedCrossRefGoogle Scholar
  122. Worgall TS (2011) Sphingolipid synthetic pathways are major regulators of lipid homeostasis. Adv Exp Med Biol 721:139–148PubMedCrossRefGoogle Scholar
  123. Yamanaka S, Johnson MD, Grinberg A, Westphal H, Crawley JN, Taniike M, Suzuki K, Proia RL (2008) Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease. Behav Brain Res 193(2): 315–319CrossRefGoogle Scholar
  124. Yamato O, Matsuki N, Satoh H, Inaba M, Ono K, Yamasaki M, Maede Y (2002) Sandhoff disease in a golden retriever dog. J Inherit Metab Dis 25(4):319–320PubMedCrossRefGoogle Scholar
  125. Young SA, Mina JG, Denny PW, Smith TK (2012) Sphingolipid and ceramide homeostasis: potential therapeutic targets. Biochem Res Int 2012:248135PubMedGoogle Scholar
  126. Yuan L, Morales CR (2011) Prosaposin sorting is mediated by oligomerization. Exp Cell Res 317(17):2456–2467PubMedCrossRefGoogle Scholar
  127. Zeidan YH, Hannun YA (2010) The acid sphingomyelinase/ceramide pathway: biomedical significance and mechanisms of regulation. Curr Mol Med 10(5):454–466PubMedCrossRefGoogle Scholar
  128. Zeidan YH, Wu BX, Jenkins RW, Obeid LM, Hannun YA (2008) A novel role for protein kinase C delta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. FASEB J 22(1):183–193PubMedCrossRefGoogle Scholar
  129. Zhang H, Li D, Su Y, Jiang S, Xu Y, Jiang K, Cui D (2012) Identification of the N-acylsphingosine amidohydrolase 1 gene (ASAH1) for susceptibility to schizophrenia in a Han Chinese population. World J Biol Psychiatry 13(2):106–113PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Genetics and Genomic SciencesMount Sinai School of MedicineNew YorkUSA

Personalised recommendations