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Galactose Intolerance and the Risk Ofcataract 439 Br J Ophthalmol: first published as 10.1136/bjo.66.7.438 on 1 July 1982. Downloaded from British Journal ofOphthalmology, 1982, 66, 438-441 Galactose intolerance and the risk of cataract A. F. WINDER,' P. FELLS,' R. B. JONES,' R. D. KISSUN,' I. S. MENZIES,2 AND J. N. MOUNT2 From the 'Institute of Ophthalmology and Moorfields Eye Hospital, London EC], and the 2Department of Clinical Chemistry, St Thomas's Hospital, London SE] SUMMARY Cataracts may arise in association with various major and minor disorders restricting galactose metabolism, and the risk is broadly associated with the degree of galactose intolerance. A family is described in which a girl presented at the age of 73/4 years with cataracts, galactosuria, and partial deficiencies of the enzymes galactokinase and galactose-1-phosphate uridyl transferase. Galactose intolerance as determined by an oral test was impaired and fluctuated with variation in activity of the above galactose enzymes. Minor defects were also present in the parents and a maternal half-brother. The child has a compound disorder of galactose metabolism differing from those previously described. Assessment of galactose tolerance may be useful in the investigation of families with an incidence of cataract. Various disorders restricting galactose metabolism hepatic conversion of galactose to glucose phos- may be associated with the development of cataract, phates, are not alone associated with cataract,67 apparently via osmotically induced damage conse- though combination defects as above are not quent to galactikol accumulation within the lens.' The described. http://bjo.bmj.com/ association with cataract is very strong for homo- Within the defined genetic disorders the risk of zygous galactokinase deficiency and moderate for cataract is broadly correlated with the degree of heterozygotes, with expression predominantly and galactose intolerance. Thus homozygotes for galac- perhaps entirely restricted to the first year of life.23 tokinase deficiency or galactosaemia, and double The association is also strong for galactosaemia- heterozygotes for galactosaemia and low-activity homozygous galactose-1-phosphate uridyl-trans- forms of the transferase such as the Rennes variant,8 ferase deficiency-and for some rare variant forms show galactose intolerance and cataracts, as is also associated with considerable reduction in the activity found with some cases of heterozygous galactokinase on September 24, 2021 by guest. Protected copyright. of this enzyme; Heterozygotes for galactosaemia are deficiency.F" Heterozygotes for uridyl transferase occasionally detected on screening of patients with galactosaemia are not biochemically intolerant.' 10 cataract,4 but observations within known affected Interestingly, double heterozygotes forgalactosaemia families suggest that the risk is at most slight. The and the Duarte variant, with about 25% residual Duarte/normal heterozygote representing the com- transferase activity, may show mild biochemical monest of the variant forms carries about 75% of the galactose intolerance,'2"4 as do individuals addition- mean normal activity for galactose-1-phosphate ally -heterozygous for galactokinase deficiency,5 16 uridyl transferase and is not at particular risk of though cataract or other clinical stigmata may not cataract. Minor maternal deficiency or low-normal anse. activity of this transferase or particularly of galac- Thus an association between galactose intolerance tokinase may also be associated with congenital and the risk of cataract is more evident with moderate cataracts in an apparently enzymatically normal or severe intolerance. This association is further child,5 through undefined influences during preg- supported by a study over 3 years of a child with nancy. Deficiencies of other enzymes such as UDP cataracts, trace galactosuria, galactose intolerance, galactose-4-epimerase, which also affect the mainly and partial deficiencies of both the above enzymes. She was initially thought to be a double heterozygote Correspondence to Dr A, F. Winder, Institute of Ophthalmology, for galactokinase and galactose-1-phosphate uridyl 17-25 Cayton Street, London ECIV 9AT. transferase deficiency, a combination which has since 438 Br J Ophthalmol: first published as 10.1136/bjo.66.7.438 on 1 July 1982. Downloaded from Galactose intolerance and the risk ofcataract 439 Am. - NW, OF t.. ""W i kkkL .i Fig. 1 Cataracts in a child with galactose intolerance andpartial deficiencies ofgalactokinase and galactose-l-phosphate uridyl transferase. The opacities are lamellar, with nuclear elements, and more evident in the left lens. Left; right eye. Right: left eye. been described.'5 16 Of late, however, intolerance to incorporating 200 mg of the