Clinical Information

The mucopolysaccharidoses (MPS) are a group of disorders caused by a deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAG). Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in MPS disorders.

Sanfilippo syndrome (MPS type III) is an autosomal recessive MPS with 4 recognized types (A-D). Each type is caused by a deficiency in 1 of 4 enzymes involved in the degradation of heparan sulfate resulting in its intra- and extra-cellular accumulation. Though biochemically different, the clinical presentation of all types is indistinguishable. Sanfilippo syndrome is characterized by severe central nervous system degeneration, but other symptoms seen in MPS, such as coarse facial features and skeletal involvement, tend to be milder. It is important to note the variability in severity for MPSIII. In some patients, only moderate intellectual disability can be observed even at the end of the third decade of life. However, onset of clinical features usually occurs between 2 and 6 years in a child who previously appeared normal. The presenting symptoms are most commonly developmental delay and severe behavioral problems. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by age 20, although individuals with an attenuated phenotype may have a longer life expectancy and remain functional into their third and fourth decades.

Sanfilippo syndrome type B is due to a deficiency of the enzyme N-acetyl-alpha-D-glucosaminidase (alpha-hexosaminidase), caused by variants in the NAGLU gene. Affected individuals demonstrate elevations of heparan sulfate in blood and urine (MPSBS / Mucopolysaccharidosis, Blood Spot and MPSQU / Mucopolysaccharides Quantitative, Random, Urine). Diagnostic sequencing and deletion/duplication studies of the NAGLU gene (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify NAGLU Gene List ID: IEMCP-KG2Q99) is available for patients with an enzyme deficiency.

Elevations in serum of alpha-N-acetylglucosaminidase and other hydrolases may be seen in patients with mucolipidosis II/III (I-cell disease).(1) I-cell disease is an autosomal recessive lysosomal storage disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay. Measurement of alpha-N-acetylglucosaminidase activity is not the preferred diagnostic test for I-cell disease but may be included in the testing strategy.