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):143–152CrossRefGoogle 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.200702115 CrossRefPubMedPubMedCentralGoogle 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.21.122303.120013 CrossRefPubMedGoogle 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.2012.04.012 CrossRefPubMedPubMedCentralGoogle 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.M110641200 CrossRefPubMedGoogle Scholar