Galactosemia Cataract*

GALACTOSEMIA CATARACT* REPORT OF A CASE HAROLD F. FALLS, M.D., W.

GEORGE H. LOWRKY, M.D.,

CLAYTON ANDERSON, JR.,

AND

M.D.

Ann Arbor, Michigan Galactosemia is of considerable import­ ance to the ophthalmologist in view of the well-recognized toxic and cataractogenic effect of the monosaccharide in experimental animals. Galactosemia, in the human, is an extremely rare congenital anomaly of carbo­ hydrate metabolism. The essential features of this clinical entity are: hepatomegaly, splenomegaly, galactosuria, albuminuria, diarrhea, vomit­ ing, failure to gain weight or to grow, and development of cataracts. Occasionally secondary features of the syndrome may be seen, such as icterus, anemia, osteoporosis, lethargy, and absence of the tendon reflexes. The development of either nuclear or zonular lenticular opacification has been ob­ served in nearly half of the reported cases of galactosemia. The removal of galactose from the diet results in improvement of all the signs and symptoms of the disease. It is of interest that the opacification of the lens may partially or completely disappear, pro­ viding dietetic treatment is initiated be­ fore irreversible cataractous formation has developed. It is the purpose of this paper to report the occurrence of galactosemia in a white infant, a girl, aged eight weeks. LITERATURE

It may be conservatively estimated that less than 12 cases of authenticated galacto­ semia are available for study in the litera­ ture. * From the Departments of Ophthalmology and Pediatrics of the University Hospital, and the De­ partment of Human Heredity of the Laboratory of Vertebrate Biology, University of Michigan. Sup­ port for this research was provided by the Horace H. Rackham School of Graduate Studies.

Most authors feel that the first accepted case of galactosemia was reported by F. Goppert1 in 1917. The patient was two years and five months of age when first observed. Two siblings of this child had died early in life presenting icterus and enlarged livers. A third sibling, who survived, also had hepatomegaly. Goppert made no statement concerning the eyes of the children. In 1908, Von Reuss2 reported galacto­ suria in an eight months' old infant who presented cirrhosis of the liver at autopsy. This author believed that this was a case of alcoholic cirrhosis, since the child had been fed tea and cognac daily since four months of age. G. Fanconi,3 in 1933, reported an affected child, the second youngest of 12 siblings. Two of these siblings had zonular cataracts. The reported patient was found to have had bilateral zonular cataract requiring surgical interference. It is interesting to note that the parents of the above sibship were first cousins. Neurofibromatosis was described in the patient, one sibling, and the mother. Mason and Turner/ in 1935, recorded chronic galactosemia in a Negro male child, the youngest of seven children. Cataracts are not mentioned in the original report, but were admitted in a personal communication to Bruck and Rapoport. Norman and Fashena 5 (1943) reported chronic hypergalactosemia in a white male infant of 11 weeks. No ocular pathology was described. Mellinkoff and his collaborators6 (1945) published a typical case of galactosemia in a two months' old white male. The ocular findings were carefully enumerated. They stated: "The lens presented a sharp zone of demarcation in that the nucleus was more

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1272 HAROLD F. FALLS, GEORGE H. LOWREY AND W. CLAYTON ANDERSON, JR. highly retractile; there was no actual opac­ ity, however." When milk was removed from the patient's diet all pathologic symp­ toms and signs disappeared, including the lens changes. Goldbloom and Brickman7 reported two cases of galactosemia in 1946. The first case, a six months' old male, presented in addi­ tion to the usual signs and symptoms, bi­ lateral dense central lenticular opacification. The cataract became less dense with the pas­ sage of time, but surgery was necessary at the age of six and one-half years. The sec­ ond case, in a white girl, aged three and onehalf months, also exhibited "bilateral pin­ point cataracts." The authors felt that the cataracts had regressed somewhat when the child was seen at the age of nine and onehalf months. Goldstein and Ennis 9 (1948) reported galactosemia in a white male infant aged two and one-half months. They state "bi­ lateral zonular cataracts were observed." When seen at six and one-half months of age, after treatment, the "cataracts had com­ pletely disappeared." Greenman and Rathbun 8 reported an 18week-old white male presenting bilateral nuclear cataracts, hepatomegaly, splenomeg­ aly, and ascites. "Clinical improvement was evident almost immediately after the with­ drawal of galactosc from the diet. Only vestigial cataracts and moderate hepatomeg­ aly were present four months afterwards."

