Sanfilippo Syndrome (mucopolysaccharidoses type III or MPS III) is an autosomal recessive inborn error of metabolism caused by a deficiency in one of four lysosomal enzymes (defining subtypes A–D) involved in the degradation of the mucopolysaccharide heparan sulfate. The absence of any one of these enzymes results in the accumulation of heparan sulfate in multiple tissues leading to progressive central nervous system (CNS) degeneration. Of the four, Sanfilippo A is the most common, and is caused by a deficiency in the enzyme heparan N-sulfatase. The disease is characterized by severe, progressive neurodegeneration in most patients with mild somatic disease (Valstar, 2008). The clinical features are summarized in Table 1 below.
Table 1: Clinical Features of Sanfilippo (MPS-III)
| Affected Organ/System/Domain |
Feature |
| Head, Eyes, Ears, Nose & Throat |
Mild coarse facial features, synophrys, clear corneas, frequent otitis media & hearing loss, fleshy nasal tip, everted lower lip |
| Cardiovascular |
Asymmetric septal hypertrophy, cardiomegaly |
| Respiratory |
Frequent upper respiratory infections |
| Gastrointestinal |
Frequent diarrhea, mild hepatomegaly, mild splenomegaly |
| Skeletal |
Mild dysostosis multiplex, thickened ribs, dense calvaria, joint stiffness, joint contractures, range from normal to short stature |
| Skin, Hair, Nails |
Hirsutism, coarse hair |
| Genitourinary |
Inguinal hernia, umbilical hernia or both |
| Neurologic |
- Developmental regression by 1.5 to 3 years
- Severe behavioral problems at age 3 to 4
- Mental retardation
- Hyperactivity
- Aggressive behavior
- Seizures
- Sleep disturbances
|
All types of Sanfilippo syndrome belong to the group of nine well-characterized lysosomal storage diseases called mucopolysaccharidoses (MPS), the rare inherited metabolic disorders caused by deficiencies in enzymes that metabolize mucopolysaccharides/glycosaminoglycans (GAG) outlined in Table 2 (Futerman and van Meer, 2004; Hopkin and Grabowski, 2008). GAG are long, unbranched polysaccharides containing multiple repeats of disaccharide units usually consisting of a hexose or a hexuronic acid moiety linked to a hexosamine moiety. Deficiencies in the enzymes involved in Sanfilippo syndrome types A through D prevent the step-wise degradation of the mucopolysaccharide heparan sulfate, and result in the accumulation of partially broken down heparan sulfate in cells and tissues (Cleary and Wraith, 1993; Kelly, 1976; Van Hoof, 1974).
Table 2: Mucopolysaccharidoses
| MPS Type |
Disease |
Enzyme Defect |
| MPS I |
Hurler, Scheie, Hurler/Scheie |
α-L-iduronidase |
| MPS II |
Hunter |
Iduronate sulfatase |
| MPS III |
Sanfilippo |
- Heparan-N-sulfatase (A)
- N-Acetyl-alpha-glucosaminidase (B)
- Acetyl-CoA: α-glucosaminide acetyltransferase (C)
- N-acetylglucosamine 6-sulfatase (D)
|
| MPS IV |
Morquio |
- Galactosamine-6-sulfatase (A)
- B-Galactosidase (B)
|
| MPS VI |
Maroteaux-Lamy |
N-acetylgalactosamine 4-sulfatase |
| MPS VII |
Sly |
β-glucuronidase |
| IX |
Natowicz |
Hyaluronidase |
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