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Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: Biochemical signs of combined sphingolipidoses

  • Metabolic Diseases
  • Published:
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Abstract

We describe a patient who presented shortly after birth with hyperkinetic behaviour, myoclonia, respiratory insufficiency and hepatosplenomegaly. Gaucher-like storage cells were found in bone marrow. A liver biopsy showed massive lysosomal storage morphologically different to that in known lipid storage disorders. Biochemically, the patient had partial deficiencies of β-galactocerebrosidase, β-glucocerebrosidase and ceramidase in skin fibroblast extracts, but the sphingomyelinase activity was normal. Glucosyl ceramide and ceramide were elevated in liver tissue. Loading of cultured fibroblasts with radioactive sphingolipid precursors indicated a profound defect in ceramide catabolism. Immunological studies in fibroblasts showed a total absence of cross-reacting material to sphingolipid activator protein 2 (SAP-2). The patient died at 16 weeks of age. The fetus from his mother's next pregnancy was similarly affected. The possibility that the disorder results from a primary defect at the level of SAP-2 is discussed. We have named this unique disorder SAP deficiency.

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Abbreviations

GalCG:

β-galactocerebrosidase

GCG:

β-glucocerebrosidase

SAP:

sphingolipid activator protein

SAPD:

SAP deficiency

TLC:

thin layer chromatography

References

  1. Berent SL, Radin NS (1981) β-Glucosidase activator protein from bovine spleen (“coglucosidase”). Arch Biochem Biophys 208: 248–260

    PubMed  Google Scholar 

  2. Berent SL, Radin NS (1981) Mechanism of action of glucocerebrosidase by co-β-glucosidase (glucosidase activator protein). Biochim Biophys Acta 664:572–582

    PubMed  Google Scholar 

  3. Brady RO (1978) Glucosyl ceramide lipidosis: Gaucher disease. In: Stanbury JB, Wyngaarden JB, Fredrickson DS (eds) The metabolic basis of inherited disease, 4th edn. McGraw-Hill, New York, pp 731–746

    Google Scholar 

  4. Christomanou H, Kleinschmidt T (1985). Isolation of two forms of an activator protein for the enzymic sphingomyelin degradation from human Gaucher spleen. Biol Chem. Hoppe Seyler 366:245–256

    PubMed  Google Scholar 

  5. Christomanou H, Aignesberger A, Linke RP (1986) Immunochemical characterization of two activator proteins stimulating enzymic sphingomyelin degradation in vitro. Absence of one of them in a human Gaucher disease variant. Biol Chem. Hoppe Seyler 367:879–890

    PubMed  Google Scholar 

  6. Conzelmann E, Sandhoff K (1978) AB variant of infantile GM2 gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proc. Natl Acad Sci USA 75:3979–3983

    PubMed  Google Scholar 

  7. Conzelmann E, Sandhoff K (1979) Purification and characterization of an activator protein for the degradation of glycolipids GM2 and GA2 by hexosaminidase A. Hoppe Seyler's Z Physiol Chem 360:1837–1849

    PubMed  Google Scholar 

  8. Conzelmann E, Burg J, Stephan, G, Sandhoff K (1982) Complexing of glycolipids and their transfer between membranes by the activator protein for degradation of lysosomal ganglioside GM2. Eur J Biochem 123:455–464

    PubMed  Google Scholar 

  9. Fischer G, Jatzekewitz H (1978) The activator of cerebroside-sulphatase. A. model of the activation. Biochim Biophys Acta 528:69–76

    PubMed  Google Scholar 

  10. Fürst W, Machleidt W, Sandhoff K (1988) The precursor of sulfatide activator protein is processed to three different proteins. Biol Chem Hoppe Seyler 369:317–328

    PubMed  Google Scholar 

  11. Fujibayashi S, Wenger DA (1985) Studies on a sphingolipid activator protein (SAP-2) in fibroblasts from patients with lysosomal storage diseases, including Niemann-Pick disease type C. Clin Chim Acta 146:147–156

    PubMed  Google Scholar 

  12. Fujibayashi S, Kao F-T, Jones C, Morse H, Law M, Wenger DA (1985) Assignment of the gene for sphingolipid activator protein-2 (SAP-2) to human chromosome 10. Am J Hum Genet 37:741–748

