Abstract— Lipids and certain lysosomal enzymes were measured in the cerebral gray and white matter and in the liver of unaffected controls and six patients with mucopolysaccharidosis (MPS). Three of the patients had MPS Type I (Hurler), one Type II (Hunter), one Type IIIA (Sanfilippo A) and one Type V (Scheie). The glycosaminoglycans (GAG) of those tissues have been fully characterized previously (Constantopouloset al., 1976). Results of the present study: the normally minor brain monosialogangliosides GM2 and GM3 were markedly increased in the gray and to a lesser extent in the white matter of all the patients, except the patient with MPS Type V. On an average GM2 comprised 8.2 and 6.3, and GM3 11.8 and 6.0% of the total ganglioside neuraminic acid of the gray and white matter respectively in all patients with MPS I, II, and IIIA (normal subjects had less than 1). Ceramide dihexoside was also increased in the gray matter of the patients with MPS I, MPS II and MPS IIIA. The sphingolipid abnormalities were found only in tissues containing excessive amounts of partially degraded dermatan and heparan sulfates or heparan sulfate alone. Of the six acid hydrolases assayed, the activity of /f‐glucosaminidase was increased in both brain and liver, while that of α‐galactosidase and β‐galactosidase was diminished, particularly in the liver. These results suggest that the partially degraded heparan sulfate (and perhaps the dermatan sulfate) which accumulate in the tissues of the patients with MPS may inhibit catabolic enzymes of various sphingolipids. In turn, accumulation of sphingolipids could be responsible at least for some of the brain damage and the mental retardation in MPS I, II and IIIA.

Brain cellular fractions were prepared in bulk from four nonneurological patients and from five patients with mucopolysaccharidosis (MPS). Glycosaminoglycans and lipids were isolated and chemically analyzed. Results of the present study: in the normal controls glycosaminoglycans as pg per mg protein (mean) were 2.2 in neuronal perikarya, 2.0 in astroglia, 2.1 in oligodendroglia, 3.3 in neuropile from gray matter, and 3.2 in a mixed fraction from white matter. In the partially myelinated axons from gray and white matter of an 8-month-old infant, the concentration was 6.9 and 2.6 pg per mg protein, compared with 2.8 and 0.8 pg per mg protein, respectively, in the adult patients. It was estimated that chondroitin sulfates constituted more than onehalf of the total glycosaminoglycan. Hyaluronic acid, heparan sulfate, and dermatan sulfate were also present in all cell types and fractions. Cholesterol, phospholipids, cerebrosides, sulfatide and gangliosides were present in all cell types and fractions, but differed widely in concentration. There was a four-to sixfold increase in the concentration of total glycosaminoglycans in the neuronal perikarya of patients with MPS IH, 11, and IIIA. The increased glycosaminoglycans were heparan sulfate in MPS IIIA, and dermatan sulfate plus heparan sulfate in MPS IH and 11. Similar changes were found in the astroglia and in the other brain fractions of those patients. The concentration of the gangliosides GMZ, GM3, GD3, and ceramide dihexoside was markedly increased in the neurons and other brain fractions of the same patients. The quantities of GM3, GMz, and GD3 together amounted to 65% of the total gangliosides of the neurons, indicating changes of the same magnitude seen in the gangliosidoses. All these patients exhibited mental retardation. The concentration and composition of glycosaminoglycans, gangliosides, and neutral hexosyl ceramides in the neuronal perikarya of the patient with MPS IS was normal. There was only a small increase of dermatan sulfate content in the neuropile, mixed fraction, and myelinated axons from the white matter and some increase of ceramide dihexoside content in the myelinated axons. This patient was an adult of normal intelligence.

A disease discovered in three Plott Hound littermates was found to be associated with a profound and specific deficiency of a-L-iduronidase (mucopolysaccharide a-L-iduronohydrolase; EC 3.2.1.76) in fibroblasts and leukocytes. The pedigree was consistent with autosomal recessive inheritance. A markedly increased amount of dermatan sulfate and heparan sulfate was excreted in urine. Fibroblasts cultured from the skin of the affected dogs accumulated excessive asS-labeled mucopolysaccharide; this accumulation could be decreased to a normal level by exogenous human high-uptake a-L-iduronidase (Hurler corrective factor) as well as by secretions of normal human or canine fibroblasts. The correction was inhibited by mannose 6-phosphate. Maturation of a-L-iduronidase in normal canine fibroblasts followed the pathway previously observed in human fibroblasts; no crossreactive material was observed in the cells or in secretions from the fibroblasts of the affected dogs. The canine disorder thus resembles mucopolysaccharidosis I in all biochemical parameters tested; the clinical appearance of the animals is closest to HurlerScheie syndrome, a form of ac-L-iduronidase deficiency of intermediate severity. The animal model should prove valuable for therapeutic experiments.

No abstract