AUTHOR INFORMATION

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Authored by Paul Richard Harmatz, MD, Consulting Staff, Department of Gastroenterology and Nutrition, Children’s Hospital Oakland

Coauthored by Donald Nash, PhD †, Former Professor, Department of Biology, Colorado State University; Surendra Varma, MD, Vice-Chairman and Program Director, University Distinguished Professor, Department of Pediatrics, Texas Tech University School of Medicine

Paul Richard Harmatz, MD, is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society of Human Genetics, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research

Edited by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Paul Richard Harmatz, MD
Editor's Email:	Karl S Roth, MD

eMedicine Journal, June 19 2003, VOLUME 4, Number 6

INTRODUCTION

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Background: The mucopolysaccharidoses (MPSs) are a group of inherited lysosomal storage disorders that are caused by the deficiency of specific lysosomal enzymes and the lysosomal accumulation of glycosaminoglycans (GAGs or mucopolysaccharides). Each type of MPS is associated with a particular enzymatic deficiency, although the various disorders share many clinical features. Because the MPSs are ubiquitous, multiple organ systems can be involved, resulting in hearing and visual defects, cardiovascular functional impairments, hepatosplenomegaly, and dysostosis multiplex. Severe mental retardation can also occur and is usually associated with Hurler syndrome (MPS-IH), Hunter syndrome (MPS-II), and Sanfilippo syndrome (MPS-III). Although the MPSs are rare individually, the overall incidence is approximately 1 in 25,000 people.

Diagnosis is made by determination of the specific enzymatic activity in cultured fibroblasts or leukocytes. Prenatal diagnosis using cultured amniocytes or chorionic villi is also possible.

MPS type III, or Sanfilippo syndrome, can result from the deficiency of one of four enzymes that are necessary to degrade heparan sulfate. The four subgroups of MPS III are as follows: type IIIA (Sanfilippo A), type IIIB (Sanfilippo B), type IIIC (Sanfilippo C), and type IIID (Sanfilippo D). The other types of MPSs are discussed in the respective articles (see Differentials).

Pathophysiology: The clinical features of the disorder, including effects on the central nervous system, result from the progressive lysosomal accumulation of heparan sulfate.

Four enzymes are involved in the different types of Sanfilippo syndrome. Type A is a lack of heparan N-sulfatase, type B is a lack of alpha-N-acetylglucosaminidase, type C is a lack of acetyl-CoA:alpha-glucosaminide acetyltransferase, and type D is a lack of the enzyme N-acetylglucosamine-6-sulfatase. Distinguishing the clinical effects due to the different enzymes is not possible; a precise identification of the specific type of Sanfilippo syndrome must rely on enzyme assays. As a result of the enzyme deficiencies, an increase in the urinary excretion of heparan sulphate and chondroitin sulfate occurs.

Frequency:

• Internationally: In 1999, Poorthius et al reported an incidence of 4.5:100,000 live births for all MPSs in the Netherlands. MPS IIIA had an estimated birth prevalence of 1.16:100,000. As a group, MPS III accounted for 47% of all cases of MPS diagnosed and had a combined birth prevalence of 1.89:100,000 live births. In 1997, Nelson reported a much lower incidence of 1:280,000 for Sanfilippo syndrome in Northern Ireland.

Mortality/Morbidity: The disease is progressive and results in severe central nervous system degeneration, progressing to a vegetative state. Death usually occurs in persons younger than 20 years, primarily from aspiration pneumonia. Type A is the most severe form, and death usually occurs during the teen years.

Race: The MPS disorders are panracial.

Sex: MPS III is inherited as an autosomal recessive trait, affecting males and females equally. Therefore, no sex predilection exists.

Age: Children with Sanfilippo syndrome are born without any clinical symptoms. Typically, the first behavioral problems emerge in children older than 2 years. Neurologic degeneration usually begins in children older than 6 years (sometimes even earlier). Death may not occur until after puberty.

