Lysosomal Free Sialic Acid Storage Disorders: Salla Disease and ISSD

  • Amanda Helip-Wooley
  • Robert Kleta
  • William A. Gahl

Salla disease and infantile free sialic acid storage disease (ISSD) are rare disorders of free sialic acid storage characterized by accumulation of the monosaccharide sialic acid (N-acetylneuraminic acid) in lysosomes. These disorders should be distinguished from sialuria in which free sialic acid accumulates in the cytoplasm. All three disorders present with increased excretion of free sialic acid in the urine. Only Salla disease and ISSD are discussed here in detail.


Sialic Acid Lysosomal Membrane Lysosomal Storage Disorder Chorionic Villus Sample Coarse Facial Feature 


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  1. Aula, N., Jalanko, A., Aula, P., and Peltonen, L., 2002, Unraveling the molecular patho-genesis of free sialic acid storage disorders: altered targeting of mutant sialin, Mol Genet Metab 77: 99.CrossRefPubMedGoogle Scholar
  2. Aula, N., Kopra, O., Jalanko, A., and Peltonen, L., 2004, Sialin expression in the CNS implicates extralysosomal function in neurons, Neurobiol Dis 15: 251.CrossRefPubMedGoogle Scholar
  3. Aula, N., Salomaki, P., Timonen, R., Verheijen, F., Mancini, G., Mansson, J. E., Aula, P., and Peltonen, L., 2000, The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation, Am J Hum Genet 67: 832.CrossRefPubMedGoogle Scholar
  4. Aula, P., and Gahl, W., 2001, Disorders of Free Sialic Acid Storage. In The Metabolic and Molecular Bases of Inherited Disease, C. Scriver, A. Beaudet, W. Sly, and D. Valle, Eds. (New York, McGraw-Hill), pp. 5109-5120.Google Scholar
  5. Aula, P., Autio, S., Raivio, K., Rapola, J., Thoden, C., Koskela, S., and Yamashina, I., 1979, “Salla Disease”. A new lysosomal storage disorder, Arch Neurol 36: 88.Google Scholar
  6. Biancheri, R., Verbeek, E., Rossi, A., Gaggero, R., Roccatagliata, L., Gatti, R., van Diggelen, O., Verheijen, F. W., and Mancini, G. M., 2002, An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease, Clin Genet 61: 443.CrossRefPubMedGoogle Scholar
  7. Bonifacino, J., and Dell’Angelica, E., 1999, Molecular bases for the recognition of tyrosine-based sorting signals, J Cell Biol 145: 923.CrossRefPubMedGoogle Scholar
  8. Cherqui, S., Kalatzis, V., Trugnan, G., and Antignac, C., 2001, The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif, J Biol Chem 276: 13314.CrossRefPubMedGoogle Scholar
  9. Clements, P., Taylor, J., and Hopwood, J., 1988, Biochemical characterization of patients and prenatal diagnosis of sialic acid storage disease for three families., J Inherit Metab Dis 11: 30.CrossRefPubMedGoogle Scholar
  10. Daneman, A., Stringer, D., and Reillly, B., 1983, Neonatal ascites due to lysosomal storage disease, Radiology 149: 463.PubMedGoogle Scholar
  11. Gillan, J. E., Lowden, J. A., Gaskin, K., and Cutz, E., 1984, Congenital ascites as a presenting sign of lysosomal storage disease, J Pediatrics 104: 225.CrossRefGoogle Scholar
  12. Haataja, L., Schleutker, J., Laine, A. P., Renlund, M., Savontaus, M. L., Dib, C., Weissenbach, J., Peltonen, L., and Aula, P., 1994, The genetic locus for free sialic acid storage disease maps to the long arm of chromosome 6, Am J Hum Genet 54: 1042.PubMedGoogle Scholar
  13. Hancock, L., Horwitz, A., and Dawson, G., 1983, N-acetylneuraminic acid and sialoglycoconjugate metabolism in fibroblasts from a patient with generalized N-acetylneuraminic acid storage disease, Biochem Biophys Acta 760: 42.PubMedGoogle Scholar
  14. Havelaar, A. C., Mancini, G. M., Beerens, C. E., Souren, R. M., and Verheijen, F. W., 1998, Purification of the lysosomal sialic acid transporter. Functional characteristics of a monocarboxylate transporter, J Biol Chem 273: 34568.CrossRefPubMedGoogle Scholar
  15. Irie, A., Koyama, S., Kozutsumi, Y., Kawasaki, T., and Suzuki, A., 1998, The molecular basis for the absence of N-glycolylneuraminic acid in humans, J Biol Chem 273: 15866.CrossRefPubMedGoogle Scholar
  16. Kleta, R., Aughton, D. J., Rivkin, M. J., Huizing, M., Strovel, E., Anikster, Y., Orvisky, E., Natowicz, M., Krasnewich, D., and Gahl, W. A., 2003, Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children, Am J Med Genet 120A: 28.CrossRefPubMedGoogle Scholar
