Evaluation of Patients Referred to Children's Medical Center Laboratory for Diagnosis of Mucopolysaccharidoses: Eight Years' Experience from Iran

Abstract

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases, resulting from deficiencies of enzymes responsible for Glycosaminoglycans (GAGs) degradation. This leads to accumulation of GAGs in tissues and their excretion in urine, with a wide variety of manifestations. Early diagnosis of MPSs is strictly recommended due to available therapy that can slow down disease progression during the early ages. This study aimed to evaluate patients with suspected MPS referred to Children's Medical Center laboratory over eight years. We also evaluated the usefulness of urine GAG as a screening test for identification of such patients. A total of 1414 patients (40% female, 60% male, with mean age 3.1 ± 4.1years) have participated in this study. The urinary GAG analysis (uGAG) was performed by 1, 9-dimethyl-methylene blue (DMMB) and Berry spot test (BST). All patients with positive and mild positive results or with disease-related symptoms were evaluated in terms of definitive diagnosis, received treatments, morbidity, and mortality rate. In 407 (36.5%) patients uGAG were positive or mild positive, of which 26.3% suffered from one of the types of MPSs, 28.5% suffered from other diseases, 32.9% were undiagnosed, 12.3% were apparently healthy, and 19 died. The negative predictive value of uGAG test in our study was 100%. About 21% of MPSs patients received enzyme replacement therapy, while four patients underwent stem cell transplants. The rest received supportive care. We concluded that a combination of DMMB and BST methods has acceptable sensitivity for screening suspicious MPS patients.

Keywords

berry spot test - dimethylmethylene blue - glycosaminoglycan - mucopolysaccharidoses

Ethical Approval

The study was approved by the Ethics Committee of Tehran University of Medical Sciences.

The researchers complied with the ethical principles of the Declaration of Helsinki. The Ethics Code is IR.TUMS.CHMC.REC.1399.006.

Informed Consent

All participants or their parents, whenever needed, signed informed consent forms.

