Ultrastructural and biochemical aspects of the Sanfilippo syndrome,--type III genetic mucopolysaccharidosis.

The Sanfilippo Syndrome (SS) is a recessively inherited connective tissue disorder expressed in early life. It is classified as a genetic mucopolysaccharidosis (MPS) because the underlying defect involves the catabolism of heparan sulfate (HS), one of the glycosaminoglycans (GAG). Four variant forms, i.e., type A, B, C, and D, each associated with a different enzymatic defect, have been recognized in affected children. Biochemical studies show that characteristically HS accounts for most of the increased amounts of GAG excreted in the urine and those stored in viscera and brain. Gangliosides GM2, GM3 and GD2 are elevated considerably in the brain. Morphologically, the very water-soluble substances accumulating in the viscera are metachromatic, and consist ultrastructurally of finely granulo-floccular (or filamentous) material which is bound in cytoplasmic vacuoles. These substances are considered to represent the GAG. In the central nervous system (CNS) the stored substances are not soluble in water or alcohol and xylol, give a PAS-positive reaction, and stain for lipids and with luxol fast blue. Ultrastructurally, they consist of membranous arrays which often are of the "zebra body" variety. The CNS-inclusions are considered to represent the stored gangliosides; they were found also in small numbers in viscera of older children with SS. The search for a common denominator in the pathogenetic mechanism(s) culminating in both types of inclusions, continues.