Genetics of Mucopolysaccharidosis Type III

Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Bruce Buehler, MD more...

Updated: May 14, 2009

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Background
Pathophysiology
Epidemiology
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Background

The mucopolysaccharidoses (MPSs) are a rare group of inherited lysosomal storage disorders that are caused by the deficiency or absence of specific lysosomal enzymes. The absence of these enzymes allows for the accumulation of complex carbohydrates in the body's cells and tissues and in the cellular organelles, the lysosomes. These complex carbohydrates are known as mucopolysaccharides or glycosaminoglycans (GAGs) and serve as the building blocks for connective tissues in the body.

The mucopolysaccharidoses comprise a group of 7 metabolic disorders, known as mucopolysaccharidosis types I-VII (mucopolysaccharidosis V is now considered a form of type I and is known as mucopolysaccharidosis IS). Each lysosomal storage disorder is associated with a defined enzymatic deficiency, although as a group, these disorders share many clinical features. Without the proper enzymatic degradation of the mucopolysaccharides, clinical symptoms, such as auditory and visual defects, cardiovascular functional impairments, hepatosplenomegaly, and dysostosis multiplex, occur due to their accumulation in organ systems.

Severe mental retardation also occurs and is usually associated with Hurler syndrome (mucopolysaccharidosis IH), Hunter syndrome (mucopolysaccharidosis II), and Sanfilippo syndrome (mucopolysaccharidosis III). Although lysosomal storage diseases are rare individually, the estimated incidence of all types of mucopolysaccharidosis disorders combined is 1 in 20,000 live births.

Mucopolysaccharidosis III, or Sanfilippo syndrome, was described in 1963 by a US-trained pediatrician named Sylvester Sanfilippo. Considered to be the most common of mucopolysaccharidosis disorders, Sanfilippo syndrome results from the deficiency or absence of 4 different enzymes that are necessary to degrade the GAG heparan sulfate. Each enzyme deficiency defines a different form of Sanfilippo syndrome, as follows: type IIIA (Sanfilippo A), type IIIB (Sanfilippo B), type IIIC (Sanfilippo C), and type IIID (Sanfilippo D).^[1]The other mucopolysaccharidosis disorders are discussed in respective articles (see Differentials).

Pathophysiology

The clinical features of Sanfilippo syndrome, including the significant impact on the CNS, result from the progressive lysosomal accumulation of the GAG heparan sulfate.^[2]

Four enzymes are involved in the different forms of Sanfilippo syndrome. Individuals with type A lack the enzyme heparan sulfate sulfatase. Individuals with type B lack the enzyme N -acetyl-alpha-D-glucosaminidase (NAG).^[3]Patients with type C lack acetyl-CoA:alpha-glucosaminide acetyltransferase. Patients with type D lack the enzyme N- acetylglucosamine-6-sulfatase. As a result of these differing enzyme deficiencies, an increase in the urinary excretion of heparan sulfate occurs.

The particular form of Sanfilippo syndrome cannot be determined based on clinical features. Precise identification of the specific form of Sanfilippo syndrome must rely on enzymatic assays (see Workup).

Frequency

International

In 1997, Nelson reported an incidence of 1 case per 280,000 live births (0.36 cases per 100,000 live births) for Sanfilippo syndrome in Northern Ireland.^[4]In 1999, Poorthuis et al reported an incidence of 4.5 cases per 100,000 live births for all mucopolysaccharidosis disorders in the Netherlands.^[5]Mucopolysaccharidosis III accounted for 47% of all cases of mucopolysaccharidosis diagnosed and had a birth prevalence of 1.89 cases per 100,000 live births. In this study, mucopolysaccharidosis IIIA had an estimated birth prevalence of 1.16 cases per 100,000.

In 1999, Meikle et al cited a prevalence of mucopolysaccharidosis IIIA of 1 in 114,000 live births; the prevalence of mucopolysaccharidosis IIIB is 1 in 211,000 live births.^[6]Mucopolysaccharidosis IIIC and mucopolysaccharidosis IIID were much rarer, at 1 in 1,407,000 and 1 in 1,056,000 live births, respectively. A 2000 registry compiled by MPS Australia cited an incidence of 1 case per 66,000 live births for all forms of Sanfilippo syndrome. Within this combined statistic, the incidence reported for each form of mucopolysaccharidosis III equaled the prevalence cited by Meikle et al in 1999.

Mortality/Morbidity

Sanfilippo syndrome has a progressive process with a devastating prognosis. Over time, patients develop CNS degeneration and progress to a vegetative state. Death usually occurs before age 20 years, primarily from cardiopulmonary arrest due to airway obstruction and/or pulmonary infection. Type IIIA is the most severe form; most patients with this form die during their teenage years.

Race

The mucopolysaccharidoses are panracial.

Sex

All forms of mucopolysaccharidosis III are inherited in an autosomal recessive Mendelian pattern. The gene mutations are located in the autosomes and not in the sex chromosomes;^[7]therefore, Sanfilippo syndrome affects males and females equally.

Age

Children with Sanfilippo syndrome are born without clinical features of a metabolic disorder. In the toddler years, aggressive behavioral problems emerge, with marked overactivity and destructive tendencies. Mild somatic features, such as mild organomegaly, little to no corneal clouding, and orthopedic abnormalities, may be seen. Neurologic degeneration usually begins in children aged 6 years or older (sometimes even younger). Death may not occur until after puberty.

Proceed to Clinical Presentation

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.

Acknowledgments

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

References

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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.

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