nonmetabolised sugar galactose as determined by an oral test has improved 3-0-Me-glucose is administered in the fasting state in parallel with a reduction in the degree of deficit for (Menzies and Mount, in preparation). Results are both enzymes, and a family study has confirmed that expressed as the ratio of galactose to 3-0-Me-glucose known monogenic, disorders are not involved. The present in the urine output over the next 5 hours. child represents a new and possibly acquired Normal adults and juveniles have galactose/3-O-Me- syndrome, and the further implications of galactose glucose excretion ratios below 6, mean value http://bjo.bmj.com/ intolerance in relation to cataract are discussed. approximately 2-0. Retarded galactose metabolism (intolerance) increases this ratio, and our patient was Case report clearly intolerant with an excretion ratio of 10-6. PRESENTATION AND INITIAL ASSESSMENT FURTHER ASSESSMENT A girl aged 73/4 was referred for assessment of a left The child had been born by lower segment caesarian intermittent divergent squint: bilateral lamellar cat- section at 32 weeks owing to cessation ofgrowth. Her aracts with a nuclear element, left more than right, weight at birth was 2 lb 6 oz (1077 g). She had incu- on September 24, 2021 by guest. Protected copyright. were then observed (Fig. 1). Routine investigation of bator support for some weeks and returned home at 2 juvenile cataract'7 included blood for calcium, pro- months. The mother had a definite rubella contact tein, and glucose-all normal-and urine for sugars during early pregnancy. The child was rather small. by thin-layer chromatography-galactose identified. but general physical examination was otherwise Enzyme studies on fresh erythrocytes then fol- normal. Visual acuity was R 6/12, L 3/60. The fundi lowed."8"' They indicated borderline deficiency of were not clearly seen, but there was no evidence of galactokinase at 1-0 ,uM galactose consumed/g retrolental fibroplasia. There were some behavioural Hb/hour (normal>1 0 unit) and clear deficiency of and reading difficulties at school, and the child still galactose-1-phosphate uridyl transferase activity at preferred assistance with dressing. 13-6 ,uM galactose consumed/g Hb/hour (normal>18 It was not established that the cataracts and possibly units). These deficiencies were confirmed 3 months also the behavioural problems arose in consequence later with values of0-9 and 11-6 units, respectively, by of the galactose intolerance. However, a trial of an improved method for the transferase.20AII data galactose restriction was undertaken as systemicgalac- cited were derived from consistent triplicate determi- tose problems were evident, the cataracts were not nations for galactokinase and duplicate or triplicate extensive and were of uncertain duration, and in view values for transferase activity. of the clear evidence of regression of early galactose- Galactose tolerance was assessed by a new dependent cataracts on dietary control.2 Good family procedure in which an oral load of 20 g galactose compliance was reported. After 12 months the opaci- Br J Ophthalmol: first published as 10.1136/bjo.66.7.438 on 1 July 1982. Downloaded from A. F. Winder, P. Fells, R. B. Jones, R. D. Kissun, I. S. Menzies, and J. N. Mount 440 ties and behavioural problems remained unchanged assessment in young children. However, the adult and the diet was discontinued. Galactose intolerance range normally applies beyond about age 5 years, and was confirmed 3 months later, the galactose/3-0-Me- particularly in view of the increase in activity later glucose excretion ratio then being 13 8. recorded, and the family data, our patient cannot be regarded as a heterozygote for galactokinase FAMILY STUDIES deficiency. The further electrophoretic analysis and Our patient is the only child of healthy unrelated family studies also exclude heterozygous galactose-1- English parents. The mother showed normal erythor- phosphate uridyl transferase deficiency and known cyte galactokinase activity and borderline transferase low-activity variant forms of this enzyme. However, deficiency at 17-5 ,uM galactose consumed/g Hb/h the presence of other genetic influences is indicated (normal>18). The father showed normal transferase by the marginal enzyme deficiencies in the parents activity with borderline galactokinase activity at 09 and the acceptable but reduced galactose tolerance in ,uM galactose consumed/g Hb/h (normal>10). But the maternal half-brother. Galactose tolerance is neither parent was galactose intolerant, showing related to liver function, but gross abnormalities were galactose/3-0-Me-glucose excretion ratios of 2-1 and excluded at a late stage. It remains possible that these 1-33 respectively. A maternal half-brother then aged or other now diminished
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