  17. Kleta, R., Morse, R., Orvisky, E., Krasnewich, D., Alroy, J., Ucci, A., Bernardini, I., Wenger, D., and Gahl, W., 2004, Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity, Mol Genet Metab 82: 137.CrossRefPubMedGoogle Scholar
  18. Kornfeld, S., Kornfeld, R., Neufeld, E., and O’Brien, P., 1964, The feedback control of sugar nucleotide biosynthesis in liver, Proc Natl Acad Sci USA 52: 371.CrossRefPubMedGoogle Scholar
  19. Lake, B., Young, E., and Nicolaides, K., 1989, Prenatal diagnosis of infantile sialic acid storage disease in a twin pregnancy, J Inherit Metab Dis 12: 152.CrossRefPubMedGoogle Scholar
  20. Lemyre, E., Russo, P., Melancon, S. B., Gagne, R., Potier, M., and Lambert, M., 1999, Clinical spectrum of infantile free sialic acid storage disease, Am J Med Genet 82: 385.CrossRefPubMedGoogle Scholar
  21. Mancini, G., Beerens, C., Galjaard, H., and Verheijen, F., 1992, Functional reconstitution of the lysosomal sialic acid carrier into proteoliposomes, Proc Natl Acad Sci USA 89: 6609.CrossRefPubMedGoogle Scholar
  22. Mancini, G., de Jonge, H., Galjaard, H., and Verheijen, F., 1989, Characterization of a proton-driven carrier for sialic acid in the lysosomal membrane. Evidence for a group-specific transport system for acidic monosaccharides, J Biol Chem 264: 15247.PubMedGoogle Scholar
  23. Mancini, G., Verheijen, F., and Galjaard, H., 1986, Free N-acetylneuraminic acid storage disorders: evidence for defective NANA transport across the lysosomal membrane, Hum Genet 73: 214.CrossRefPubMedGoogle Scholar
  24. Mendla, K., Baumkotter, J., Rosenau, C., Ulrich-Bott, B., and Cantz, M., 1988, Defective lysosomal release of glycoprotein-derived sialic acid in fibroblasts from patients with sialic acid storage disease, Biochem J 250: 261.PubMedGoogle Scholar
  25. Morin, P., Sagne, C., and Gasnier, B., 2004, Functional characterization of wild-type and mutant human sialin, EMBO J 23: 4560.CrossRefPubMedGoogle Scholar
  26. Parazzini, C., Arena, S., Marchetti, L., Menni, F., Filocamo, M., Verheijen, F., Mancini, G., Triulzi, F., and Parini, R., 2003, Infantile sialic acid storage disease: Serial ultrasound and magnetic resonance imaging features, AJNR Am J Neuroradiol 24: 398.PubMedGoogle Scholar
  27. Pueschel, S., O’Shea, P., Alroy, J., Ambler, M., Dangond, F., Daniel, P., and Kolodny, E., 1988, Infantile sialic acid storage disease associated with renal disease, Pediatr Neurol 4: 207.CrossRefPubMedGoogle Scholar
  28. Rapoport, I., Chen, Y., Cupers, P., Shoelson, S., and Kirchhausen, T., 1998, Dileucine-based sorting signals bind to the beta chain of AP-1 at a site distinct and regulated differently from the tyrosine-based motif-binding site., EMBO J 17: 2148.CrossRefPubMedGoogle Scholar
  29. Renlund, M., and Aula, P., 1987, Prenatal detection of Salla disease based upon increased free sialic acid in amniocytes, Am J Med Genet 28: 377.CrossRefPubMedGoogle Scholar
  30. Renlund, M., Aula, P., Raivio, K. O., Autio, S., Sainio, K., Rapola, J., and Koskela, S. L., 1983a, Salla disease: A new lysosomal storage disorder with disturbed sialic acid metabolism, Neurology 33: 57.Google Scholar
  31. Renlund, M., Chester, M. A., Lundblad, A., Aula, P., Raivio, K. O., Autio, S., and Koskela, S. L., 1979, Increased urinary excretion of free N-acetylneuraminic acid in thirteen patients with Salla disease, Eur J Biochem 101: 245.CrossRefPubMedGoogle Scholar
  32. Renlund, M., Chester, M. A., Lundblad, A., Parkkinen, J., and Krusius, T., 1983b, Free N-acetylneuraminic acid in tissues in Salla disease and the enzymes involved in its metabolism, Eur J Biochem 130: 39.CrossRefGoogle Scholar
  33. Renlund, M., Kovanen, P. T., Raivio, K. O., Aula, P., Gahmberg, C. G., and Ehnholm, C., 1986a, Studies on the defect underlying the lysosomal storage of sialic acid in Salla disease. Lysosomal accumulation of sialic acid formed from N-acetyl-mannosamine or derived from low density lipoprotein in cultured mutant fibroblasts, J Clin Invest 77: 568.CrossRefGoogle Scholar
  34. Renlund, M., Tietze, F., and Gahl, W. A., 1986b, Defective sialic acid egress from isolated fibroblast lysosomes of patients with Salla disease, Science 232: 759.CrossRefGoogle Scholar
