pp 1-12 | Cite as

The Second Case of Saposin A Deficiency and Altered Autophagy

  • Melis Kose
  • Secil Akyildiz Demir
  • Gulcin Akinci
  • Cenk Eraslan
  • Unsal Yilmaz
  • Serdar Ceylaner
  • Eser Sozmen Yildirim
  • Volkan Seyrantepe
Research Report
Part of the JIMD Reports book series


Krabbe disease is a lysosomal storage disease caused by galactosylceramidase deficiency, resulting in neurodegeneration with a rapid clinical downhill course within the first months of life in the classic infantile form. This process may be triggered by the accumulation of galactosylceramide (GalCer) in nervous tissues. Both the enzyme galactosylceramidase and its in vivo activator molecule, saposin A, are essential during GalCer degradation. A clinical manifestation almost identical to Krabbe disease is observed when, instead of the galactosylceramidase protein, the saposin A molecule is defective. Saposin A results from posttranslational processing of the precursor molecule, prosaposin, encoded by the PSAP gene. Clinical and neuroimaging findings in a 7-month-old child strongly suggested Krabbe disease, but this condition was excluded by enzymatic and genetic testing. However, at whole exome sequencing, the previously undescribed homozygous, obviously pathogenic PSAP gene NM_002778.3:c.209T>G(p.Val70Gly) variant was determined in the saposin A domain of the PSAP gene. Fibroblast studies showed GalCer accumulation and the activation of autophagy for the first time in a case of human saposin A deficiency. Our patient represents the second known case in the literature and provides new information concerning the pathophysiology of saposin A deficiency and its intralysosomal effects.



We thank Centogene AG for whole exome sequencing analyses.


  1. Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ et al (2016) Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell 15(1):77–88. Scholar
  2. Bradova V, Smid F, Ulrich-Bott B, Roggendorf W, Paton BC, Harzer K (1993) Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease. Hum Genet 92(2):143–152Google Scholar
  3. Deconinck N, Messaaoui A, Ziereisen F, Kadhim H, Sznajer Y, Pelc K et al (2008) Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency. Eur J Paediatr Neurol 12(1):46–50. Scholar
  4. Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerod L, Fisher EM et al (2007) Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 179(3):485–500. Scholar
  5. Harzer K, Paton BC, Christomanou H, Chatelut M, Levade T, Hiraiwa M, O'Brien JS (1997) Saposins (sap) A and C activate the degradation of galactosylceramide in living cells. FEBS Lett 417(3):270–274Google Scholar
  6. Harzer K, Knoblich R, Rolfs A, Bauer P, Eggers J (2002) Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta 317(1–2):77–84Google Scholar
  7. Kishimoto Y, Hiraiwa M, O'Brien JS (1992) Saposins: structure, function, distribution, and molecular genetics. J Lipid Res 33(9):1255–1267Google Scholar
  8. Kolter T, Sandhoff K (2005) Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu Rev Cell Dev Biol 21:81–103. Scholar
  9. Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A (2012) Autophagy in lysosomal storage disorders. Autophagy 8(5):719–730. Scholar
  10. Lim SM, Choi BO, Oh SI, Choi WJ, Oh KW, Nahm M et al (2016) Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease. Oncotarget 7(46):74496–74509. Scholar
  11. Matsuda J, Vanier MT, Saito Y, Tohyama J, Suzuki K, Suzuki K (2001) A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse. Hum Mol Genet 10(11):1191–1199Google Scholar
  12. Morimoto S, Martin BM, Yamamoto Y, Kretz KA, O'Brien JS, Kishimoto Y (1989) Saposin A: second cerebrosidase activator protein. Proc Natl Acad Sci U S A 86(9):3389–3393Google Scholar
  13. Orsini JJ, Martin MM, Showers AL, Bodamer OA, Zhang XK, Gelb MH, Caggana M (2012) Lysosomal storage disorder 4+1 multiplex assay for newborn screening using tandem mass spectrometry: application to a small-scale population study for five lysosomal storage disorders. Clin Chim Acta 413(15–16):1270–1273. Scholar
  14. Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, Ballabio A (2011) Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 20(19):3852–3866. Scholar
  15. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H et al (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131–24145. Scholar
  16. Ribbens JJ, Moser AB, Hubbard WC, Bongarzone ER, Maegawa GH (2014) Characterization and application of a disease-cell model for a neurodegenerative lysosomal disease. Mol Genet Metab 111(2):172–183. Scholar
  17. Sandhoff K (2016) Neuronal sphingolipidoses: membrane lipids and sphingolipid activator proteins regulate lysosomal sphingolipid catabolism. Biochimie 130:146–151. Scholar
  18. Sandhoff R, Hepbildikler ST, Jennemann R, Geyer R, Gieselmann V, Proia RL et al (2002) Kidney sulfatides in mouse models of inherited glycosphingolipid disorders: determination by nano-electrospray ionization tandem mass spectrometry. J Biol Chem 277(23):20386–20398. Scholar
  19. Seranova E, Connolly KJ, Zatyka M, Rosenstock TR, Barrett T, Tuxworth RI, Sarkar S (2017) Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. Essays Biochem 61(6):733–749. Scholar
  20. Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, Medina D et al (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17(1):119–129. Scholar
  21. Spiegel R, Bach G, Sury V, Mengistu G, Meidan B, Shalev S et al (2005) A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab 84(2):160–166Google Scholar
  22. Sun Y, Grabowski GA (2013) Altered autophagy in the mice with a deficiency of saposin A and saposin B. Autophagy 9(7):1115–1116. Scholar
  23. Sun Y, Qi X, Grabowski GA (2003) Saposin C is required for normal resistance of acid beta-glucosidase to proteolytic degradation. J Biol Chem 278(34):31918–31923. Scholar
  24. Sun Y, Zamzow M, Ran H, Zhang W, Quinn B, Barnes S et al (2013) Tissue-specific effects of saposin A and saposin B on glycosphingolipid degradation in mutant mice. Hum Mol Genet 22(12):2435–2450. Scholar
  25. Ward C, Martinez-Lopez N, Otten EG, Carroll B, Maetzel D, Singh R et al (2016) Autophagy, lipophagy and lysosomal lipid storage disorders. Biochim Biophys Acta 1861(4):269–284. Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Melis Kose
    • 1
  • Secil Akyildiz Demir
    • 2
  • Gulcin Akinci
    • 3
  • Cenk Eraslan
    • 4
  • Unsal Yilmaz
    • 3
  • Serdar Ceylaner
    • 5
  • Eser Sozmen Yildirim
    • 6
  • Volkan Seyrantepe
    • 2
  1. 1.Pediatric Metabolism DepartmentBehçet Uz Children Research and Training HospitalIzmirTurkey
  2. 2.Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
  3. 3.Pediatric Neurology DepartmentBehçet Uz Children Research and Training HospitalIzmirTurkey
  4. 4.Neuroradiology DepartmentEge University Faculty of MedicineIzmirTurkey
  5. 5.Intergen Genetic Diagnosis CentreAnkaraTurkey
  6. 6.Clinical ChemistryEge University Faculty of MedicineIzmirTurkey

Personalised recommendations