Publication History

Received: 11 January 2021

Accepted: 14 June 2021

Article published online:
06 December 2021

• References

• 1 Zhou J, Lin J, Leung WT, Wang L. A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management. Intractable Rare Dis Res 2020; 9 (01) 1-9
• 2 Khan SA, Peracha H, Ballhausen D. et al. Epidemiology of mucopolysaccharidoses. Mol Genet Metab 2017; 121 (03) 227-240
• 3 Hunter C. A Rare Disease in Two Brothers. Proc R Soc Med 1917; 10 (Sect Study Dis Child): 104-116
• 4 Giugliani R. Mucopolysacccharidoses: From understanding to treatment, a century of discoveries. Genet Mol Biol 2012; 35 (4 (suppl), suppl): 924-931
• 5 Brailsford JF. Brailsford JF. Chondro-osteo-dystrophy: roentgenographic and clinical features of a child with dislocation of vertebrae. Am. J. Surg. 7:404, 1929. Clin Orthop Relat Res 1976; (114) 4-9
• 6 Scheie HG, Hambrick Jr GW, Barness LA. A newly recognized forme fruste of Hurler's disease (gargoylism). Am J Ophthalmol 1962; 53: 753-769
• 7 Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr 1973; 82 (02) 249-257
• 8 Natowicz MR, Short MP, Wang Y. et al. Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med 1996; 335 (14) 1029-1033
• 9 Sanfilippo SJ, Podosin R, Langer L, Good R. Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type). presented at: American Pediatric Society. 1963 https://www.sciencedirect.com/science/article/abs/pii/S0022347663802796
• 10 Brante G. Gargoylism; a mucopolysaccharidosis. Scand J Clin Lab Invest 1952; 4 (01) 43-46 DOI: 10.3109/00365515209060631.
• 11 Dorfman A, Lorincz AE. OCCURRENCE OF URINARY ACID MUCOPOLYSACCHARIDES IN THE HURLER SYNDROME. Proc Natl Acad Sci U S A 1957; 43 (06) 443-446
• 12 Meyer K, Grumbach MM, Linker A, Hoffman P. Excretion of sulfated mucopolysaccharides in gargoylism (Hurler's syndrome). Proc Soc Exp Biol Med 1958; 97 (02) 275-279
• 13 Teller WM, Burke EC, Rosevear JW, McKENZIE BF. Urinary excretion of acid mucopolysaccharides in normal children and patients with gargoylism. J Lab Clin Med 1962; 59: 95-101
• 14 McKusick VA. The nosology of the mucopolysaccharidoses. Am J Med 1969; 47 (05) 730-747
• 15 Oshima A, Kyle JW, Miller RD. et al. Cloning, sequencing, and expression of cDNA for human beta-glucuronidase. Proc Natl Acad Sci U S A 1987; 84 (03) 685-689
• 16 Parini R, Deodato F. Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int J Mol Sci 2020; 21 (08) E2975
• 17 Concolino D, Deodato F, Parini R. Enzyme replacement therapy: efficacy and limitations. Ital J Pediatr 2018; 44 (Suppl. 02) 120
• 18 Delgadillo V, O'Callaghan MdelM, Artuch R, Montero R, Pineda M. Genistein supplementation in patients affected by Sanfilippo disease. J Inherit Metab Dis 2011; 34 (05) 1039-1044
• 19 Sawamoto K, Chen HH, Alméciga-Díaz CJ, Mason RW, Tomatsu S. Gene therapy for Mucopolysaccharidoses. Mol Genet Metab 2018; 123 (02) 59-68
• 20 Fecarotta S, Gasperini S, Parenti G. New treatments for the mucopolysaccharidoses: from pathophysiology to therapy. Ital J Pediatr 2018; 44 (Suppl. 02) 124 DOI: 10.1186/s13052-018-0564-z.
• 21 Pearse Y, Iacovino M. A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise. Med Res Arch 2020;8(02):
• 22 Mabe P, Valiente A, Soto V, Cornejo V, Raimann E. Evaluation of reliability for urine mucopolysaccharidosis screening by dimethylmethylene blue and Berry spot tests. Clin Chim Acta 2004; 345 (1-2): 135-140 DOI: 10.1016/j.cccn.2004.03.015.
• 23 Jafaryazdi R, Teimourian S. Mucopolysaccharidosis VI diagnosis by laboratory methods. J Lab Med 2018; 42 (05) 163-169
• 24 Lage S, Prieto JA, Andrade F, Sojo A, Sanjurjo P, Aldámiz-Echevarría LJ. Reliability of a visual test for the rapid detection of mucopolysaccharidoses: GAG-test(®). J Clin Lab Anal 2011; 25 (03) 179-184
• 25 Kubaski F, de Oliveira Poswar F, Michelin-Tirelli K. et al. Diagnosis of Mucopolysaccharidoses. Diagnostics (Basel) 2020; 10 (03) E172
• 26 Lukacs Z. Mucopolysaccharides. In: Blau N, Duran M, Gibson KM. eds. Laboratory Guide to the Methods in Biochemical Genetics. 1 ed.. Springer; 2008: 292-297 (287–324).
• 27 Jafaryazdi R, Shams S, Isaian A, Setoodeh A, Teimourian S. Identification of eleven different mutations including six novel, in the arylsulfatase B gene in Iranian patients with mucopolysaccharidosis type VI. Mol Biol Rep 2019; 46 (03) 3417-3426
• 28 Shams S, Barazandeh Tehrani M, Civallero G. et al. Diagnosing Mucopolysaccharidosis type IV a by the fluorometric assay of N-Acetylgalactosamine-6-sulfate sulfatase activity. J Diabetes Metab Disord 2017; 16 (01) 37
• 29 Moghadam S, Ghahvechi M, Mozafari F. et al. Mucopolysaccharidosis Type I in Children, a Forgotten Diagnosis Responsible for Undiagnosed Musculoskeletal Complaints: Report of Two Cases. Acta medica 2019 2019; 62 (04) 161-165
• 30 Bower L, Manley G. Urinary excretion of glycosaminoglycans and hydroxyproline in Paget's disease of bone, compared with neoplastic invasion of bone. J Clin Pathol 1981; 34 (10) 1097-1101
• 31 Satake S, Ototani N, Isemura M, Yosizawa Z. Enzymatic determination of urinary glycosaminoglycans from orthopedic patients. Tohoku J Exp Med 1983; 140 (01) 89-96
• 32 Endreffy I, Dicsö F. Glycosaminoglycan excretion in connective tissue diseases. Clin Biochem 1988; 21 (02) 135-138
• 33 Fateen E, Ismail MF, Ahmed El-Boghdady N, Aglan M, Ibrahim M, Radwan A. Differential diagnosis of mucopolysaccharidosis and oligosaccharidosis of a sample of Egyptian children. Bulletin of Faculty of Pharmacy, Cairo University 2018; 56 (02) 213-217 DOI: 10.1016/j.bfopcu.2018.10.005.
• 34 Iwata S, Sukegawa K, Sasaki T. et al. Mass screening test for mucopolysaccharidoses using the 1,9-dimethylmethylene blue method: positive interference from paper diapers. Clin Chim Acta 1997; 264 (02) 245-250 DOI: 10.1016/s0009-8981(97)00084-3.
• 35 Tomatsu S, Okamura K, Maeda H. et al. Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis 2005; 28 (02) 187-202 DOI: 10.1007/s10545-005-5673-3.
• 36 Piraud M, Boyer S, Mathieu M, Maire I. Diagnosis of mucopolysaccharidoses in a clinically selected population by urinary glycosaminoglycan analysis: a study of 2,000 urine samples. Clin Chim Acta 1993; 221 (1-2): 171-181
• 37 Di Natale P, Annella T, Daniele A. et al. Biochemical diagnosis of mucopolysaccharidoses: experience of 297 diagnoses in a 15-year period (1977-1991). J Inherit Metab Dis 1993; 16 (02) 473-483 DOI: 10.1007/BF00710300.
• 38 Shawky R, Elsayed N, Ibrahim D, Seifeldin N. Profile of genetic disorders prevalent in northeast region of Cairo, Egypt. Articles. Egyptian Journal of Medical Human Genetics 2012; 13 DOI: 10.1016/j.ejmhg.2011.10.002.
• 39 Fateen E, Ibrahim M, Gouda A, Youssef Z. Biochemical diagnosis of mucopolysaccharidoses over 11 years: the Egyptian experience. Middle East J Med Genet 2014; 3 (01) 16-23 DOI: 10.1097/01.MXE.0000438178.09181.43.
• 40 Whitley CB, Spielmann RC, Herro G, Teragawa SS. Urinary glycosaminoglycan excretion quantified by an automated semimicro method in specimens conveniently transported from around the globe. Mol Genet Metab 2002; 75 (01) 56-64 DOI: 10.1006/mgme.2001.3271.