Abstract
Lysosomal free sialic acid storage diseases are recessively inherited allelic neurodegenerative disorders that include Salla disease (SD) and infantile sialic acid storage disease (ISSD) caused by mutations in the SLC17A5 gene encoding for a lysosomal membrane protein, sialin, transporting sialic acid from lysosomes. The classical form of SD, enriched in the Finnish population, is related to the p.R39C designed SallaFIN founder mutation. A more severe phenotype is due both to compound heterozygosity for the p.R39C mutation and to different mutations. The p.R39C has not been reported in ISSD. We identified the first case of SD caused by the homozygosity for p.K136E (c.406A>G) mutation, showing a severe clinical picture, as demonstrated by the early age at onset, the degree of motor retardation, the occurrence of peripheral nerve involvement, as well as cerebral hypomyelination. Recently, in vitro functional studies have shown that the p.K136E mutant produces a mislocalization and a reduced activity of the intracellular sialin. We discuss the in vivo phenotypic consequence of the p.K136E in relation to the results obtained by the in vitro functional characterization of the p.K136E mutant. The severity of the clinical picture, in comparison with the classical SD, may be explained by the fact that the p.K136E mutation mislocalizes the protein to a greater degree than p.R39C. On the other hand, the presence of a residual transport activity may account for the absence of hepatosplenomegaly, dysostosis multiplex, and early lethality typical of ISSD and related to the abolished transport activity found in this latter form.
Similar content being viewed by others
References
Aula P, Gahl WA (2001) Disorders of free sialic acid storage. In: Scriver CR, Beaudet AL, Sly WE, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 5109–5120
Mancini GM, Beerens CE, Aula PP, Verheijen FW (1991) Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides. J Clin Invest 87:1329–1335
Mancini GM, Verheijen FW, Beerens CE, Renlund M, Aula P (1991) Sialic acid storage disorders: observations on clinical and biochemical variation. Dev Neurosci 13:327–330
Aula N, Salomaki P, Timonen R, Verheijen F, Mancini G, Mansson JE, Aula P, 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 67:832–840
Mancini GM, Hu P, Verheijen FW, van Diggelen OP, Janse HC, Kleijer WJ, Beemer FA, Jennekens FG (1992) Salla disease variant in a Dutch patient. Potential value of polymorphonuclear leucocytes for heterozygote detection. Eur J Pediatr 151:590–595
Biancheri R, Verbeek E, Rossi A, Gaggero R, Roccatagliata L, Gatti R, van Diggelen O, Verheijen FW, Mancini GM (2002) An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease. Clin Genet 61:443–447
Varho TT, Alajoki LE, Posti KM, Korhonen TT, Renlund MG, Nyman SR, Sillanpaa ML, Aula PP (2002) Phenotypic spectrum of Salla disease, a free sialic acid storage disorder. Pediatr Neurol 26:267–273
Kleta R, Aughton DJ, Rivkin MJ, Huizing M, Strovel E, Anikster Y, Orvisky E, Natowicz M, Krasnewich D, Gahl WA (2003) Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children. Am J Med Genet A 120:28–33
Alajoki L, Varho T, Posti K, Aula P, Korhonen T (2004) Neurocognitive profiles in Salla disease. Dev Med Child Neurol 46:832–837
Sonninen P, Autti T, Varho T, Hamalainen M, Raininko R (1999) Brain involvement in Salla disease. Am J Neuroradiol 20:433–443
Haataja L, Parkkola R, Sonninen P, Vanhanen SL, Schleutker J, Aarimaa T, Turpeinen U, Renlund M, Aula P (1994) Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder. Neuropediatrics 25:238–244
Linnankivi T, Lonnqvist T, Autti T (2003) A case of Salla disease with involvement of the cerebellar white matter. Neuroradiology 45:107–109
Robinson RO, Fensom AH, Lake BD (1997) Salla disease—rare or underdiagnosed? Dev Med Child Neurol 39:153–157
Biancheri R, Rossi A, Mancini MG, Minetti C (2004) Cerebellar white matter involvement in Salla disease. Neuroradiology 46:587–588
Parazzini C, Arena S, Marchetti L, Menni F, Filocamo M, Verheijen FW, Mancini GM, Triulzi F, Parini R (2003) Infantile sialic acid storage disease: serial ultrasound and magnetic resonance imaging features. Am J Neuroradiol 24:398–400
Verheijen FW, Verbeek E, Aula N, Beerens CE, Havelaar AC, Joosse M, Peltonen L, Aula P, Galjaard H, van der Spek PJ, Mancini GM (1999) A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet 23:462–465
Froissart R, Cheillan D, Bouvier R, Tourret S, Bonnet V, Piraud M, Maire I (2005) Clinical, morphological and molecular aspects of sialic acid storage disease manifesting in utero. J Med Genet Apr 1 [Epub ahead of print]
Morin P, Sagne C, Gasnier B (2004) Functional characterization of wild-type and mutant human sialin. EMBO J 23:4560–4570
Wreden CC, Wlizla M, Reimer RJ (2005) Varied mechanisms underlie the free sialic acid storage disorders. J Biol Chem 280:1408–1416
Cardo PP, Lombardo C, Gatti R (1985) A simple detection of sialic acid storage disorders by urinary ‘free’ and ‘total’ sialic acid determinations. Clin Chim Acta 150:129–135
Varho T, Jaaskelainen S, Tolonen U, Sonninen P, Vainionpaa L, Aula P, Sillanpaa M (2000) Central and peripheral nervous system dysfunction in the clinical variation of Salla disease. Neurology 55:99–104
Acknowledgements
The samples were obtained from the “Cell Line and DNA Bank from Patients Affected by Genetic Diseases” collection (http://www.gaslini.org/labdppm.htm) supported by Italian Telethon grants (project no. GTF04002). The authors thank Dr. O.P. van Diggelen (Department of Clinical Genetics, Erasmus University and Academic Hospital, Rotterdam) for having evaluated free sialic acid levels in fibroblasts.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Biancheri, R., Rossi, A., Verbeek, H.A. et al. Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla disease. Neurogenetics 6, 195–199 (2005). https://doi.org/10.1007/s10048-005-0011-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-005-0011-3