Advertisement

Molecular and Cellular Biochemistry

, Volume 458, Issue 1–2, pp 27–37 | Cite as

Biochemical, machine learning and molecular approaches for the differential diagnosis of Mucopolysaccharidoses

  • Srilatha Kadali
  • Shaik Mohammad Naushad
  • Akella Radha Rama Devi
  • Vijaya Lakshmi BodigaEmail author
Article

Abstract

This study was aimed to construct classification and regression tree (CART) model of glycosaminoglycans (GAGs) for the differential diagnosis of Mucopolysaccharidoses (MPS). Two-dimensional electrophoresis and liquid chromatography–tandem mass spectrometry (LC–MS/MS) were used for the qualitative and quantitative analysis of GAGs. Specific enzyme assays and targeted gene sequencing were performed to confirm the diagnosis. Machine learning tools were used to develop CART model based on GAG profile. Qualitative and quantitative CART models showed 96.3% and 98.3% accuracy, respectively, in the differential diagnosis of MPS. The thresholds of different GAGs diagnostic of specific MPS types were established. In 60 MPS positive cases, 46 different mutations were identified in six specific genes. Among 31 different mutations identified in IDUA, nine were nonsense mutations and two were gross deletions while the remaining were missense mutations. In IDS gene, four missense, two frameshift, and one deletion were identified. In NAGLU gene, c.1693C > T and c.1914_1914insT were the most common mutations. Two ARSB, one case each of SGSH and GALNS mutations were observed. LC–MS/MS-based GAG pattern showed higher accuracy in the differential diagnosis of MPS. The mutation spectrum of MPS, specifically in IDUA and IDS genes, is highly heterogeneous among the cases studied.

Keywords

Mucopolysaccharidoses Glycosaminoglycans LC–MS/MS CART model Machine learning tools Mutation analysis 

Notes

Acknowledgements

We thank Mr. Rajeev Sindhi, MD, Sandor Lifesciences Pvt. Ltd. for providing necessary infrastructure for the study. We thank all the families who had participated in the study.

Author contributions

SK participated in the study design, analysis, interpretation of data, and drafting the manuscript. SMN performed statistical analysis, interpretation of the data, and drafting of the manuscript. ARRD participated in recruitment of the patients, interpretation of clinical reports, and counseled the affected families. VLB carried out the conception and design of the study, interpretation of data, and final approval of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests (financial or non-financial) in the present study.

Ethical approval

The study was approved by the Institutional ethical committee for biomedical research, Institute of Genetics and Faculty of Science, Osmania University. This study complied with the ethical principles outlined in the Declaration of Helsinki.

Informed consent

Informed written consents were obtained from patients/guardians along with detailed clinical history during their enrollment for the study.

