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. 2005 Apr 1;42(11):829–836. doi: 10.1136/jmg.2004.029744

Clinical, morphological, and molecular aspects of sialic acid storage disease manifesting in utero

R Froissart 1, D Cheillan 1, R Bouvier 1, S Tourret 1, V Bonnet 1, M Piraud 1, I Maire 1
PMCID: PMC1735939  PMID: 15805149

Abstract

Background: Sialic acid storage diseases (SASDs) are caused by the defective transport of free sialic acid outside the lysosome. Apart from the Salla presentation in Finland, SASD is a very rare form of lysosomal storage disease (LSD) with approximately 35 cases, all diagnosed after birth, having been reported worldwide. We report a series of 12 French patients with very early manifestations, including eight fetuses diagnosed in utero.

Results: Ultrasound examination, fetal autopsy, or clinical examination showed prominent ascites, rarely progressing to complete hydrops, and highlighted the early severity of bone disease. Dramatic increase of free sialic acid in various biological samples confirmed the diagnosis in all cases. Storage staining affinities and storage distribution in placenta and fetal organs allowed differential diagnosis from other LSDs but cannot differentiate between SASD, sialidosis, and galactosialidosis. Fourteen different mutations were identified, showing the molecular heterogeneity of SASD in the French population. We found that the previously described p.Y306X mutation generated two different transcripts, and we identified seven novel mutations: three deletions (del exon 7, del exons10+11 and c.1296delT), one splice site mutation (c.1350+1G→T) one nonsense mutation (p.W339X), and two missense mutations (p.R57C and p.G127E).

Conclusions: The severity of our patients' genotypes is in agreement with their phenotypes but not with the importance and early appearance of the very frequent in utero manifestations. Minimal fetal disease in some patients and a reported case of heterogeneity of fetal involvement within a family suggest that factors other than the genotype influence fetal manifestations.

