A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease—an ultra-orphan multisystemic lysosomal storage disorder

Abstract

Purpose

Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5.

Methods

Analysis of published cases with SASD (N = 116) respecting STROBE criteria. Main outcome parameters: survival and diagnostic delay. Phenotype, phenotype–biomarker associations, and geographical patient distribution were explored.

Results

Median age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years. The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds. Cluster analysis of disease features suggested a continuous phenotypic spectrum. Patient distribution was panethnic.

Conclusion

Combination of neurologic symptoms, visceromegaly, and dysmorphic features and/or nonimmune hydrops fetalis should prompt specific tests for SASD, reducing diagnostic delay. The present quantitative data inform clinical studies and may stimulate and accelerate development of specific therapies. Biomarker–phenotype association is particularly important for both counseling parents and study design.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Age of onset of sialic acid storage disease (SASD) and age at diagnosis.
Fig. 2: Estimated survival distributions for patients with sialic acid storage disease (SASD).
Fig. 3: Estimated age of disease onset for patients with sialic acid storage disease (SASD).

References

  1. 1.

    Verheijen FW, Verbeek E, Aula N, et al. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet. 1999;23:462–5.

  2. 2.

    Pertti A, Gahl WA. Disorders of free sialic acid storage. In: Valle D, editor. The online metabolic and molecular bases of inherited disease 2018. https://ommbid.mhmedical.com/content.aspx?sectionid=62655871&bookid=971&Resultclick=2. Accessed 15 March 2018.

  3. 3.

    Mancini GM, Beerens CE, Aula PP, et al. Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides. J Clin Invest. 1991;87:1329–35.

  4. 4.

    Aula P, Autio S, Raivio KO, et al. “Salla disease”: a new lysosomal storage disorder. Arch Neurol. 1979;36:88–94.

  5. 5.

    Tondeur M, Libert J, Vamos E, et al. Infantile form of sialic acid storage disorder: clinical, ultrastructural, and biochemical studies in two siblings. Eur J Pediatr. 1982;139:142–7.

  6. 6.

    Miyaji T, Echigo N, Hiasa M, et al. Identification of a vesicular aspartate transporter. Proc Natl Acad Sci USA. 2008;105:11720–4.

  7. 7.

    Prolo LM, Vogel H, Reimer RJ. The lysosomal sialic acid transporter sialin is required for normal CNS myelination. J Neurosci. 2009;29:15355–65.

  8. 8.

    Stroobants S, Van Acker NG, Verheijen FW, et al. Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice. Exp Neurol. 2017;291:106–19.

  9. 9.

    Orphanet Report Series. Prevalence of rare diseases: bibliographic data. June 2017, no. 1. http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. Accessed 31 December 2017.

  10. 10.

    US Food and Drug Administration. Search orphan drug designations and approvals. 2017. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/. Accessed 31 December 2017.

  11. 11.

    Mechler K, Mountford WK, Hoffmann GF, et al. Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med. 2015;17:965–70.

  12. 12.

    Zielonka M, Garbade SF, Kolker S, et al. Quantitative clinical characteristics of 53 patients with MPS VII: a cross-sectional analysis. Genet Med. 2017;19:983–8.

  13. 13.

    Zielonka M, Garbade SF, Kolker S, et al. A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features. Genet Med. 2018;20:524–30.

  14. 14.

    von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7.

  15. 15.

    Hothorn T, Hornik K, Zeileis A. Unbiased recursive partitioning: a conditional inference framework. J Comput Graph Stat. 2006;15:651–74.

  16. 16.

    Ries M, Moore DF, Robinson CJ, et al. Quantitative dysmorphology assessment in Fabry disease. Genet Med. 2006;8:96–101.

  17. 17.

    Kahle D, Wickham H. ggmap: spatial visualization with ggplot2. R J. 2013;5:144–61.

  18. 18.

    Gimovsky AC, Luzi P, Berghella V. Lysosomal storage disease as an etiology of nonimmune hydrops. Am J Obstet Gynecol. 2015;212:281–90.

  19. 19.

    Helip-Wooley A, Kleta R, Gahl WA. Lysosomal free sialic acid storage disorders: Salla disease and ISSD. In: Barranger JAC-SM, editor. Lysosomal storage disorders. New York: Springer; 2007. p. 499–511.

  20. 20.

    Adams D, Gahl WA. Free sialic acid storage disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle, WA: University of Washington; 1993.

  21. 21.

    Hinderlich S, Weidemann W, Yardeni T, et al. UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE): a master regulator of sialic acid synthesis. Top Curr Chem. 2015;366:97–137.

  22. 22.

    Mancini GM, Verheijen FW, Beerens CE, et al. Sialic acid storage disorders: observations on clinical and biochemical variation. Dev Neurosci. 1991;13:327–30.

  23. 23.

    Sidransky E. Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab. 2004;83:6–15.

  24. 24.

    Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363:1991–2003.

  25. 25.

    Harutyunyan M, Huang Y, Mun KS, et al. Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations. Am J Physiol Lung Cell Mol Physiol. 2018;314:L529–L543.

  26. 26.

    Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016;86:890–7.

  27. 27.

    Hua Y, Vickers TA, Okunola HL, et al. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008;82:834–48.

  28. 28.

    Hinderhofer K, Mechler K, Hoffmann GF, et al. Critical appraisal of genotype assessment in molybdenum cofactor deficiency. J Inherit Metab Dis. 2017;40:801–11.

  29. 29.

    Mechler K, Mountford WK, Hoffmann GF, et al. Pressure for drug development in lysosomal storage disorders—a quantitative analysis thirty years beyond the US Orphan Drug Act. Orphanet J Rare Dis. 2015;10:46.

  30. 30.

    Wagner JA, Dahlem AM, Hudson LD, et al. Application of a dynamic map for learning, communicating, navigating, and improving therapeutic development. Clin Transl Sci. 2018;11:166–174.

Download references

Acknowledgements

M.Z. received support from the Physician-Scientist Program at Ruprecht-Karls-University Heidelberg Faculty of Medicine.

Author information

Correspondence to Matthias Zielonka MD.

Ethics declarations

DISCLOSURE

The authors declare no conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zielonka, M., Garbade, S.F., Kölker, S. et al. A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease—an ultra-orphan multisystemic lysosomal storage disorder. Genet Med 21, 347–352 (2019). https://doi.org/10.1038/s41436-018-0051-3

Download citation

Keywords

  • Sialic acid storage disease
  • SLC17A5
  • Natural history
  • Drug development
  • Orphan disease

Further reading