References

  1. 1.
    Byers S, Rozaklis T, Brumfield LK, Ranieri E, Hopwood JJ (1998) Glyosaminoglycan accumulation and excretion in the Mucopolysaccharoses: characterization and basis of a diagnostic test for MPS. Mol Genet Meta 65:282–290CrossRefGoogle Scholar
  2. 2.
    Wraith JEd (2006) Mucopolysaccharidoses and oligosaccharidoses. In: Fernandes J, Saudubray JM, van den Berghe G, Walter JH (eds) Inborn metabolic diseases. Springer, Heidelberg, pp 495–507CrossRefGoogle Scholar
  3. 3.
    Coutinho MF, Lacerda L, Alves S (2012) Glycosaminoglycan storage disorders: a review. Biochem Res Int 16Google Scholar
  4. 4.
    Neufeld EF, Muenzer J (2001) The mucopolysaccharidoses, Scriver CR, Beaudet AL, Sly WS, Valle D (eds), The metabolic and molecular bases of inherited diseases. 8th edn, vol 3. McGraw-Hill, New YorkGoogle Scholar
  5. 5.
    Lehman TJ, Miller N, Norquist B, Underhil L, Keutzer J (2011) Diagnosis of the mucopolysaccharidoses. Rheumatology 50:41–48CrossRefGoogle Scholar
  6. 6.
    Auray-Blais C, Bherer P, Gagnon R, Young SP, Zhang HH, An Y, Charke JT, Millington DS (2011) Efficient analysis of urinary glycosaminoglycans by LC-MS/MS in mucopolysaccharidoses type I, II and VI. Mol Genet Metab 102:49–56CrossRefPubMedGoogle Scholar
  7. 7.
    Kadali S, Patlotla RD, Kolusu A, Undamatla KT, Gummadi MR, Undamatla J (2016) The utility of two dimensional electrophoresis in diagnosis of mucopolysaccharidosis disorders. Clin Chim Acta 457:36–40CrossRefPubMedGoogle Scholar
  8. 8.
    Kubaski F, Osago H, Manson RW, Yamaguchi S, Kobayashi H, Tsuchiya M, Orii T, Tomatsu S (2017) Glycosaminoglycans detection methods: applications of mass spectrometry. Mol Genet Metab 120:67–77CrossRefPubMedGoogle Scholar
  9. 9.
    Plastores GM (2008) Laronidase (Aldurazyme): enzyme replacement therapy for Mucopolysaccharidosis type I. Expert Opin Biol Ther 8:1003–1009CrossRefGoogle Scholar
  10. 10.
    Jameson E, Jones S, Remmington T (2016) Enzyme replacement therapy with laronidase (Aldurazyme) for treating Mucopolysaccharidosis type I. Cochrane Database Syst RevGoogle Scholar
  11. 11.
    De Silva EM, Strufaldi MW, Andriolo RB, Silva LA (2011) Enzyme replacement therapy with idursulfase for Mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database Syst RevGoogle Scholar
  12. 12.
    Kubaski F, Yabe H, Suzuki Y, Seto T, Hamazaki T, Mason RW, Xie L, Onsten TGH, Leistner-segal S, Giugliani R, Dung VC, Nqo CBT, Yamaguchi S, Montano AM, Orii KE, Fukao T, Shintaku H, Orii T, Tomatsu S (2017) Hemotopoietic stem cell transplantation for patients with Mucopolysaccharidosis II. Biol Blood Marrow Transplant 23:1795–1803CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hendriksz CJ, Burton B, Fleming TR, Harmatz P, Hughes D, Jones SA, Lin SP, Mengel E, Scarpa M, Valayannopoulos V, Giugliani R, Investigatotors STRIVE, Slasor P, Lounsbury D, Dummer W (2014) Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (Mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis 37:979–990CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Harmatz P, Whitley CB, Waber L, Pais R, Steiner R, Plecko B, Kaplan P, Simon J, Butensky E, Hopwood JJ (2004) Enzyme replacement therapy in Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Pediatr 144:575–580CrossRefGoogle Scholar
  15. 15.
    Herskhovitz E, Young E, Rainer J, Hall CM, Lidchi V, Chong K, Vellodi A (1999) Bone marrow transplantation for Maroteaux-lamy syndrome (MPS VI): long-term follow-up. J Inherit Metab Dis 22:50–62CrossRefPubMedGoogle Scholar
  16. 16.
    Chuang CK, Lin SP, Chung SF (2001) Diagnostic screening for Mucopolysaccharidoses by the Dimethylmethylene blue method and two dimensional electrophoresis. Zhonghua Yi Xue Za Zhi (Taipei) 64:15–22Google Scholar
  17. 17.
    Jaffe M (1886) About the precipitation caused by pikrinic acid in normal urine and about a new reaction of creatinine Physiol Chem 10:391Google Scholar
  18. 18.
    Auray-Blais C, Lavoie P, Tomatsu S, Valayannopoulos V, Mitchell JJ, Raiman J, Beaudoin M, Maranda B, Charkem JT (2016) UPLC-MS/MS detection of disaccharides derived from glycosaminoglycans as biomarkers of muopolysaccharidoses. Anal Chim Acta 939:139–148CrossRefGoogle Scholar
  19. 19.
    Chuang CK, Lin HY, Wang TJ, Tsai CC, Liu HL, Lin SP (2014) A modified liquid chromatography/tandem mass spectrophotometry method for predominant disaccharide units of urinary glycosaminoglycans in patients with mucopolysaccharidoses. Orphanet J Rare Dis 936:139–148Google Scholar
  20. 20.