she began to vomit all or most of every feeding. She was taken off breast milk and several changes in the formula were made. At varying intervals evaporated milk, Alacta, and boiled skimmed milk formulas were tried without success. Due to weight loss and dehydration she was ad­ mitted to the local hospital for parenteral fluid administration. T h e child was hospitalized for five days and was discharged on an evaporated milk formula. A severe diarrhea developed shortly after and it was observed that the abdomen was distended and "hard." The patient was readmitted to the local hospital and a paracentesis was performed on August S, 1949, with removal of 600 cc. of slightly cloudy fluid from the abdomen. In spite of therapy, diarrhea and vomiting continued. T h e patient was transferred to the University of Michigan Hospital on August 8, 1949. Physical examination revealed an eight weeks' old infant who appeared malnourished and dehy­ drated. T h e abdomen was distended with fluid which was draining from the paracentesis wound. The liver edge was smooth and sharp and extended to the level of the umbilicus at the midclavicular line. T h e admission weight was nine pounds, three ounces. T h e remainder of the examination was not remarkable. The child took an evaporated milk formula fairly well but vomited at frequent intervals. The diarrhea continued for several days after admission. Laboratory findings. URINE. Repeated urinalysis revealed marked melaturia with qualitative Bene­ dict's solution. This reducing substance was demon­ strated to be galactose (negative yeast fermenta­ tion, typical osozone crystal formation, negative pentose tests). Albuminuria was present as were frequent granular casts. BLOOD. Hemoglobin 8.5; R.B.C., 2,600,000; W.B.C., 13,200; prothrombin time (Quick) 100 percent of normal; blood urea nitrogen, 34.6 mg. percent (following hydration). Total protein, 4.4 gm.; albumin: globulin ratio, 2 : 1 . GLUCOSE TOLERANCE TEST (1.75 gm. glucose per

Kg.):

CASE REPORT L. B., a white female infant, was admitted to the pediatric ward of the University Hospital on August 8, 1949, at the age of eight weeks with a chief complaint of abdominal enlargement. Family history. Both parents were 25 years of age and were in excellent health. The father was told he had iiad rheumatic fever at 19 years of age but he has been asymptomatic since. There were no siblings and no history of a similar disease occur­ ring in any member of the family. Present illness. T h e patient was born at term and the delivery was uncomplicated. T h e birth weight was eight pounds, four ounces. T h e child was discharged from the hospital at four days of age on alternate breast and formula Baker's milk feedings. She did well until the seventh day of life when

Fasting ! /2 hour 1 hour 2 hours 3 hours

Total Blood Sugar 35 mg.% 46 mg.% 97 mg.% 103 mg.% 74 mg.%

GALACTOSE TOLERANCE TEST (3.5 gm. galactose) :

Total Galactose Blood Sugar Blood Sugar Fasting 86 mg.% — Yz hour 125 mg.% — 1 hour 164 mg.% 69 mg.% 2 hours 218 mg.% 136 mg.% 3 hours 264 mg.% — After the diagnosis of galactose intolerance was established (at eight weeks of age, the youngest

GALACTOSEMIA CATARACT reported), the patient was given a lactose- and galactose-free diet. This consisted of casec and nutramigen with added carbohydrate and water to approximate the protein and caloric content of an adequate evaporated milk formula. Within a week there was a marked reduction in ascites. The urine became sugar- and albumin-free and has remained so. Blood urea nitrogen one week after the new diet was initiated was 15.3 mg. percent. All gastro­ intestinal symptoms subsided. Ophthalmologic examination. The patient was referred to the Department of Ophthalmology on August 19, 1949, as soon as the diagnosis of galactosemia was established. The external examination showed no ocular pathologic condition. The funduscopic examina­ tion presented a sharply outlined zonular area of increased density of an opalescent nebular nature just beneath the capsule in both lenses. In addition it was evident that the nuclear areas were likewise somewhat opalescent in character. The discs, vessels, and macular areas were normal in appearance bilaterally. COMMENT

Galactosemia is an anomaly of carbohy­ drate metabolism in which the metabolism of galactose is impaired, resulting in an ac­ cumulation of this monosaccharide in the blood stream with the resultant excretion in the urine. As mentioned by Goldstein and Ennis, 9 it appears that there is a mutual antagonism between the two sugars—galactose and glucose. In fact it has been questioned or hypothecated that excessive quantities of galactose may interfere with normal oxida­ tion of glucose. Since it is believed that the liver is the site of conversion of galactose to glucose we have, in the presence of galactosemia, in­ direct evidence of impaired liver function. The metabolic error may thus be a decreased rate of conversion of galactose to glucose, most likely an enzymatic want or defect. The resultant accumulation of galactose in the blood stream produces toxic manifesta­ tions. It is strongly suggested that toxic manifestations—cataract, albuminuria, loss of tendon reflexes, and so forth—are due to the local presence of excessive galactose in the tissues. D. B. Kirby 1 0 and his associates have capably demonstrated that galactose is di­ rectly toxic to lens tissue. Mitchell 11 and

