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.

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SUMMARY The electron microscopic appearances of the corneoscleral and iris tissue removed at operation from a child with Hurler disease and glaucoma showed distinctive swollen cells with intracellular inclusions similar to those which are observed in other tissues in these patients and which are due to abnormal lysosomal storage of mucopolysaccharides. Some recent observations on the possible relationship between mucopolysaccharides and the drainage of fluid from the anterior chamber are briefly reviewed and correlated with the present observations. The development of glaucoma in this patient is thought to be associated with the presence of the mucopolysaccharidecontaining cells in the region of the aqueous drainage channels.

SUMMARY Biochemical and pathological observations on tissues from two patients with Hurler disease (mucopolysaccharidosis IH; a-L-iduronidase deficiency) who had been treated by fibroblast transplants as a means of enzyme replacement treatment are reported.These results and those obtained in three surgical specimens [ligamentum flavum with dura mater from a case of Scheie disease (mucopolysaccharidosis IS; a-L-iduronidase deficiency); a fetus with Hurler disease; and tonsil from a patient with Hunter disease (mucopolysaccharidosis II; a-L-idurono-2-sulphate sulphatase deficiency)] illustrate the inadequacy of routine histological processing to demonstrate the abnormal glycosaminoglycan accumulation in this group of diseases. A combined approach using histochemistry and electron microscopy enables the extent of both extracellular and intracellular involvement to be assessed. The fetus (20 wk gestation) already showed evidence of Hurler disease.The pathological appearances in both of the fibroblast-transplanted patients were those which would have been expected in patients dying with unmodified Hurler disease. There was no detectable a-L-iduronidase activity in the brain, liver, kidney or in fibroblasts cultured from either the transplantation sites or from remote subcutaneous sites in either of the transplanted patients.These results are discussed from the viewpoint of their bearing on the pathophysiology of the mucopolysaccharidoses and proposals for their treatment by enzyme replacement.

We describe the case of an otherwise healthy 7-year-old girl whose mother noticed that she intermittently smelt of fish. This was due to the intermittent excretion of trimethylamine which could be precipitated by choline ingestion and by eating fish. Excluding eggs, liver and salt-water fish from the diet relieved the symptom. After a standard 15 g choline load, the child's father, but not her mother, excreted amounts of trimethylamine which were intermediate between those excreted by the patient and normal control subjects.