    Zhang H, Young SP, Auray-Blais C, Orchard PJ, Tolar J, Millington DS (2011) Analysis of glycosaminoglycans in cerebrospinal fluid from patients with mucopolysaccharidoses by isotope-dilution ultra-performance liquid chromatography–tandem mass spectrometry. Clin Chem 57:1005–1012CrossRefPubMedGoogle Scholar
  21. 21.
    Hopwood JJ, Muller V, Smithson A, Baggett N (1979) A fluorometric assay using 4-methylumbelliferyl α-l-iduronide for the estimation of α-l-iduronidase activity and the detection of Hurler and Scheie syndrome. Clin Chim Acta 92:257–265CrossRefPubMedGoogle Scholar
  22. 22.
    Voznyi YV, Keulemans JL, Van Diggelen OP (2001) A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease). J Inherit Metab Dis 24:675–680CrossRefPubMedGoogle Scholar
  23. 23.
    Karpova EA, Voznyi YaV, Keulemns JL, Hoogeveen AT, Winchester B, Tsyetkova IV, van Diggelen OP (1996) A fluorimetric enzyme assay for the diagnosis of Sanfilippo disease type A (MPS IIIA). J Inherit Metab Dis 19:278–285CrossRefPubMedGoogle Scholar
  24. 24.
    Mauri V, Lotfi P, Segatori L, Sardiello M (2013) A rapid and sensitive method for measuring N-Acetylglucosaminidase activity in cultured cells. PLoS ONE 8(6), e68060CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Voznyi YV, Karpova EA, Dudukina TV, Tsyetkova IV, Boer AM, Janse HC, van Diggelen OP (1993) A fluorimetric enzyme assay for the diagnosis of Sanfilippo disease type C (MPS IIIC). J Inherit Metab Dis 16:465–472CrossRefPubMedGoogle Scholar
  26. 26.
    He W, Voznyi YaV, Boer AM, Kleijer WJ, van Diggelen OP (1993) A fluorimetric enzyme assay for the diagnosis of Sanfilippo disease type D (MPS IIID). J Inherit Metab Dis 16:935–941CrossRefPubMedGoogle Scholar
  27. 27.
    van Diggelen OP, Zhai H, Kleijer WJ, Janse HC, Poorthuis BJ, van Pelt J, Kamerling JP, Galiaard H (1990) A fluorimetric enzyme assay for the diagnosis of Morquio disease type A (MPS IV A). Clin Chim Acta 187:131–139CrossRefPubMedGoogle Scholar
  28. 28.
    Nowakowski RW, Thompson JN, Baker HJ (1988) Diagnosis of feline GM1 gangliosidosis by enzyme assay of cultured conjunctival cells. Invest Ophthalmol Vis Sci 29:487–490PubMedGoogle Scholar
  29. 29.
    Christomanou H, Sandhoff K (1977) A sensitive fluorescence assay for the simultaneous and separate determination of arylsulphatases A and B. Clin Chim Acta 79:527–531CrossRefPubMedGoogle Scholar
  30. 30.
    Natowicz MR, Isman F, Prence EM, Cedrone P, Allen JJ (2003) Rapid prenatal testing for human beta-glucuronidase deficiency (MPS VII). Genet Test 7:241–243CrossRefPubMedGoogle Scholar
  31. 31.
    Sharma GB, Robertson DD, Laney DA, Gambello MJ, Terk M (2016) Machine learning based analytics of micro-MRI trabecular bone microarchitecture and texture in type I Gaucher disease. J Biomech 49:1961–1968CrossRefPubMedGoogle Scholar
  32. 32.
    Mashima R, Sakai E, Tanaka M, Kosagu M, Okuyama T (2016) The levels of urinary glycosaminoglycans of patients with attenuated and severe type of mucopolysaccharidosis II determined by liquid chromatography-tandem mass spectrometry. Mol Genet Metab Rep 7:87–91CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Uttarilli A, Ranganath P, Matta D, Md Nurul Jain J, Prasad K, Babu AS, Girish KM, Verma IC, Phadke SR, Mandal K, Puri RD, Aggarwal S, Danda S, Sankar VH, Kappor S, Bhat M, Gowrishankar K, Hasan AQ, Nair M, Nampoothiri S, Dalal A (2016) Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with Mucopolysachharidoses type I and type II. Clin Genet 90(6):496–508CrossRefPubMedGoogle Scholar
  34. 34.
    Mathew J, Jagadeesh SM, Bhat M, Udhaya Kumar S, Thiyagarajan S, Srinivasa S (2015) Mutations in ARSB in MPS VI patients in India. Mol Genet Metab rep 4:53–61CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bidchol AM, Dalal A, Shah H, Nampoothiri SS, Kabra S, Gupta M, Danda N, Gowrishankar S, Phadke K, Kapoor SR, Kamate S, Verma M, Puri IC, Sankar RD, Devi VH, Patil AR, Ranganath SJ, Jain P, Agarwal SJ, Singh M, Mishra A, Tamhankar P, Gopinath PM, Nagarajam PM, Satyamoorthy HA, Girish K KM (2014) GALNS mutations in Indian patients with mucopolysaccharidosis IVA. Am J Med Genet A 164A:2793–2801CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Srilatha Kadali
    • 1
    • 2
  • Shaik Mohammad Naushad
    • 2
  • Akella Radha Rama Devi
    • 3
  • Vijaya Lakshmi Bodiga
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Biology, Institute of Genetics & Hospital for Genetics DiseasesOsmania UniversityHyderabadIndia
  2. 2.Department of Biochemical GeneticsSandor Lifesciences Pvt. LtdHyderabadIndia
  3. 3.Rainbow Children’s HospitalHyderabadIndia

Personalised recommendations