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Symptoms and signs
MPS III is characterized by severe deterioration of the central nervous system, resulting in a variety of symptoms. Individuals with Sanfilippo syndrome usually start to show the symptoms between the age of 2 to 6. Speech problems, hyperactivity, aggressive behavior, developmental delays, hirsutism, sleep disturbances, seizures are the common manifestation of the syndrome at the initial stage. After the age of 10, patients start to experience increasingly severe symptoms including loss of motor and cognitive skills and somatic diseases. Patients later enter vegetative state, eventually leading to death in their 30s. Individuals with MPS III tend to have mild skeletal abnormalities; osteonecrosis of the femoral head may be present in patients with severe form. Optical nerve atrophy, deafness, otitis can be seen in moderate to severe individuals. Other characteristics include coarse facial features, thick lips, synophrys, and stiff joints. Chronic diarrheam enlarged liver and spleen are also common. It is difficult to clinically distinguish differences among the four types of Sanflippo syndrome. However, MPS IIIA is usually the most severe subtype, characterized by earliest onset, rapid clinical progression with sever symptoms, and short survival.
Pathophysiology and Genetics
Glycosaminoglycans (GAG) are polysaccharides that contain repeating disaccharides and sulfate groups. GAG are attached to serine and threonine at the surface of proteoglycans, which are found in the extracellular matrix and the cell membrane, or stored in the secretory granules. GAG are stored in the cell lysosome, and degraded by glycosidases, sulfatases and acetyltransferases. Deficiency in these enzyme leads to the four subtypes of MPS III.
All four subtypes of Sanfilippo syndrome have autosomal recessive inheritance. Impaired enzymatic activities are due to multiple mutations. The SGSH gene, which is located on chromosome 17q25.3, encodes heparan-N-sulfate; deficiency of the enzyme is responsible for MPS IIIA. A total of 137 mutations that causes this form of Sanfilippo syndrome have been found so far. MPS IIIA is more common in Northern Europe. The NAGLU gene, located on chromosome 17q21.2, encodes alpha-N-acetylglucosaminidase, deficiency of which results in MPS IIIB. To date, 152 mutations were identified to cause MPS IIIB. This form of the syndrome is more common in Southern Europe. The HGSNAT gene which encodes CoA:alpha-glucosaminidase N-acetyltransferase is located on chromosome 8p11.21, causing MPS IIIC. 64 mutations associated with this form have been described so far. Deficiency of N-acetylglucosamine 6-sulfatase that leads to MPS IIID is due to mutations in the GNS gene, which is located on chromosome 12q14.3. 23 mutations have been identified. In general, MPS IIIA and B are the most common form of Sanfilippo syndrome.
| MPS-III type | gene | enzyme | chromosomal region |
|---|---|---|---|
| MPS-III A | SGSH | heparan N-sulfatase | 17q25.3 |
| MPS-III B | NAGLU | N-acetyl-alpha-D-glucosaminidase | 17q21.2 |
| MPS-III C | HGSNAT | acetyl-CoA:alpha-glucosaminide N-acetyltransferase | 8p11.21 |
| MPS-III D | GNS | N-acetylglucosamine-6-sulfatase | 12q14.3 |