Medscape is available in 5 Language Editions – Choose your Edition here.


Genetics of Mucopolysaccharidosis Type III Clinical Presentation

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
Updated: Oct 05, 2015


Patients with Sanfilippo syndrome are born without symptoms and typically have normal development for the first 2 years of life. In all subtypes of this syndrome, CNS disease predominates, with less skeletal and soft tissue involvement compared with the other mucopolysaccharidoses (MPSs). Type IIIA has the most CNS involvement. This subtype represents the most severe form of Sanfilippo syndrome with an earlier and more rapid onset of symptoms than others within mucopolysaccharidosis III. Note the following:

  • Onset of symptoms usually occurs between age 2 and 6 years in a previously healthy-appearing child. Some patients may show developmentally delays in infancy. Growth parameters are normal or accelerated prior to age 3 years, with growth delays seen in older children.
  • Initial symptoms present as behavioral changes. Patients are hyperactive and show aggressive and destructive behaviors. More aggressive behaviors have been reported in females when compared with male patients.
  • Sleep disturbances are common.
  • Mental development slows after the toddler years; then, progressive deterioration occurs in regard to gait and speech articulation. Some patients may never speak.
  • Seizures may occur but are usually well-controlled with medication.
  • During the early school years, symptoms worsen and patients show shortened attention spans and difficulties with concentration. Mental and physical disabilities prevent most children from progressing in their school academics.
  • By age 10 years, patients are severely limited in their activities and movement. Most children with type IIIA have severe neurological impairment by age 6 years. Recurrent or chronic diarrhea occurs in mucopolysaccharidosis III patients. The etiology for this abnormal gut motility is thought to be due to lysosomal glycosaminoglycans (GAG) storage in the neurons of the myenteric plexus of the small intestine.
  • Respiratory compromise can occur and is related to airway obstruction due to anatomical changes, excessive thick secretions, and neurologic impairment. Upper respiratory tract infections and sinopulmonary disease are common.


The striking clinical features of coarse facial features and skeletal abnormalities seen in the mucopolysaccharidoses are not as apparent in patients with mucopolysaccharidosis III. Mild facial coarsening may be present, and the skeletal differences are typically subtle. Corneal clouding, as seen in the other mucopolysaccharidoses, is not usually present. However, classic clinical features are an abundance of coarse facial and body hair (hirsutism). Note the following[11] :

  • Head, eyes, ears, nose, and throat (HEENT)
    • Mild coarse facial features
    • Synophrys
    • Clear corneas (some patients may have mild corneal opacities)
    • Hearing loss with speech delay
  • Cardiac
    • Asymmetric septal hypertrophy
    • Cardiomegaly
  • Gastrointestinal
    • Mild hepatomegaly
    • Mild splenomegaly
  • Genitourinary
    • Inguinal hernia,
    • Umbilical hernia
  • Skeletal
    • Dense calvaria
    • Mild dysostosis multiplex (constellation of characteristic skeletal abnormalities seen in mucopolysaccharidoses)
    • Joint stiffness
  • Neurological
    • Mentally challenged
    • Behavioral and sleep disturbances
    • Severe progressive neurologic degeneration


The deficiency or lack of a specific lysosomal enzyme is responsible for each subtype of Sanfilippo syndrome. Specifically, for type IIIA, the enzyme is heparan sulfate sulfatase; for type IIIB, the enzyme is N -acetyl-alpha-D-glucosaminidase; for type IIIC, the enzyme is acetyl-CoA:alpha-glucosaminide acetyltransferase; and for type IIID, the enzyme is N -acetylglucosamine-6-sulfatase.

Heparan sulfate accumulates in the lysosomes of tissues and organs, causing the diverse morphological abnormalities seen in mucopolysaccharidosis type III patients. Large amounts of heparan sulfate are excreted in the urine.

The enzymatic defects defining all subtypes of Sanfilippo syndrome are inherited as autosomal recessive disorders; this genetic inheritance is also true of the other mucopolysaccharidoses, except for mucopolysaccharidosis type II or Hunter syndrome, which has X-linked recessive inheritance. Due to the autosomal recessive inheritance pattern, biological parents of an affected child have a 25% risk of having another affected child with each pregnancy.

