Genetics of Mucopolysaccharidosis Type III Workup
- Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD more...
Biochemical differentiation of the different subtypes of mucopolysaccharidosis (MPS) type III is possible, and diagnosis is confirmed by specific enzymatic assay.
Enzymatic activity for all subtypes of Sanfilippo syndrome can be assayed in cultured skin fibroblasts and in peripheral blood leukocytes. If mucopolysaccharidosis type III is suspected, enzymatic cell analysis is the recommended test.
In all subtypes of mucopolysaccharidosis type III, urinary excretion of heparan sulfate is increased. To measure the concentration of glycosaminoglycans or glycosaminoglycans (GAGs) in the urine, a total quantitative test and a fractionation test should be performed using electrophoresis or chromatography. Ideally, a first-morning urine specimen should be analyzed because a concentrated urine specimen is needed to avoid a false-negative result due to dilutional effect. This sample recommendation is especially important for the diagnosis of mucopolysaccharidosis type III because of the low urinary GAG levels and smaller heparan fragments seen in this syndrome. Urinary GAG levels are higher in newborns and infants than in older children. Interpretation of results must include age-specific controls and fractionation to properly identify pathologic GAG levels (ie, heparan sulfate) from normal GAG levels present in the urine (ie, chondroitins).
Prenatal diagnosis can also be performed by measuring for the specific enzymatic activity in cultured amniocytes or chorionic villi cells.
See the list below:
Neuroimaging to diagnosis hydrocephalus and to look for changes in brain structure (See the image below)
Echocardiography to assess for asymmetric septal hypertrophy, cardiomegaly, and valvular disease
Abdominal imaging, such as ultrasonography or CT scanning, to evaluate for organomegaly
Radiographic skeletal survey to identify cases of dysostosis multiplex
See the list below:
Electroencephalography (EEG) to diagnose seizure activity
Audiologic evaluation to identify patients with hearing loss
Polysomnography for those patients who demonstrate clinical signs of airway obstruction due to anatomical changes, such as obstructive sleep apnea
Zhang WM, Shi HP, Meng Y, Li BT, Qiu ZQ, Liu JT. [Postnatal and prenatal diagnosis of mucopolysaccharidosis type III (Sanfilippo syndrome)]. Zhonghua Er Ke Za Zhi. 2008 Jun. 46(6):407-10. [Medline].
Fan X, Tkachyova I, Sinha A, Rigat B, Mahuran D. Characterization of the biosynthesis, processing and kinetic mechanism of action of the enzyme deficient in mucopolysaccharidosis IIIC. PLoS One. 2011. 6(9):e24951. [Medline]. [Full Text].
Ouesleti S, Brunel V, Ben Turkia H, Dranguet H, Miled A, Miladi N, et al. Molecular characterization of MPS IIIA, MPS IIIB and MPS IIIC in Tunisian patients. Clin Chim Acta. 2011 Nov 20. 412(23-24):2326-31. [Medline].
Valstar MJ, Neijs S, Bruggenwirth HT, Olmer R, Ruijter GJ, Wevers RA, et al. Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations. Ann Neurol. 2010 Dec. 68(6):876-87. [Medline].
Vitry S, Ausseil J, Hocquemiller M, Bigou S, Dos Santos Coura R, Heard JM. Enhanced degradation of synaptophysin by the proteasome in mucopolysaccharidosis type IIIB. Mol Cell Neurosci. 2009 May. 41(1):8-18. [Medline].
Ohmi K, Kudo LC, Ryazantsev S, Zhao HZ, Karsten SL, Neufeld EF. Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proc Natl Acad Sci U S A. 2009 May 5. [Medline]. [Full Text].
Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997 Dec. 101(3):355-8. [Medline].
Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999 Jul-Aug. 105(1-2):151-6. [Medline].
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20. 281(3):249-54. [Medline].
Blanch L, Weber B, Guo XH, et al. Molecular defects in Sanfilippo syndrome type A. Hum Mol Genet. 1997 May. 6(5):787-91. [Medline].
