Biopolym. Cell. 2014; 30(5):388-393.
http://dx.doi.org/10.7124/bc.0008B6
Molecular Biomedicine
Specificities of Sanfilippo A syndrome laboratory diagnostics
1, 2Trofimova N. S., 1, 2Olkhovich N. V., 1, 2Gorovenko N. G.
  1. Center of Metabolic Diseases,
    National Children's Specialized Hospital Okhmatdyt
    28/1, Chornovola Str., Kyiv, Ukraine, 01135
  2. Institute of Genetic and Regenerative Medicine, NAMS of Ukraine
    67, Vyshgorodska Str., Kyiv, Ukraine, 04114

Abstract

Mucopolysaccharidosis type IIIA (MPS IIIA) occurs due to the deficiency of lysosomal enzyme heparan-N-sulfatase (sulfamidase), which is caused by mutations in the SGSH gene. Aim. To identify the characteristics of biochemical diagnosis of MPS IIIA and determine the prevalence of major mutations R74C and R245H in the SGSH gene in Ukrainian patients. Methods. After all the required phases of laboratory diagnosis of this disease, the diagnosis of MPS IIIA was confirmed in 12 patients from 12 families. The level of sulfamidase activity in leukocytes did not exceed 36 % of the control in all patients. Due to very low sulfamidase activity in leukocytes it is sometimes difficult to interpret the results of the analysis which may lead to false-negative or false-positive diagnosis of MPS IIIA. Results. The analysis of the results of molecular investigation of the patients' samples showed that the incidence of mutation R74C was 17/24 (70.8 %), the incidence of mutation R245H was 2/24 (8.3 %). The total incidence of major mutations R74S and R245H among the patients with MPS IIIA in Ukraine was the highest among European countries – 11 out of 12 patients, these mutations were found in at least one allele. Conclusions. Given very high prevalence of major mutations R74S and R245H in the SGSH gene among the patients with MPS IIIA in Ukraine – 79.1 % – it is appropriate to have the screening of mutations in the diagnostic algorithm along with the definition of biochemical sulfamidase activity to prevent false-negative or false-positive diagnosis of Sanfilippo syndrome A.
Keywords: mucopolysaccharidosis, glycosaminoglycans, heparan-N-sulfatase, gene, genotype, allele
Full text: (PDF, in English)

References

[1] Scriver CR, Beaudet AL, Sly WS, Valle D. The metabolic and molecular basis of inherited diseases. New York, McGraw-Hill, 2001; 6338 p.
[2] Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, Kohlsch?tter A, Kampmann C, Beck M. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28(6):1011-7.
[3] Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, Niezen-Koning KE, van Diggelen OP. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105(1-2):151-6.
[4] Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-54.
[5] Di Natale P, Pontarelli G, Villani GR, Di Domenico C. Gene symbol: SGSH. Disease: Sanfilippo type A syndrome, mucopolysaccharidosis IIIA. Hum Genet. 2006;119(6):679.
[6] Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat. 2001;18(4):264-81.
[7] Beesley CE, Young EP, Vellodi A, Winchester BG. Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations. J Med Genet. 2000;37(9):704-7.
[8] Blanch L, Weber B, Guo XH, Scott HS, Hopwood JJ. Molecular defects in Sanfilippo syndrome type A. Hum Mol Genet. 1997;6(5):787-91.
[9] Weber B, Guo XH, Wraith JE, Cooper A, Kleijer WJ, Bunge S, Hopwood JJ. Novel mutations in Sanfilippo A syndrome: implications for enzyme function. Hum Mol Genet. 1997;6(9):1573-9.
[10] Krasnopolskaya KD, Zuckerman GL. Methodical recommendations MPH USSR. Moscow, 1983; 30 p.
[11] Wenger DA, Williams C. Screening for lysosomal disorders. Techniques in Diagnostics of Human Biochemical Genetics: a laboratory manual. Ed. FA Hommes.New York, Wiley-Liss, 1991; 587–619.
[12] Dawson RMC, Elliott DC, Elliott WH, Jones KM. Data for biochemical research, 3nd ed. Oxford, Clarendon Press, 1986; 580 p.
[13] Bunge S, Ince H, Steglich C, Kleijer WJ, Beck M, Zaremba J, van Diggelen OP, Weber B, Hopwood JJ, Gal A. Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A). Hum Mutat. 1997;10(6):479-85.
[14] Voskoboeva EY. DNA-diagnostics of inherited mucopolysaccharidoses. Medical genetics. 2006; 5(10):33–7.
[15] Kroepfl T, Milos I, Paul K, Plecko B, Paschke E. The frequency of common mutations among patients with mucopolysaccharidosis types I, II and IIIA diagnosed in Austria over the last 17 years. Clin Genet. 2001;60(5):393-4.
[16] Esposito S, Balzano N, Daniele A, Villani GR, Perkins K, Weber B, Hopwood JJ, Di Natale P. Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects. Biochim Biophys Acta. 2000;1501(1):1-11.
[17] Chab?s A, Montfort M, Mart?nez-Campos M, D?az A, Coll MJ, Grinberg D, Vilageliu L. Mutation and haplotype analyses in 26 Spanish Sanfilippo syndrome type A patients: possible single origin for 1091delC mutation. Am J Med Genet. 2001;100(3):223-8.