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Selected References

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  1. Aula N., Salomäki P., Timonen R., Verheijen F., Mancini G., Månsson J. E., Aula P., Peltonen L. The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. Am J Hum Genet. 2000 Aug 17;67(4):832–840. doi: 10.1086/303077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aula Nina, Jalanko Anu, Aula Pertti, Peltonen Leena. Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin. Mol Genet Metab. 2002 Sep-Oct;77(1-2):99–107. doi: 10.1016/s1096-7192(02)00124-5. [DOI] [PubMed] [Google Scholar]
  3. Beck M., Braun S., Coerdt W., Merz E., Young E., Sewell A. C. Fetal presentation of Morquio disease type A. Prenat Diagn. 1992 Dec;12(12):1019–1029. doi: 10.1002/pd.1970121207. [DOI] [PubMed] [Google Scholar]
  4. Berra B., Gornati R., Rapelli S., Gatti R., Mancini G. M., Ciana G., Bembi B. Infantile sialic acid storage disease: biochemical studies. Am J Med Genet. 1995 Jul 31;58(1):24–31. doi: 10.1002/ajmg.1320580107. [DOI] [PubMed] [Google Scholar]
  5. Biancheri R., Verbeek E., Rossi A., Gaggero R., Roccatagliata L., Gatti R., van Diggelen Op, Verheijen F. W., Mancini G. M. S. An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease. Clin Genet. 2002 Jun;61(6):443–447. doi: 10.1034/j.1399-0004.2002.610608.x. [DOI] [PubMed] [Google Scholar]
  6. Bouvier R., Maire I. Diagnostic des maladies de surcharge lysosomiale à révélation foetale. Ann Pathol. 1997 Sep;17(4):277–280. [PubMed] [Google Scholar]
  7. Carbillon L., Largillière C., Bucourt M., Scheuer-Niro B., Levaillant J. M., Uzan M. Ultrasound assessment in a case of sialic acid storage disease. Ultrasound Obstet Gynecol. 2001 Sep;18(3):272–274. doi: 10.1046/j.0960-7692.2001.00515.x. [DOI] [PubMed] [Google Scholar]
  8. Daneman A., Stringer D., Reilly B. J. Neonatal ascites due to lysosomal storage disease. Radiology. 1983 Nov;149(2):463–467. doi: 10.1148/radiology.149.2.6414044. [DOI] [PubMed] [Google Scholar]
  9. Echenne B., Vidal M., Maire I., Michalski J. C., Baldet P., Astruc J. Salla disease in one non-Finnish patient. Eur J Pediatr. 1986 Sep;145(4):320–322. doi: 10.1007/BF00439413. [DOI] [PubMed] [Google Scholar]
  10. Hale L. P., van de Ven C. J., Wenger D. A., Bradford W. D., Kahler S. G. Infantile sialic acid storage disease: a rare cause of cytoplasmic vacuolation in pediatric patients. Pediatr Pathol Lab Med. 1995 May-Jun;15(3):443–453. doi: 10.3109/15513819509026980. [DOI] [PubMed] [Google Scholar]
  11. Kirchner Lieselotte, Kircher Susanne, Salzer-Muhar Ulrike, Paschke Eduard, Birnbacher Robert, Stöckler-Ipsiroglu Sylvia. Infantile sialic acid storage disease and protein-losing gastroenteropathy. Pediatr Neurol. 2003 Apr;28(4):313–317. doi: 10.1016/s0887-8994(02)00629-x. [DOI] [PubMed] [Google Scholar]
  12. Kleta Robert, Aughton David J., Rivkin Michael J., Huizing Marjan, Strovel Erin, Anikster Yair, Orvisky Eduard, Natowicz Marvin, Krasnewich Donna, Gahl William A. Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children. Am J Med Genet A. 2003 Jul 1;120A(1):28–33. doi: 10.1002/ajmg.a.20024. [DOI] [PubMed] [Google Scholar]
  13. Landau D., Cohen D., Shalev H., Pinsk V., Yerushalmi B., Zeigler M., Birk O. S. 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. 2004 Jun;82(2):167–172. doi: 10.1016/j.ymgme.2004.03.005. [DOI] [PubMed] [Google Scholar]
  14. Lefebvre G., Wehbe G., Heron D., Vautjoer Brouzes D., Choukroun J. B., Darbois Y. Recurrent nonimmune hydrops fetalis: a rare presentation of sialic acid storage disease. Genet Couns. 1999;10(3):277–284. [PubMed] [Google Scholar]
  15. Lemyre E., Russo P., Melançon S. B., Gagné R., Potier M., Lambert M. Clinical spectrum of infantile free sialic acid storage disease. Am J Med Genet. 1999 Feb 19;82(5):385–391. [PubMed] [Google Scholar]
  16. Machin G. A. Hydrops revisited: literature review of 1,414 cases published in the 1980s. Am J Med Genet. 1989 Nov;34(3):366–390. doi: 10.1002/ajmg.1320340313. [DOI] [PubMed] [Google Scholar]
  17. Parazzini Cecilia, Arena Saverio, Marchetti Lucrezia, Menni Francesca, Filocamo Mirella, Verheijen Frans W., Mancini Grazia M. S., Triulzi Fabio, Parini Rossella. Infantile sialic acid storage disease: serial ultrasound and magnetic resonance imaging features. AJNR Am J Neuroradiol. 2003 Mar;24(3):398–400. [PMC free article] [PubMed] [Google Scholar]
  18. Piraud M., Froissart R., Mandon G., Bernard A., Maire I. Amniotic fluid for screening of lysosomal storage diseases presenting in utero (mainly as non-immune hydrops fetalis). Clin Chim Acta. 1996 Apr 30;248(2):143–155. doi: 10.1016/0009-8981(95)06250-5. [DOI] [PubMed] [Google Scholar]
  19. Poulain P., Odent S., Maire I., Milon J., Proudhon J. F., Jouan H., Le Marec B. Fetal ascites and oligohydramnios: prenatal diagnosis of a sialic acid storage disease (index case). Prenat Diagn. 1995 Sep;15(9):864–867. doi: 10.1002/pd.1970150913. [DOI] [PubMed] [Google Scholar]
  20. Pueschel S. M., O'Shea P. A., Alroy J., Ambler M. W., Dangond F., Daniel P. F., Kolodny E. H. Infantile sialic acid storage disease associated with renal disease. Pediatr Neurol. 1988 Jul-Aug;4(4):207–212. doi: 10.1016/0887-8994(88)90032-x. [DOI] [PubMed] [Google Scholar]
  21. Salomäki P., Aula N., Juvonen V., Renlund M., Aula P. Prenatal detection of free sialic acid storage disease: genetic and biochemical studies in nine families. Prenat Diagn. 2001 May;21(5):354–358. doi: 10.1002/pd.68. [DOI] [PubMed] [Google Scholar]
  22. Schleutker J., Leppänen P., Månsson J. E., Erikson A., Weissenbach J., Peltonen L., Aula P. Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15. Am J Hum Genet. 1995 Oct;57(4):893–901. [PMC free article] [PubMed] [Google Scholar]
  23. Sewell A. C., Poets C. F., Degen I., Stöss H., Pontz B. F. The spectrum of free neuraminic acid storage disease in childhood: clinical, morphological and biochemical observations in three non-Finnish patients. Am J Med Genet. 1996 May 3;63(1):203–208. doi: 10.1002/(SICI)1096-8628(19960503)63:1<203::AID-AJMG36>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  24. Tylki-Szymańska Anna, Czartoryska Barbara, Lugowska Agnieszka, Verheijen Frans W., Mancini Grazia M. S., Rokicki Dariusz, Taybert Joanna, Chmielíska Elzbieta. Infantile sialic acid storage disease (ISSD): report of the first case detected in Poland. Pediatr Int. 2003 Apr;45(2):199–200. doi: 10.1046/j.1442-200x.2003.01693.x. [DOI] [PubMed] [Google Scholar]
  25. Utagawa C. Y., Sugayama S. M., Ribeiro E. M., Bertola D. R., Baba E. R., Burin M. G., Lewis E., Coelho H. C., Fensom A. H., Marques-Dias M. J. Infantile sialic acid storage disease: report of the first case in South America. Clin Genet. 1999 May;55(5):386–387. [PubMed] [Google Scholar]
  26. Valianpour Fredoen, Abeling Nicolaas G. G. M., Duran Marinus, Huijmans Jan G. M., Kulik Willem. Quantification of free sialic acid in urine by HPLC-electrospray tandem mass spectrometry: a tool for the diagnosis of sialic acid storage disease. Clin Chem. 2003 Dec 18;50(2):403–409. doi: 10.1373/clinchem.2003.027169. [DOI] [PubMed] [Google Scholar]
  27. 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. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet. 1999 Dec;23(4):462–465. doi: 10.1038/70585. [DOI] [PubMed] [Google Scholar]
  28. Vervoort R., Islam M. R., Sly W. S., Zabot M. T., Kleijer W. J., Chabas A., Fensom A., Young E. P., Liebaers I., Lissens W. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. Am J Hum Genet. 1996 Mar;58(3):457–471. [PMC free article] [PubMed] [Google Scholar]

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