The gene mutations for the 4 different types have been mapped on the human genome. Their chromosomal or cytogenetic locations are as follows[11] :

  • Type IIIA - 17q25.3
  • Type IIIB - 17q21.2
  • Type IIIC - 8p11.21
  • Type IIID - 12q14.3
Contributor Information and Disclosures

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.


Surendra Varma, MD, FAAP, FACE, DSc(Hon) Associate Dean for Graduate Medical Education and Resident Affairs, Ted Hartman Endowed Chair in Medical Education, University Distinguished Professor and Vice-Chair of Pediatrics, Professor of Physiology and Health Organization Management, Program Director Emeritus, Pediatric Residency Program, Texas Tech University Health Sciences Center School of Medicine

Surendra Varma, MD, FAAP, FACE, DSc(Hon) is a member of the following medical societies: Alpha Omega Alpha, Academic Pediatric Association, American Association of Clinical Endocrinologists, American Pediatric Society, Society for Pediatric Research, American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Sigma Xi, Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Donald Nash to the original writing and development of this article.

  1. 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].

  2. 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].

  3. 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].

  4. 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].

  5. 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].

  6. 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].

  7. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997 Dec. 101(3):355-8. [Medline].

  8. 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].

  9. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20. 281(3):249-54. [Medline].

  10. 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].

  11. National Center for Biotechnology Information. Online Mendelian Inheritance of Man. Available at Accessed: January 29, 2013.

  12. 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].

  13. Valayannopoulos V, Wijburg FA. Therapy for the mucopolysaccharidoses. Rheumatology (Oxford). 2011 Dec. 50 Suppl 5:v49-59. [Medline].

  14. 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].

  15. Man TT, Tsai PS, Rau RH, et al. Children with mucopolysaccharidoses--three cases report. Acta Anaesthesiol Sin. 1999 Jun. 37(2):93-6. [Medline].

  16. 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.

  17. Fensom AH, Benson PF. Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn. 1994 Jan. 14(1):1-12. [Medline].

  18. Jablonski S. Jablonski's Dictionary of Syndromes and Eponymic Diseases. 2nd ed. Melbourne, FL: Krieger Publishing Co; 1991.

  19. Jones KL. Storage disorders. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, Pennsylvania: WB Saunders Company; 1997. 464-5.

  20. Kakkis E, Wraith E. Clinical features and diagnosis of the mucopolysaccharidoses. UpToDate. Available at Accessed: November 6, 2007.

  21. 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].

  22. Mucopolysaccharidosis III (MPS III) Disease (Sanfilippo Syndrome). Genzyme Corporation. Available at Accessed: 04/01/2009.

  23. Mucopolysaccharidosis Type III. National Organization for Rare Disorders, Inc. Available at Accessed: 03/31/2009.

  24. National Center for Biotechnology Information. Mucopolysaccharidosis Type IIIA, IIIB, IIIC, and IIID. Online Mendelian Inheritance in Man. Available at Accessed: April 1, 2009.

  25. National Institutes of Health. Mucopolysaccharidosis Type III (Sanfilippo Syndrome). GeneTests. Available at Accessed: 03/31/2009.

  26. Scriver CR, Beaudet AL, Sly WL, et al. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995.

  27. Spitz JL. Genodermatoses. A Full Color Clinical Guide to Genetic Skin Disorders. Baltimore, Md: Williams and Wilkins; 1995.

  28. Sutton VR. Presenting features of inborn errors of metabolism. UpToDate. Available at Accessed: November 6, 2007.

  29. Therapeutic Approaches. Alliance Sanfilippo. Available at Accessed: 04/01/2009.

  30. Thoene JG, ed. Physician's Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Co; 1995.

  31. Toone JR, Applegarth DA. Carrier detection in Sanfilippo A syndrome. Clin Genet. 1988 Jun. 33(6):401-3. [Medline].

  32. 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].

Noncommunicating obstructive hydrocephalus caused by obstruction of the foramina of Luschka and Magendie. This MRI sagittal image demonstrates dilatation of lateral ventricles with stretching of corpus callosum and dilatation of the fourth ventricle.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.