    PubMed  Google Scholar 

  13. Fusch C, Huenges R, Moser HW, Sewell AC, Roggendorf W, Kustermann-Kuhn B, Poulos A, Carey WF, Harzer K (1989) A case of combined Farber and Sandhoff disease. Eur J Pediatr 148:558–562

    PubMed  Google Scholar 

  14. Harzer K (1980) Enzymic diagnosis in 27 cases with Gaucher's disease. Clin Chim Acta 106:9–15

    PubMed  Google Scholar 

  15. Harzer K (1982) Prenatal enzymic diagnosis in 24 pregnancies with risk of Krabbe disease. Clin Chim Acta 122:21–28

    PubMed  Google Scholar 

  16. Harzer K, Benz HU (1973) A simple sphingomyelinase determination for Niemann-Pick disease: differential diagnosis of types A, B and C. J Neurochem 21:999–1001

    PubMed  Google Scholar 

  17. Hernández F, Bueno M (1973) Infantile neurological Gaucher's disease in three siblings. An ultrastructural study. Virchows Arch [A] 360:27–32

    Google Scholar 

  18. Ho MW (1975) Specificity of low molecular weight glycoprotein effector of lipid glycosidase. FEBS Lett 53:243–247

    PubMed  Google Scholar 

  19. Inui K, Emmett M, Wenger DA (1983) Immunological evidence for deficiency in an activator protein for sulfatide sulfatase in a variant form of metachromatic leukodystrophy. Proc Natl Acad Sci USA 80:3074–3077

    PubMed  Google Scholar 

  20. Inui K, Kao F-T, Fujibayashi S, Jones C, Morse HG, Law ML, Wenger DA (1985) The gene coding for a sphingolipid activator protein, SAP-1, is on human chromosome 10. Hum Genet 69:197–200

    PubMed  Google Scholar 

  21. Iyer SS, Berent S, Radin NS (1983) The cohydrolases in human spleen that stimulate glucosyl ceramide β-glucosidase. Biochim Biophys Acta 748:1–7

    PubMed  Google Scholar 

  22. Kudoh T, Wenger DA (1982) Diagnosis of metachromatic leukodystrophy, Krabbe disease, and Farber disease after uptake of fatty acid-labeled cerebroside sulfate into cultured skin fibroblasts. J Clin Invest 70:89–97

    PubMed  Google Scholar 

  23. Kudoh T, Sattler M, Malmstrom J, Bitter MA, Wenger DA (1981) Metabolism of fatty acid-labeled cerebroside sulfate in cultured cells from controls and metachromatic leukodystrophy patients. J Lab Clin Med 98:704–714

    PubMed  Google Scholar 

  24. Li S-C, Kihara H, Serizawa S, Li Y-T, Fluharty AL, Mayes JS, Shapiro LJ (1985) Activator protein required for the enzymatic hydrolysis of cerebroside sulfate. Deficiency in urine of patients affected with cerebroside sulfatase activator deficiency and identity with activators for the enzymatic hydrolysis of GM1 ganglioside and globotriaosylceramide. J Biol Chem 260:1867–1871

    PubMed  Google Scholar 

  25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  Google Scholar 

  26. Mehl E, Jatzkewitz H (1964) Eine Cerebrosidsulfatase aus Schweineniere. Hoppe-Seyler's Z Physiol Chem 339:260–276

    PubMed  Google Scholar 

  27. Moser HW, Chen WH (1983) Ceramidase deficiency: Farber's lipogranulomatosis. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Gofdstein JL (eds) The metabolic basis of inherited disease 5th edn. McGraw-Hill, New York., pp 820–830

    Google Scholar 

  28. O'Brien JS, Kretz KA, Dewji N, Wenger DA, Esch F, Fluharty AL (1988) Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same genetic locus. Science 241:1098–1101

    PubMed  Google Scholar 

  29. Paton BC, Poules A (1988) Analysis of the multiple forms of Gaucher spleén sphingolipid activator protein 2. Biochem J 254:77–84

    PubMed  Google Scholar 

  30. Pellissier JF, Berard-Badier M, Pinsard N (1986) Farber's disease in two siblings, sural nerve and subcutaneous biopsies by light and electron microscopy. Acta Neuropathol 72:178–188