National Center for Biotechnology Information. Online Mendelian Inheritance of Man. Available at http://www.ncbi.nlm.nih.gov/omim. Accessed: January 29, 2013.
Kleijer WJ, Karpova EA, Geilen GC, et al. Prenatal diagnosis of Sanfilippo A syndrome: experience in 35 pregnancies at risk and the use of a new fluorogenic substrate for the heparin sulphamidase assay. Prenat Diagn. 1996 Sep. 16(9):829-35. [Medline].
Valayannopoulos V, Wijburg FA. Therapy for the mucopolysaccharidoses. Rheumatology (Oxford). 2011 Dec. 50 Suppl 5:v49-59. [Medline].
Kloska A, Narajczyk M, Jakóbkiewicz-Banecka J, Grynkiewicz G, Szeja W, Gabig-Cimińska M, et al. Synthetic genistein derivatives as modulators of glycosaminoglycan storage. J Transl Med. 2012 Jul 30. 10:153. [Medline].
Man TT, Tsai PS, Rau RH, et al. Children with mucopolysaccharidoses--three cases report. Acta Anaesthesiol Sin. 1999 Jun. 37(2):93-6. [Medline].
Connor JM, Emery AE, Rimoin DL, Pyeritz RE, eds. Emery and Rimoin's Principle and Practice of Medical Genetics. 3rd ed. New York, NY: Churchill Livingstone; 1996.
Fensom AH, Benson PF. Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn. 1994 Jan. 14(1):1-12. [Medline].
Jablonski S. Jablonski's Dictionary of Syndromes and Eponymic Diseases. 2nd ed. Melbourne, FL: Krieger Publishing Co; 1991.
Jones KL. Storage disorders. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, Pennsylvania: WB Saunders Company; 1997. 464-5.
Kakkis E, Wraith E. Clinical features and diagnosis of the mucopolysaccharidoses. UpToDate. Available at http://www.utdol.com. Accessed: November 6, 2007.
Lindor NM, Hoffman A, O'Brien JF, Hanson NP, Thompson JN. Sanfilippo syndrome type A in two adult sibs. Am J Med Genet. 1994 Nov 15. 53(3):241-4. [Medline].
Mucopolysaccharidosis III (MPS III) Disease (Sanfilippo Syndrome). Genzyme Corporation. Available at www.lysosomallearning.com/healthcare/about/lsd_hc_abt_mps3. Accessed: 04/01/2009.
Mucopolysaccharidosis Type III. National Organization for Rare Disorders, Inc. Available at http://www.rarediseases.org. Accessed: 03/31/2009.
National Center for Biotechnology Information. Mucopolysaccharidosis Type IIIA, IIIB, IIIC, and IIID. Online Mendelian Inheritance in Man. Available at http://www.ncbi.nlm.nih.gov. Accessed: April 1, 2009.
National Institutes of Health. Mucopolysaccharidosis Type III (Sanfilippo Syndrome). GeneTests. Available at http://www.geneclinics.org. Accessed: 03/31/2009.
Scriver CR, Beaudet AL, Sly WL, et al. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995.
Spitz JL. Genodermatoses. A Full Color Clinical Guide to Genetic Skin Disorders. Baltimore, Md: Williams and Wilkins; 1995.
Sutton VR. Presenting features of inborn errors of metabolism. UpToDate. Available at www.utdol.com. Accessed: November 6, 2007.
Therapeutic Approaches. Alliance Sanfilippo. Available at http://www.alliancesanfilippo.com/us/approaches.php. Accessed: 04/01/2009.
Thoene JG, ed. Physician's Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Co; 1995.
Toone JR, Applegarth DA. Carrier detection in Sanfilippo A syndrome. Clin Genet. 1988 Jun. 33(6):401-3. [Medline].
van de Kamp JJ, Niermeijer MF, von Figura K, Giesberts MA. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C). Clin Genet. 1981 Aug. 20(2):152-60. [Medline].