Genetics of Mucopolysaccharidosis Type III Clinical Presentation

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 22, 2012
 

History

Patients with Sanfilippo syndrome are born without symptoms and typically have normal development for the first 2 years of life. In all types 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 type represents the most severe form of Sanfilippo syndrome and has an earlier and more rapid onset of symptoms than the other types.

  • Onset of symptoms usually occurs at age 2-6 years in a previously healthy-appearing child. Some patients may show developmentally delays in infancy. Growth parameters are normal or accelerated prior to this age. Subsequently, growth slows at about age 3 years.
  • Initial clinical signs present as a change in behavior. Patients are hyperactive and display aggressive and destructive behaviors.
  • Sleep disturbances are very common.
  • Mental development slows after the toddler years; then, progressive deterioration occurs in regard to gait and articulation of speech. Some patients may never speak.
  • Seizures may occur but are usually well-controlled with medication.
  • During the early school years, the symptoms worsen and patients show shortened attention spans and difficulties with concentration. Mental and physical disabilities prevent most children from progressing in 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.
  • More aggressive behaviors have been reported in female patients.
  • Recurrent or chronic diarrhea occurs in these 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.
  • 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.
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Physical

The striking clinical features of coarse facial features and skeletal abnormalities seen in the other mucopolysaccharidosis disorders are not as apparent in those with Sanfilippo syndrome. Mild facial coarsening may be present, and the skeletal features are usually subtle. Corneal clouding, as is seen in the other mucopolysaccharidosis disorders, is not usually present. A salient clinical feature is an abundance of coarse facial and body hair.

  • Head, ears, eyes, nose, and throat (HEENT)
    • Mild coarse facial features
    • Synophrys
    • Clear corneas (Some patients may have mild corneal opacities.)
  • GI: Mild hepatomegaly and splenomegaly
  • Genitourinary: Inguinal hernia, umbilical hernia, or both
  • Skeletal
    • Dense calvaria
    • Mild dysostosis multiplex (constellation of characteristic skeletal abnormalities seen in mucopolysaccharidosis disorders)
    • Joint stiffness
  • Neurological
    • Severe progressive neurologic degeneration
    • Hearing loss and speech delay in severely affected individuals
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Causes

The deficiency or lack of a different particular lysosomal enzyme is responsible for each of the forms 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 and leads to the diverse morphological abnormalities. Large amounts of heparan sulfate are excreted in the urine.
  • The genetic etiology is as follows:
    • The enzymatic defects seen in all forms of Sanfilippo syndrome are inherited as autosomal recessive disorders; this is also true of the other mucopolysaccharidosis disorders, except for mucopolysaccharidosis II (ie, Hunter syndrome), which has X-linked recessive inheritance. Because of 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 locations are as follows:
      • Type IIIA - 17q25.3
      • Type IIIB - 17q21
      • Type IIIC - 8p11.1
      • Type IIID - 12q14
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Contributor Information and Disclosures
Author

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.

Coauthor(s)

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

Surendra Varma, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Medical Association, American Thyroid Association, Endocrine Society, Medical Group Management Association, New York Academy of Sciences, Sigma Xi, Society for Pediatric Radiology, Southern Society for Pediatric Research, and Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Karl S Roth, MD  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 Clinical 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, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

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, New York

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

Disclosure: Genzyme Grant/research funds PI

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

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

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