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JIMD Reports - Volume 12 pp 79–84Cite as

Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation

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Part of the book series: JIMD Reports ((JIMD,volume 12))

Abstract

Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.

Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.

Competing interests: None declared

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References

  • 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(4):832–840

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baumkötter J, Cantz M, Mendla K, Baumann W, Friebolin H, Gehler J, Spranger J (1985) N-Acetylneuraminic acid storage disease. Hum Genet 71(2):155–159

    Article  PubMed  Google Scholar 

  • 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(6):443–447

    Article  CAS  PubMed  Google Scholar 

  • Biancheri R, Rossi A, Verbeek HA, Schot R, Corsolini F, Assereto S, Mancini GM, Verheijen FW, Minetti C, Filocamo M (2005) Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla disease. Neurogenetics 6(4):195–199

    Article  CAS  PubMed  Google Scholar 

  • Coker M, Kalkan-Ucar S, Kitis O, Ucar H, Goksen-Simsek D, Darcan S, Gokben S (2009) Salla disease in Turkish children: severe and conventional type. Turk J Pediatr 51(6):605–609

    PubMed  Google Scholar 

  • Debray FG, Lefebvre C, Colinet S, Segers K, Stevens R (2011) Free sialic acid storage disease mimicking cerebral palsy and revealed by blood smear examination. J Pediatr 158(1):165

    Article  PubMed  Google Scholar 

  • Erikson A, Aula N, Aula P, Mansson JE (2002) Free sialic acid storage (Salla) disease in Sweden. Acta Paediatr 91(12):1324–1327

    Article  CAS  PubMed  Google Scholar 

  • Fois A, Balestri P, Farnetani MA, Mancini GM, Borgogni P, Margollicci MA, Molinelli M, Alessandrini C, Gerli R (1987) Free sialic acid storage disease. A new Italian case. Eur J Pediatr 146(2):195–198

    Article  CAS  PubMed  Google Scholar 

  • 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 42(11):829–836

    Article  CAS  PubMed  Google Scholar 

  • Landau D, Cohen D, Shalev H, Pinsk V, Yerushalmi B, Zeigler M, Birk OS (2004) A novel mutation in the SLC17A5 gene causing both severe and mild phenotypes of free sialic acid storage disease in one inbred Bedouin kindred. Mol Genet Metab 82(2):167–172

    Article  CAS  PubMed  Google Scholar 

  • Lemyre E, Russo P, Melancon SB, Gagne R, Potier M, Lambert M (1999) Clinical spectrum of infantile free sialic acid storage disease. Am J Med Genet 82(5):385–391

    Article  CAS  PubMed  Google Scholar 

  • Mochel F, Yang B, Barritault J, Thompson JN, Engelke UF, McNeill NH, Benko WS, Kaneski CR, Adams DR, Tsokos M et al (2009) Free sialic acid storage disease without sialuria. Ann Neurol 65(6):753–757

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mochel F, Engelke UF, Barritault J, Yang B, McNeill NH, Thompson JN, Vanderver A, Wolf NI, Willemsen MA, Verheijen FW, Seguin F, Wevers RA, Schiffmann R (2010) Elevated CSF N-acetylaspartylglutamate in patients with free sialic acid storage diseases. Neurology 74(4):302–305

    Article  CAS  PubMed  Google Scholar 

  • Morin P, Sagne C, Gasnier B (2004) Functional characterization of wild-type and mutant human sialin. EMBO J 23(23):4560–4570

    Article  CAS  PubMed  Google Scholar 

  • Myall NJ, Wreden CC, Wlizla M, Reimer RJ (2007) G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking. Mol Genet Metab 92(4):371–374

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakano C, Hirabayashi Y, Ohno K, Yano T, Mito T, Sakurai M (1996) A Japanese case of infantile sialic acid storage disease. Brain Dev 18(2):153–156

    Article  CAS  PubMed  Google Scholar 

  • Paschke E, Trinkl G, Erwa W, Pavelka M, Mutz I, Roscher A (1986) Infantile type of sialic acid storage disease with sialuria. Clin Genet 29(5):417–424

    Article  CAS  PubMed  Google Scholar 

  • Pueschel SM, O’Shea PA, Alroy J, Ambler MW, Dangond F, Daniel PF, Kolodny EH (1988) Infantile sialic acid storage disease associated with renal disease. Pediatr Neurol 4(4):207–212

    Article  CAS  PubMed  Google Scholar 

  • Ruivo R, Sharifi A, Boubekeur S, Morin P, Anne C, Debacker C, Graziano JC, Sagne C, Gasnier B (2008) Molecular pathogenesis of sialic acid storage diseases: insight gained from four missense mutations and a putative polymorphism of human sialin. Biol Cell 100(9):551–559

    Article  CAS  PubMed  Google Scholar 

  • Sonderby Christensen P, Kaad PH, Ostergaard JR (2003) Two cases of Salla disease in Danish children. Acta Paediatr 92(11):1357–1358