CLINICAL

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History: Most patients are born without symptoms and develop normally for 2 years. Because type IIIA is the most severe form and has an earlier onset and a more rapid development of symptoms, its clinical features are discussed.

• Onset of symptoms usually occurs at age 2-6 years in a previously healthy-appearing child. The first clinical symptoms are usually associated with behavioral problems, and the children are often hyperactive and experience sleep disturbances. The patients experience difficulty articulating their speech. Seizures are sometimes a symptom, but they are usually easily controlled.



• • During the early school years, the symptoms worsen and patients show a short attention span and lack of concentration. Some patients even are retarded from infancy, but mental and physical problems prevent most children from progressing very far in school.
  
  
  
  • By age 10 years, most patients become severely limited in their activities and movement. In type A syndrome, most patients experience severe mental retardation by age 6 years.
  
  
  
  • Aggressive behavior is somewhat greater in female patients than in males.
  
  
  
• Diarrhea is often a major problem in young patients but this usually disappears with age.



• Problems with recurrent upper respiratory tract infections may occur.

Physical: The somatic manifestations of Sanfilippo syndrome are not as striking as some of the other MPS disorders. Slight facial coarsening may be evident, and the skeletal features are usually subtle. The most prominent clinical feature is abundant coarse hair.

• Eye examination: Corneal clouding is not a common feature, although some patients may show mild corneal opacities.



• Neurologic examination: The syndrome is characterized by severe progressive mental and neurologic degeneration, including hearing loss and speech delay in severely affected patients.

Causes: A deficiency of one of four lysosomal enzymes is responsible for the different types of MPS type III. Specifically, for type IIIA, the enzyme is heparan N-sulfatase; for type IIIB, N-acetyl-alpha-D-glucosaminidase; for type IIIC, acetyl-CoA:alpha-glucosaminide acetyltransferase; and for type IIID, N-acetylglucosamine-G-sulfate sulfatase.

• Excess 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.



• Genetic causes are as follows:


• • The defect in type III is transmitted as an autosomal recessive trait (as is true of the other MPSs, except for type II [ie, Hunter syndrome] which is transmitted as a sex-linked recessive).
  
  
  
  • The 4 type III enzyme genes have been chromosomally mapped as follows: heparan sulphate sulphatase to band 17q25.3, N-alpha-D-glucosaminidase to band 17q21, acetyl-CoA-alpha-glucosamine N-acetyltransferase to chromosome 14, N-acetyl glucosamine-6-sulphate sulphatase to band 12q14.

  
  
  

DIFFERENTIALS

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[Mucolipidosis Type I (Alpha-Neuraminidase Deficiency-Sialidosis)]

Mucopolysaccharidosis Type II
Mucopolysaccharidosis Type IV
Mucopolysaccharidosis Type VI
Mucopolysaccharidosis Type VII

WORKUP

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Lab Studies:

• Levels of the enzymes involved in each of the 4 types of Sanfilippo syndrome may be assayed in cultured skin fibroblasts and in leukocytes. Prenatal diagnosis by measurement of the specific enzyme is also possible using cultured amniocytes or chorionic villi cells. Biochemical differentiation of subtypes within the major types is possible and a diagnosis is confirmed by specific enzymatic assay.



• Urinary excretion of heparan sulfate is increased.

Imaging Studies:

• Imaging studies may be useful for defining mild cases of dysostosis multiplex and other skeletal abnormalities.



• CT scanning shows a mild-to-moderate cortical atrophy.

TREATMENT

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Medical Care: No treatment for the underlying cause exists; treatment is supportive. Because of the varied symptoms, a multidisciplinary approach is usually indicated (see "Consultations").

Consultations:

• Treatment of individual patients may require specialists in neurology, orthopedics, pediatrics, ophthalmology, and audiology.



• Refer patients to medical geneticists for genetic diagnosis and genetic counseling.

MEDICATION

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Drug therapy currently is not a component of the standard of care for this disease. See Medical Care.

