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.
Similar content being viewed by others
References
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 65:282–290
Wraith JEd (2006) Mucopolysaccharidoses and oligosaccharidoses. In: Fernandes J, Saudubray JM, van den Berghe G, Walter JH (eds) Inborn metabolic diseases. Springer, Heidelberg, pp 495–507
Coutinho MF, Lacerda L, Alves S (2012) Glycosaminoglycan storage disorders: a review. Biochem Res Int 16
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 York
Lehman TJ, Miller N, Norquist B, Underhil L, Keutzer J (2011) Diagnosis of the mucopolysaccharidoses. Rheumatology 50:41–48
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 102:49–56
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 457:36–40
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 120:67–77
Plastores GM (2008) Laronidase (Aldurazyme): enzyme replacement therapy for Mucopolysaccharidosis type I. Expert Opin Biol Ther 8:1003–1009
Jameson E, Jones S, Remmington T (2016) Enzyme replacement therapy with laronidase (Aldurazyme) for treating Mucopolysaccharidosis type I. Cochrane Database Syst Rev
De Silva EM, Strufaldi MW, Andriolo RB, Silva LA (2011) Enzyme replacement therapy with idursulfase for Mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database Syst Rev
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 23:1795–1803
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 37:979–990
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 144:575–580
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 22:50–62
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) 64:15–22
Jaffe M (1886) About the precipitation caused by pikrinic acid in normal urine and about a new reaction of creatinine Physiol Chem 10:391
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 939:139–148
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 936:139–148
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 57:1005–1012
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 92:257–265
Voznyi YV, Keulemans JL, Van Diggelen OP (2001) A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease). J Inherit Metab Dis 24:675–680
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 19:278–285
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), e68060
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 16:465–472
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 16:935–941
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 187:131–139
Nowakowski RW, Thompson JN, Baker HJ (1988) Diagnosis of feline GM1 gangliosidosis by enzyme assay of cultured conjunctival cells. Invest Ophthalmol Vis Sci 29:487–490
Christomanou H, Sandhoff K (1977) A sensitive fluorescence assay for the simultaneous and separate determination of arylsulphatases A and B. Clin Chim Acta 79:527–531
Natowicz MR, Isman F, Prence EM, Cedrone P, Allen JJ (2003) Rapid prenatal testing for human beta-glucuronidase deficiency (MPS VII). Genet Test 7:241–243
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 49:1961–1968
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 7:87–91
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):496–508
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 4:53–61
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:2793–2801
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 information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
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.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kadali, S., Naushad, S.M., Radha Rama Devi, A. et al. Biochemical, machine learning and molecular approaches for the differential diagnosis of Mucopolysaccharidoses. Mol Cell Biochem 458, 27–37 (2019). https://doi.org/10.1007/s11010-019-03527-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-019-03527-6