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Dodge 1 5 revealed that cataract in experi­ mental animals developed rapidly and con­ sistently when the animals were fed diets containing galactose. Bellows and Chinn 14 suggested that galactose cataract is caused by the disturbances connected with the hyperglycemia and the resultant increased sugar content of the aqueous humor. T h e above-mentioned and other similar animal experimentation has contributed much to our comprehension of the pathophysiology of galactosemia. Much remains to be learned and it is hoped to obtain liver biopsy tissue with which to conduct experi­ mentation in an effort to ascertain the miss­ ing enzyme or faulty step in carbohydrate metabolism in these cases. Galactosemia may well be an innate error of metabolism, most likely exhibiting a simple autosomal recessive mode of in­ heritance. T h e presence of consanguinity and the multiple occurrence of the disease in siblings gives weight to this hypothesis. The close relationship of galactosemia to the glycogen storage diseases such as von Gierke's, a recessive error of metabolism, would also suggest a hereditary basis. T h e parents in our case were normal. The father is a member of a sibship of 14, all living and well. T h e mother is a member of a sibship of eight, one child of which died in infancy but without symptoms suggestive of galactosemia. T h e child herein reported has 21 normal first cousins. T h e reported phenomenon of reversibility of the cataracts, as well as other signs of the disease, is interesting. It is our belief that, unless the diagnosis is established very early in the course of the disease and treatment initiated immediately, permanent lens dam­ age will ensue. Follow-up ophthalmic examination on October 2 1 , 1949, revealed no specific change in the cataractous condition, but the fundu­ scopic details were more clear and detailed. It appears, thus, that galactosemia (tem­ porary and treated) produces no permanent or irreversible damage to the lens epithelium in that proliferation may resume and deposit

1274 HAROLD F. FALLS, GEORGE H. LOWREY AND W. CLAYTON ANDERSON, JR. healthy clear cortex. With the growth of new lens material and the accumulation of new cortex the original cataractous change may seem to recede in size. The reversibility of cataractous changes in animal experiments has been authoritatively observed.12'13 SUMMARY

A case of galactosemia, the youngest patient reported, is summarized. The interest

of the ophthalmologist should be stimulated in this error of carbohydrate metabolism because of the association of cataract. These cataracts are zonular in character, although nuclear changes may also result. The reversibility of symptoms and signs of galactosemia with initiation of dietary treatment make it important that the diagnosis be established as early as possible to avoid permanent tissue changes. University Hospital.

REFERENCES

1. Goppert, F.: Galaktosurie nach Milchzuckergabe bei angeborenem familiarem, chronischern Leherleiden, Berliner klin. Wchnschr., 54:473, 1917. 2. Von Reuss, A.: Zuckerausscheidung im Sauglingsalter, Wien. med. Wchnschr., 58:799, 1908. 3. Fanconi, G.: Hochgradige Galaktose-Intoleranz (Galaktose-Diabetes) bei einem Kinde mit Neurofibromatosis Recklinghausen, Jahrb. f. Kinderh., 138 :1, 1933. 4. Mason, H. H., and Turner, M. E.: Chronic galactemia: Report of case with studies on carbo­ hydrates. Am. J. Dis. Child., 50:3S9,1935. 5. Norman, F. A., and F"ashena, G. J.: Chronic hypergalactosemia. Am. J. Dis. Child., 66 :S31, 1943. 6. Mellinkoff, S., Roth, B., and Maclaggan, J.: Galactosemia with hepatic damage. J. Pediat, 27 : 338, 1945. 7. Goldbloom, A., and Brickman, H. F.: Galactemia. J. Pediat., 28:674, 1946. 8. Greenman, L., and Rathbun, J. C.: Galactose studies in an infant with idiopathic galactose intol­ erance. Pediatrics, 2 :666, 1948. 9. Goldstein, E. O., and Ennis, J. M.: Galactosemia. J. Pediat, 33 :147, 1948. 10. Kirby, D. B., Estey, E., and von Wiener, R.: A study of the effect of changes in the nutrient medium on lens epithelium cultivated in vitro. Tr. Am. Acad. Ophth., 37 :196, 1932. 11. Mitchell, H. S.: Cataract in rats fed on galactose. Proc. Soc. Exper. Biol. & Med., 32:971, 1935. 12. Jess, A.: In Shieck, F., and Bruckner, A.: Kurzes Handbuch der Ophthalmologie, Berlin, Springer, 5 :270, 1930. 13. Buschke, W.: Acute reversible cataract in chickens due to various nitro compounds. Am. J. Ophth., 30:1356, 1947. 14. Bellows, J. G., and Chinn, H.: Biochemistry of the lens: XIII. Production of lens opacities by injection of hypertonic solutions. Arch. Ophth., 25 :796-810, 1941. 15. Mitchell, H. S., and Dodge, W. M.: Cataract in rats fed on high lactose rations. J. Nutrition, 9 :37-49, 1935.

OPHTHALMIC MINIATURE

I had occasion to pass through Liege and to stay there for a time. There I performed six operations in accordance with this method, and all with the greatest success. One which I performed at Cologne on a priest of a religious order yielded a very surprising result, inasmuch as the cataract was as soft as jelly. In spite of that fact, the priest was able, fourteen days later, to read the Mass. Jacques Daviel, Sur une nouvelle method de guerir la cataracte par Vextraction du cristallin, Mem. Acad. roy. de chir., I I : 337, 1753.