AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 MPSs comprise a group of 7 metabolic disorders, known as MPS types I-VII (MPS V is now considered a form of type I and is known as MPS 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 (MPS IH), Hunter syndrome (MPS II), and Sanfilippo syndrome (MPS III). Although lysosomal storage diseases are rare individually, the estimated incidence of all types of MPS disorders combined is 1 in 20,000 live births.

MPS III, or Sanfilippo syndrome, was described in 1963 by a US-trained pediatrician named Sylvester Sanfilippo. Considered to be the most common of MPS 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). The other MPS 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.

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. 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.¹
• In 1999, Poorthuis et al reported an incidence of 4.5 cases per 100,000 live births for all MPS disorders in the Netherlands.² MPS III accounted for 47% of all cases of MPS diagnosed and had a birth prevalence of 1.89 cases per 100,000 live births. In this study, MPS IIIA had an estimated birth prevalence of 1.16 cases per 100,000.
• 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, MPS IIIA had an incidence of 1 case per 114,000 live births, and MPS IIIB had an incidence of 1 case per 211,000 live births. MPS IIIC and MPS IIID are much rarer.

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 aspiration pneumonia. Type IIIA is the most severe form; most patients with this form die during their teenage years.

Race

The MPSs are panracial.

Sex

All forms of MPS III are inherited in an autosomal recessive Mendelian pattern. The gene mutations are located in the autosomes and not in the sex chromosomes;³ 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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, most patients become severely limited in their activities and movement. Individuals 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 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.

Physical

The striking clinical features of coarse facial features and skeletal abnormalities seen in the other MPS 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 MPS 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 MPS disorders)
  • Joint stiffness
• Neurological
• • Severe progressive neurologic degeneration
  • Hearing loss and speech delay in severely affected individuals

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 III, the enzyme is D, 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 MPS disorders, except for MPS II (ie, Hunter syndrome), which has X-linked recessive inheritance. Because of the autosomal recessive inheritance pattern, parents have a 25% chance of having another affected child.
  • 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Biochemical differentiation of the different forms within mucopolysaccharidosis type III (MPS III) is possible, and diagnosis is confirmed by specific enzymatic assay.
• Enzymatic activity for all types of Sanfilippo syndrome may be assayed in cultured skin fibroblasts and in peripheral blood leukocytes. If MPS III is suspected, enzymatic cell analysis is the recommended test.
• In all forms of MPS III, urinary excretion of heparan sulfate is increased.
• • To measure the concentration of GAGs in the urine, a total quantitative test and a fractionation test should be performed using electrophoresis or chromatography.
  • A concentrated urine specimen is best to avoid a false-negative result due to a dilute urine. Ideally, a first-morning urine specimen should be analyzed. This is especially important for the diagnosis of MPS 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.⁴

Imaging Studies

• Neuroimaging to diagnosis hydrocephalus and to look for changes in brain structure
• Echocardiography to assess for asymmetric septal hypertrophy and valvular disease
• Imaging of the abdomen, such as ultrasonography or CT scanning, to evaluate for organomegaly
• Radiographic skeletal survey to identify cases of dysostosis multiplex (the spectrum of skeletal changes seen in patients with MPS disorders)

Other Tests

• Electroencephalography (EEG) to diagnose seizure activity
• Audiologic evaluation to identify patients with hearing loss
• Polysomnography for those patients who demonstrate clinical signs of obstructive sleep apnea

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No treatment for the underlying cause is available. Medical treatment is supportive and is directed toward improving the patient's quality of life. Because of the varied symptoms seen in mucopolysaccharidosis type III (MPS III), a multidisciplinary approach is indicated (see Consultations). Currently, specific therapies such as bone marrow transplantation (BMT) and enzyme replacement therapy are not options for patients with Sanfilippo syndrome.

• Bone marrow transplantation has been shown to improve the clinical outcomes of patients with MPS disorders; however this therapy has been most successful in patients with MPS I, MPS II and MPS VI. Patients with MPS III have not shown positive clinical benefit from BMT.
• Enzyme replacement therapy has been approved in the United States for patients with MPS I, MPS II, and MPS VI.

