168 SUTRITION REVIEWS [Vol. 20, LYo. 6

Two pertinent features, the acidosis and the neurological symptoms, remain unex- plained, particularly in view of the fact that other conditions associated with tyrosyl- uria are usually asymptomatic.

Another point concerns the documented occurrence of hypocalcemia in this patient.

One might ask what relationship this may have had to the convulsions, muscular rigid- ity, and electroencephalographic changes manifested by this infant.

This report by Menkes and Jervis consti- tutes an interesting addition to the growing list of metabolic errors.

ACID MUCOPOLYSACCHARIDES AND GARGOYLISM

Children ioith gargoylkrii excrete increased anioitnts oj acid ntucopoty8accharides as compared with controls of the sanie age.

It has been suggested by G. Brante (Scandinav. J. Clin. Lab. Invest. 4, 49 (1956) ) that the underlying pathological defect in gargoylism may be an inborn error of metabolism with regard to the acid muco- polysaccharides. Children affected with this disorder have a condition which is charac- terized by chondro-osteodystrophy, corneal opacities, enlargement of the liver, and men- tal deficiency. There are conditions other than gargoylism in which there may be chondro-osteodystrophy. Various investiga- tors studying patients with gargoylism found increased amounts of chondroitin sulfate B and heparitin sulfate in the urine and tissues of these individuals. Since the latter two compounds are normal constit- uents of connective tissue, it has been sug- gested that patients with gargoylism are producing normal acid mucopolysaccharides a t an accelerated rate and also storing large amounts of these products.

Increased amounts of acid mucopolysac- charides are also found in urine obtained from patients with Marfan’s syndrome, rheumatoid arthritis, diabetes mellitus, and in lupus erythematosus. Normal individuals excrete smaller amounts of this material in the urine. Recently, W. M. Teller, E. C. Burke, J. W. Rosevear, and B. F. McKenzie (J. Lab. Clin. Med. 59,95 (1966)) studied the urinary excretion of acid mucopolysac- charides in a group of “normal” children from less than a year to 14 years old and in 11 patients with known gargoylism. The children in the contrnl group were either

hospitalized because of minor illnesses or were seen during routine examinations a t a clinic.

Urine samples from the 11 patients with gargoylism were collected mainly a t their homes and sent with preservative to the laboratory for analysis. To check on the completeness of the 24 hour urine collection, the level of creatinine in each sample was determined. Whenever the level fell below 12 mg. per kg. of body weight, the specimen was discarded.

The acid mucopolysaccharides of the urine were first separated by precipitation with cetyltrimethylammonium bromide and subsequently, the acid mucopolysaccharide separated from the complex. The amount of acid mucopolysaccharide was expressed as milligrams of glucuronic acid. In the group of well children it was found that the amount of acid mucopolysaccharide ex- creted for 24 hours increased with age, with no statistical difference between the boys and the girls. A t four years of age, a mean value of 3.5 * 3.3 mg. (mean -C 2 standard deviations) of glucuronic acid per 24 hours was found. By 14 years of age, the urinary excretion of acid mucopolysaccharide ex- pressed as glucuronic acid increased to 7.3 * 5.1 ml.

On the other hand, if the ratio of acid mucopoylsaccharide to creatinine, with the creatinine expressed as gram. per 24 hours, were plotted against the age of the children, a decline of the ratio occurred as the chil-

June lM8] NUTBlTION BEVIEWS 169

dren became older, with a value of 20.8 * 11.3 occurring at one year of age, falling to 7.4 * 7 at 12 years of age. Of the 11 patients with gargoylism, eight excreted greater amounts of acid mucopolysaccharides in the urine than did well children. However, three had values in the range one would ex- pect to find in children without gargoylism. With regard to the excretion of acid muco- polysaccharide per gram of creatinine, all 11 patients had values above those which occur in well children.

The degree of clinical severity of disorder varied greatly in individuals from slight retarded growth and somewhat cloudy cor-

neas, to a complete picture of gargoylism in which there were skeletal deformities, deaf- ness, increased size of the liver, and mental retardation. However, there appears to be no correlation between the severity of the disorder and the excretion of acid muco- polysaccharide in the urine. While there ap- pears from these studies to be a correlation between the defective metabolism of con- nective tissue and an increased excretion of acid mucopolysaccharides in the patients with gargoylism, the exact nature of this defect and the mechanism by which the de- formities are produced has not yet been elucidated.

BITOT’S SPOTS AND PROTEIN MALNUTRITION

Forty& patients with Uitot’s spots were studied with regard to the concentra- tions of vitamin A and protein iu their blood. Therapy with vitamin A plus protein was superior to vitamin A therapy alone.

The history of Bitot’s spots was briefly re- viewed recently (Nutrition Reviews 19, lo4 (1961)). A considerable body of evi- dence was cited which suggests that l ) Bitot’s spots occur most frequently in mal- nourished populations, 2) these lesions do not correlate well with low concentrations of vitamin A or carotene in the blood, 3) they may not disappear after large doses of vitamin A have been given and 4) they may occur (infrequently) in well-fed healthy individuals. It was suggested that Bitot’s spots should not be used in nutri- tional surveys as an absolute indication of vitamin A deficiency.

Recently, our attention was called to an article published in India which is in ac- cord with these views (K. Bagchi, K. Hal- der, and S. R. Chowdhury, J . Indian Med. Assn. 33, 4Ol (1969) ) .

These authors were concerned with the relative ineffectiveness of vitamin A alone in the treatment of keratomalacia and Bitot’s spots. They were impressed with the fact that many of these patients had ob- vious protein malnutrition. Accordingly, they designed a study of 46 patients with

Bitot’s spots in order to compare the ef- fects of therapy with vitamin A alone to those of therapy with vitamin A and pro- tein.

The clinical features of these cases were classical. The early ocular lesions were characterized by brown or chocolate dis- coloration of the sclerae. These pigmented spots occupied the same position as that of Bitot’s spots and in untreated patients gradually changed into the latter. The pig- mented patches were slightly thickened and their surface was wrinkled, but they were not as elevated as Bitot’s spots. Another difference was the presence of engorged capillaries in the pigmented spots. Those lesions left untreated gradually became less vascular, less pigmented, and acquired an opaque layer of keratinized cells, finally assuming the typical yellow foamy appear- ance of Bitot’s spot.

Earliest changes were thought to be re- lated to vascular engorgement. A single dilated capillary was observed to arise from the outer canthus of the eye, extend s’long the equator and, midway to the cor- nea, to break up into several branches which