    PubMed  Google Scholar 

  31. Peters SP, Coyle P, Coffee CJ, Glew RH, Kuhlenschmidt MS, Rosenfeld L, Lee YC (1977) Purification and properties of a-heat-stable glucocerebrosidase activating factor from control and Gaucher spleen. J Biol Chem 252:563–573

    PubMed  Google Scholar 

  32. Poulos A, Ranicri E, Shankaran P, Callahan JW (1984) Studies on the activation of the enzymatic hydrolysis of sphingomyelin liposomes. Biochim Biophys Acta 793:141–148

    PubMed  Google Scholar 

  33. Ranieri E, Paton B, Poulos A (1986) Preliminary evidence for a processing error in the biosynthesis of Gaucher activator in mucolipidosis disease types II and III. Biochem J 233:763–772

    PubMed  Google Scholar 

  34. Sandhoff K (1984) Function and relevance of activator proteins for glycolipid degradation. In: Barranger JA, Brady RO (eds) Molecular basis of lysosomal storage disorders. Academic Press, Orlando, pp 19–49

    Google Scholar 

  35. Shapiro LJ, Aleck KA, Kaback MM, Itabashi H, Desnick RJ, Brand N, Stevens RL, Fluharty AL, Kihara H (1979) Metachromatic leukodystrophy without arylsulfatase A deficiency. Pediatr Res 13:1179–1181

    PubMed  Google Scholar 

  36. Stevens RL, Fluharty AL, Kihara H, Kaback MM, Shapiro LJ, Marsh B, Sandhoff K, Fischer G (1981) Cerebroside sulfatase activator deficiency induced metachromatic leukodystrophy. Am J Hum Genet 33:900–906

    PubMed  Google Scholar 

  37. Vaccaro AM, Muscillo M, Gallozzi E, Salvioli R, Tatti M, Suzuki K (1985) An endogenous activator protein in human placenta for enzymatic degradation of glucosylceramide. Biochim Biophys Acta 836:157–166

    PubMed  Google Scholar 

  38. Vaccaro AM, Muscillo M, Salvioli R, Tatti M, Gallozzi E, Suzuki K (1987) The binding of glucosylceramidase to glucosylceramide is promoted by its activator protein. FEBS Lett 216:190–194

    PubMed  Google Scholar 

  39. Vaccaro AM, Ciaffoni F, Mandara I, Suzuki K (1988) Presence of activator proteins for the enzymatic degradation of glucosylceramide in several human tissues. Clin Chim Acta 172:323–334

    PubMed  Google Scholar 

  40. Vogel A, Fürst W, Ab0-Hashish MA, Lee-Vaupel M, Conzelmann E, Sandhoff K (1987) Identity of the activator proteins for the enzymatic hydrolysis of sulfatide., ganglioside GM1, and globotriaosylceramide. Arch Biochem Biophys 259:627–638

    PubMed  Google Scholar 

  41. Wenger DA, Sattler M, Roth S (1982) A protein activator of galactosylceramide β-galactosidase. Biochim Biophys Acta 712:639–649

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Hirnforschung der Universität, Schwärzlocher Strasse 79, D-7400, Tübingen, Federal Republic of Germany

    K. Harzer, B. Kustermann-Kuhn & W. Roggendorf

  2. Department of Chemical Pathology, Adelaide Children's Hospital, 5006, North Adelaide, South Australia

    B. C. Paton & A. Poulos

  3. Abteilung für Genetische Beratung am Gesundheitsamt Bremen, und Institut für Humangenetik der Universität, D-2800, Bremen, Federal Republic of Germany

    T. Grisar

  4. Abteilung für Kinderheilkunde, Zentralkrankenhaus., St.-Jürgen-Strasse, D-2800, Bremen, Federal Republic of Germany

    M. Popp

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  1. K. Harzer
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Harzer, K., Paton, B.C., Poulos, A. et al. Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: Biochemical signs of combined sphingolipidoses. Eur J Pediatr 149, 31–39 (1989). https://doi.org/10.1007/BF02024331

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  • DOI: https://doi.org/10.1007/BF02024331

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