Consultations

• the treatment of individual patients requires consultation with pediatric neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedic specialists.
• Pediatric surgical consultation is indicated for those patients in need of hernia repair.
• Neurosurgical evaluation is indicated for those patients who show clinical signs of cervical cord compression or other nerve compression disorders (ie, claw hand deformity).
• Refer patients and their families to a developmental pediatrician to help with behavioral concerns and to establish routines for nighttime sleep.
• Patients and their families need evaluation by a medical genetics team for diagnosis and counseling.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Currently, drug therapy is not part of the standard of care for this disorder.
• Sedative medications and melatonin have been used in these patients to help improve quality of sleep in conjunction with establishing a strict bedtime regimen in a quiet, dark room. See Medical Care.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• This progressive disorder has a devastating prognosis. Severe CNS degeneration occurs, with progression to a vegetative state.
• Most patients do not live beyond age 20 years, with death primarily due to respiratory complications.

Patient Education

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

• Alliance Sanfilippo
• Canadian Society for Mucopolysaccharide and Related Diseases, Inc
• Children Living with Inherited Metabolic Diseases (CLIMB)
• Hide and Seek Foundation for Lysosomal Disease Research
• National Organization for Rare Disorders (NORD)
• National MPS Society
• Society for Mucopolysaccharide Diseases

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Patients with mucopolysaccharidosis (MPS) disorders have greater risks for complications during general anesthesia.⁵ Complications during anesthesia have been attributed to excessive oral secretions and airway obstruction due to abnormal airway anatomy. Prior to any surgical intervention, proper precautions in regard to airway management are critical for patients with MPS.
• Families must be counseled about the recurrence risk after the birth of an affected child.

Special Concerns

• Because the MPS disorders share clinical features but have different genetic etiologies, determining the type of MPS in an affected patient is important. 
• Distinguishing between MPS II (Hunter syndrome), which has X-linked recessive inheritance, and the other MPS disorders, which have autosomal recessive inheritance, is especially critical in regard to citing recurrent risks for the biological parents of an affected child. 

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. Dec 1997;101(3):355-8. [Medline].
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. Jul-Aug 1999;105(1-2):151-6. [Medline].
3. Blanch L, Weber B, Guo XH, et al. Molecular defects in Sanfilippo syndrome type A. Hum Mol Genet. May 1997;6(5):787-91. [Medline].
4. 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. Sep 1996;16(9):829-35. [Medline].
5. Man TT, Tsai PS, Rau RH, et al. Children with mucopolysaccharidoses--three cases report. Acta Anaesthesiol Sin. Jun 1999;37(2):93-6. [Medline].
6. Connor JM, Emery AE, Rimoin DL, Pyeritz RE, eds. Emery and Rimoin's Principle and Practice of Medical Genetics. 3^rd ed. New York, NY: Churchill Livingstone; 1996.
7. Fensom AH, Benson PF. Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn. Jan 1994;14(1):1-12. [Medline].
8. Jablonski S. Jablonski's Dictionary of Syndromes and Eponymic Diseases. 2^nd ed. Melbourne, FL: Krieger Publishing Co; 1991.
9. Jones KL. Storage disorders. In: Smith's Recognizable Patterns of Human Malformation. 5^th ed. Philadelphia, Pennsylvania: WB Saunders Company; 1997:464-5.
10. Kakkis E, Wraith E. Clinical features and diagnosis of the mucopolysaccharidoses. UpToDate. Available at www.utdol.com. Accessed November 6, 2007.
11. Lindor NM, Hoffman A, O'Brien JF, Hanson NP, Thompson JN. Sanfilippo syndrome type A in two adult sibs. Am J Med Genet. Nov 15 1994;53(3):241-4. [Medline].
12. 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 November 2, 2007.
13. National Institutes of Health. Mucopolysaccharidosis Type III (Sanfilippo Syndrome). GeneTests. Available at http://www.genetests.org. Accessed 2000.
14. Scriver CR, Beaudet AL, Sly WL, et al. The Metabolic Basis of Inherited Disease. 7^th ed. New York, NY: McGraw-Hill; 1995.
15. Spitz JL. Genodermatoses. In: A Full Color Clinical Guide to Genetic Skin Disorders. Baltimore, Md: Williams and Wilkins; 1995.
16. Sutton VR. Presenting features of inborn errors of metabolism. UpToDate. Available at www.utdol.com. Accessed November 6, 2007.
17. Thoene JG, ed. Physician's Guide to Rare Diseases. 2^nd ed. Montvale, NJ: Dowden Publishing Co; 1995.
18. Toone JR, Applegarth DA. Carrier detection in Sanfilippo A syndrome. Clin Genet. Jun 1988;33(6):401-3. [Medline].
19. 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. Aug 1981;20(2):152-60. [Medline].

Article Last Updated: Apr 24, 2008