FOLLOW-UP

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Prognosis:

• The disease is progressive and usually leads to patients undergoing severe central nervous system degeneration, progressing to a vegetative state. Death usually occurs in persons younger than 20 years, primarily from aspiration pneumonia. Type A is the most severe form, and death usually occurs during the teen years.

Patient Education:

• Support groups and organizations patients might find helpful include the following:


• • Med Help International
  
  
  
  • March of Dimes
  
  
  
  • National Organization for Rare Disorders
  
  
  
  • National MPS Society
  
  
  
  • Genetic Alliance
  
  
  

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Patients with MPS may have unusual sensitivity to anesthesia. Take precautions prior to any surgery with patients who have even a mild form of MPS.



• Families must be counseled about the recurrence risk after the birth of an affected child.

Special Concerns:

• Because the MPSs are due to different genetic causes and share some features in common, determination of the precise genetic cause is essential. Making a distinction between MPS-II, ie, Hunter syndrome, (a sex-linked recessive) and the other MPSs (autosomal recessives) is especially critical.

TEST QUESTIONS

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CME Question 1: What is the main clinical problem associated with Sanfilippo syndrome?

A: Hydrocephalus
B: Central nervous system degeneration
C: Seizures
D: Joint stiffening
E: Corneal clouding

The correct answer is B: Neurologic degeneration begins some time after the child is aged 6 years.

CME Question 2: In which of the following mucopolysaccharidoses (MPSs) is corneal clouding not commonly observed?

A: Hurler syndrome (type I-H)
B: Scheie syndrome (type I-S)
C: Hurler-Scheie syndrome (type I-H/S)
D: Sanfilippo syndrome (type III)
E: Maroteaux-Lamy syndrome (type VI)

The correct answer is D: Patients with Sanfilippo syndrome have clear corneas, whereas some degree of cornea clouding is observed in the other syndromes.

Pearl Question 1 (T/F): Sanfilippo type A is the most severe of the types of Sanfilippo syndrome.

The correct answer is True: Patients with Sanfilippo types B, C, and D usually have less severe symptoms than patients with type A, which has an earlier onset and a more rapid development of symptoms.

Pearl Question 2 (T/F): Although the 4 major types of Sanfilippo syndrome have different features, they all are deficient in the same enzyme.

The correct answer is False: Each of the 4 types is due to a different enzyme deficiency controlled by a different gene. Type A is a lack of heparan N-sulfatase, type B is a lack of alpha-N-acetylglucosaminidase, type C is a lack of acetyl-CoA:alpha-glucosaminide acetyltransferase, and type D is a lack of the enzyme N-acetylglucosamine-6-sulfatase.

Pearl Question 3 (T/F): The major clinical features in Sanfilippo syndrome are course facial features.

The correct answer is False: The main clinical problems are behavioral in nature and only a mild dysmorphism occurs. Children are often hyperactive and experience sleep disturbances.

Pearl Question 4 (T/F): Sanfilippo syndrome can be diagnosed prenatally.

The correct answer is True: As is true of the other mucopolysaccharidoses (MPSs), Sanfilippo syndrome can be diagnosed either from amniotic fluid cells or from chorionic villi cells.

BIBLIOGRAPHY

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• 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].
• 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].
• GeneTests: Mucopolysaccharidosis Type III (Sanfilippo Syndrome). 2000; Available at: http://genetests.org.
• Jablonski S: Jablonski's Dictionary of Syndromes and Eponymic Diseases. 2nd ed. Melbourne, Fla: Krieger Publishing Co; 1991.
• 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].
• Lindor NM, Hoffman A, O'Brien JF, et al: Sanfilippo syndrome type A in two adult sibs. Am J Med Genet 1994 Nov 15; 53(3): 241-4[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].
• National Center for Biotechnology Information: Mucopolysaccharidosis Type III (Sanfilippo Syndrome). Available at: http://www3.ncbi.nlm.nih.gov/Omim[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].
• 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.
• 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].

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