pp 1-12 | Cite as
The Second Case of Saposin A Deficiency and Altered Autophagy
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.
- 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
- 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. https://doi.org/10.1083/jcb.200702115CrossRefGoogle Scholar
- 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
- 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
- Kishimoto Y, Hiraiwa M, O'Brien JS (1992) Saposins: structure, function, distribution, and molecular genetics. J Lipid Res 33(9):1255–1267Google Scholar
- 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. https://doi.org/10.1146/annurev.cellbio.21.122303.120013CrossRefGoogle Scholar
- 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
- 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
- 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. https://doi.org/10.1016/j.cca.2012.04.012CrossRefGoogle Scholar
- 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. https://doi.org/10.1074/jbc.M110641200CrossRefGoogle Scholar
- 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