  35. Salomaki, P., Aula, N., Juvonen, V., Renlund, M., and Aula, P., 2001, Prenatal detection of free sialic acid storage disease: Genetic and biochemical studies in nine families, Prenat Diagn 21: 354.CrossRefPubMedGoogle Scholar
  36. Schauer, R., Sommer, U., Kruger, D., van Unen, H., and Traving, C., 1999, The terminal enzymes of sialic acid metabolism: Acylneuraminate-pyruvate-lyases, Biosci Rep 19: 373.CrossRefPubMedGoogle Scholar
  37. Schleutker, J., Laine, A. P., Haataja, L., Renlund, M., Weissenbach, J., Aula, P., and Peltonen, L., 1995, Linkage disequilibrium utilized to establish a refined genetic position of the Salla disease locus on 6q14-q15, Genomics 27: 286.CrossRefPubMedGoogle Scholar
  38. Seyrantepe, V., Poupetova, H., Froissart, R., Zabot, M., Maire, I., and Pshezhetsky, A., 2003, Molecular pathology of NEU1 gene in sialidosis, Hum Mutat 22: 343.CrossRefPubMedGoogle Scholar
  39. Sperl, W., Gruber, W., Quatacker, J., Monnens, L., Thoenes, W., Fink, F. M., and Paschke, E., 1990, Nephrosis in two siblings with infantile sialic acid storage disease, Eur J Pediatr 149: 477.CrossRefPubMedGoogle Scholar
  40. Stevenson, R., Lubinsky, M., Taylor, H., Wenger, D., Schroer, R., and Olmstead, P., 1983, Sialic acid storage disease with sialuria: Clinical and biochemical features in the severe infantile type, Pediatrics 72: 441.PubMedGoogle Scholar
  41. Stone, D. L., and Sidransky, E., 1999, Hydrops fetalis: Lysosomal storage disorders in extremis, Adv Pediatr 46: 409.PubMedGoogle Scholar
  42. Thomas, G., Scocca, J., Libert, J., Vamos, E., Miller, C., and Reynolds, L., 1983, Alterations in cultured fibroblasts of sibs with an infantile form of free (unbound) sialic acid storage disorder, Pediatr Res 17: 307.CrossRefPubMedGoogle Scholar
  43. Tietze, F., Seppala, R., Renlund, M., Hopwood, J. J., Harper, G. S., Thomas, G. H., and Gahl, W. A., 1989, Defective lysosomal egress of free sialic acid (N-acetylneur-aminic acid) in fibroblasts of patients with infantile free sialic acid storage disease, J Biol Chem 264: 15316.PubMedGoogle Scholar
  44. Tondeur, M., Libert, J., Vamos, E., Van Hoof, F., Thomas, G. H., and Strecker, G., 1982, Infantile form of sialic acid storage disorder: Clinical, ultrastructural, and biochemical studies in two siblings, Eur J Pediatr 139: 142.CrossRefPubMedGoogle Scholar
  45. Vamos, E., Libert, J., Elkhazen, N., Jauniaux, E., Hustin, J., Wilkin, P., Baumkotter, J., Mendla, K., Cantz, M., and Strecker, G., 1986, Prenatal diagnosis and confirmation of infantile sialic acid storage disease, Prenat Diagn 6: 437.CrossRefPubMedGoogle Scholar
  46. Varho, T., Jaaskelainen, S., Tolonen, U., Sonninen, P., Vainionpaa, L., Aula, P., and Sillanpaa, M., 2000, Central and peripheral nervous system dysfunction in the clinical variation of Salla disease, Neurology 55: 99.PubMedGoogle Scholar
  47. Varho, T., Komu, M., Sonninen, P., Holopainen, I., Nyman, S., Manner, T., Sillanpaa, M., Aula, P., and Lundbom, N., 1999, A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla disease. Neurology 52: 1668.PubMedGoogle Scholar
  48. Varho, T. T., Alajoki, L. E., Posti, K. M., Korhonen, T. T., Renlund, M. G., Nyman, S. R., Sillanpaa, M. L., and Aula, P. P., 2002, Phenotypic spectrum of Salla disease, a free sialic acid storage disorder, Pediatr Neurol 26: 267.CrossRefPubMedGoogle Scholar
  49. Verheijen, F. W., Verbeek, E., Aula, N., Beerens, C. E., Havelaar, A. C., Joosse, M., Peltonen, L., Aula, P., Galjaard, H., van der Spek, P. J., and Mancini, G. M., 1999, A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases, Nat Genet 23: 462.CrossRefPubMedGoogle Scholar
  50. Weiss, P., Tietze, F., Gahl, W., Seppala, R., and Ashwell, G., 1989, Identification of the metabolic defect in sialuria, J Biol Chem 264: 17635.PubMedGoogle Scholar
  51. Wreden, C. C., Wlizla, M., and Reimer, R. J., 2005, Varied mechanisms underlie the free sialic acid storage disorders, J Biol Chem 280: 1408.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Amanda Helip-Wooley
    • 1
  • Robert Kleta
    • 1
  • William A. Gahl
    • 1
  1. 1.Section on Human Biochemical Genetics, Medical Genetics BranchNational Human Genome Research Institute, NIHBethesdaUSA

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