    Article  CAS  PubMed  Google Scholar 

  • Stamatos NM, Liang F, Nan X, Landry K, Cross AS, Wang LX, Pshezhetsky AV (2005) Differential expression of endogenous sialidases of human monocytes during cellular differentiation into macrophages. FEBS J 272(10):2545–2556

    Article  CAS  PubMed  Google Scholar 

  • Tylki-Szymanska A, Czartoryska B, Lugowska A, Verheijen FW, Mancini GM, Rokicki D, Taybert J, Chmielinska E (2003) Infantile sialic acid storage disease (ISSD): report of the first case detected in Poland. Pediatr Int 45(2):199–200

    Article  PubMed  Google Scholar 

  • 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(4):462–465

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Zhang J, Bian H, Wu P, Kuvelkar R, Kung TT, Crawley Y, Egan RW, Billah MM (2004) Induction of lysosomal and plasma membrane-bound sialidases in human T-cells via T-cell receptor. Biochem J 380(Part 2):425–433

    Article  CAS  PubMed  Google Scholar 

  • Wreden CC, Wlizla M, Reimer RJ (2005) Varied mechanisms underlie the free sialic acid storage disorders. J Biol Chem 280(2):1408–1416

    Article  CAS  PubMed  Google Scholar 

  • Yarovaya N, Schot R, Fodero L, McMahon M, Mahoney A, Williams R, Verbeek E, de Bondt A, Hampson M, van der Spek P, Stubbs A, Masters CL, Verheijen FW, Mancini GM, Venter DJ (2005) Sialin, an anion transporter defective in sialic acid storage diseases, shows highly variable expression in adult mouse brain, and is developmentally regulated. Neurobiol Dis 19(3):351–365

    Article  CAS  PubMed  Google Scholar 

  • Ylitalo V, Hagberg B, Rapola J, Månsson JE, Svennerholm L, Sanner G, Tonnby B (1986) Salla disease variants. Sialoylaciduric encephalopathy with increased sialidase activity in two non-Finnish children. Neuropediatrics 17(1):44–47

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Metabolics and Newborn Screening, University of Ottawa, Children’s Hospital of Eastern Ontario, 401 Smyth Road, K1H 8L1, Ottawa, ON, Canada

    Matthew A. Lines & Michael T. Geraghty

  2. Departments of Biochemistry, Paediatrics and Children’s Health Research Institute, University of Western Ontario, London, ON, Canada

    C. Anthony Rupar & Jack W. Rip

  3. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Uppland, Sweden

    Berivan Baskin

  4. Division of Molecular Genetics, The Hospital for Sick Children, Toronto, ON, Canada

    Peter N. Ray

  5. Robarts Research Institute and Department of Medicine, University of Western Ontario, London, ON, Canada

    Robert A. Hegele

  6. Department of Pathology, University of Ottawa, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    David Grynspan & Jean Michaud

Authors
  1. Matthew A. Lines
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  2. C. Anthony Rupar
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  3. Jack W. Rip
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  4. Berivan Baskin
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  5. Peter N. Ray
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  6. Robert A. Hegele
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  7. David Grynspan
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  8. Jean Michaud
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  9. Michael T. Geraghty
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Corresponding author

Correspondence to Michael T. Geraghty .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. College of Pharmacy, Washington State University Clinical Pharmacology, Pullman, Washington, USA

    K Michael Gibson

  3. Department of Biochemistry Genetics Unit, University of Oxford, Oxford, United Kingdom

    Garry Brown

  4. Department of Pediatrics IGMD, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Eva Morava

  5. Center for Child and Adolescent Medicine Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Verena Peters

Appendices

Synopsis

The sequential ascertainment of two unrelated Canadian Inuit patients homozygous for the same SLC17A5 mutation raises the possibility of a founder mutation for infantile sialic acid storage disease (ISSD) in this population.

Author Contributions

Matthew Lines: Primary authorship of manuscript

Tony Rupar and Jack Rip: Enzymatic analyses and assistance with writing

Berivan Baskin and Peter Ray: Molecular analyses

David Grynspan and Jean Michaud: Description of pathological findings and preparation of histologic images

Michael Geraghty: Corresponding author, study design, critical appraisal, assistance with writing

Guarantor

Michael Geraghty

Compliance with Ethics Guidelines

Matthew Lines, Tony Rupar, Jack Rip, Berivan Baskin, Peter Ray, Robert Hegele, David Grynspan, Jean Michaud, and Michael Geraghty each declare that they have no conflict of interest.

This manuscript is a retrospective case series containing no identifying patient information, and data were collected in the course of provisioning the routine standard of clinical care (rather than as part of a research study). All procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000.

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© 2013 SSIEM and Springer-Verlag Berlin Heidelberg 2013

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Lines, M.A. et al. (2013). Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Volume 12. JIMD Reports, vol 12. Springer, Cham. https://doi.org/10.1007/8904_2013_247

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  • DOI: https://doi.org/10.1007/8904_2013_247

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-03460-7

  • Online ISBN: 978-3-319-03461-4

  • eBook Packages: MedicineMedicine (R0)

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