Galactosemic cataract

A galactosemic cataract is cataract which is associated with the consequences of galactosemia.Thus, from these experiments it would appear that the loss of amino acids in the lens when exposed to galactose is primarily due to the osmotic swelling of the lens brought about by dulcitol retention.Apoptosis in lens epithelial cells (LEC) is linked to cataract formation. A galactosemic cataract is cataract which is associated with the consequences of galactosemia. The presence of presenile cataract, noticeable in galactosemic infants as young as a few days old, is highly associated with two distinct types of galactosemia: GALT deficiency and to a greater extent, GALK deficiency.:4 An impairment or deficiency in the enzyme, galactose-1-phosphate uridyltransferase (GALT), results in classic galactosemia, or Type I galactosemia. Classic galactosemia is a rare (1 in 47,000 live births), autosomal recessive disease that presents with symptoms soon after birth when a baby begins lactose ingestion. Symptoms include life-threatening illnesses such as jaundice, hepatosplenomegaly (enlarged spleen and liver), hypoglycemia, renal tubular dysfunction, muscle hypotonia (decreased tone and muscle strength), sepsis (presence of harmful bacteria and their toxins in tissues), and cataract among others.:516 The prevalence of cataract among classic galactosemics is markedly less than among galactokinase-deficient patients due to the extremely high levels of galactitol found in the latter. Classic galactosemia patients typically exhibit urinary galactitol levels of only 98 to 800 mmol/mol creatine compared to normal levels of 2 to 78 mmol/mol creatine.:21 Galactokinase (GALK) deficiency, or Type II galactosemia, is also a rare (1 in 100,000 live births), autosomal recessive disease that leads to variable galactokinase activity levels: ranging from high GALK efficiency to undetectably-low GALK efficiency. The early onset of cataract is the main clinical manifestation of Type II galactosemics, most likely due to the high concentration of galactitol found in this population. GALK deficient patients exposed to high-galactose diets show extreme levels of galactitol in blood and urine. Studies on galactokinase-deficient patients have shown that nearly two-thirds of ingested galactose can be accounted for by galactose and galactitol levels in the urine. Urinary levels of galactitol in these subjects approach 2500 mmol/mol creatine as compared to 2 to 78 mmol/mol creatine in control patients.:22A decrease in activity in the third major enzymes of galactose metabolism, UDP galactose-4'-epimerase (GALE), is the cause of Type III galactosemia. GALE deficiency is an extremely rare, autosomal recessive disease that appears to be most common among the Japanese population (1 in 23,000 live births among Japanese population). While the link between GALE deficiency and cataract prevalence seems to be ambiguous, experiments on this topic have been conducted. A recent 2000 study in Munich, Germany analyzed the activity levels of the GALE enzyme in various tissues and cells in patients with cataract. The experiment concluded that while patients with cataract seldom exhibited an acute decrease in GALE activity in blood cells, 'the GALE activity in the lens of cataract patients was, on the other hand, significantly decreased'. The study's results are depicted below. The extreme decrease in GALE activity in the lens of cataract patients seems to suggest an irrefutable connection between Type III galactosemia and cataract development. Galactosemia is one of the most mysterious of the heavily-researched metabolic diseases. It is a hereditary disease that results in a defect in, or absence of, galactose-metabolizing enzymes. This inborn error leaves the body unable to metabolize galactose, allowing toxic levels of galactose to build up in human body blood, cells, and tissues. Although treatment for galactosemic infants is a strict galactose-free diet, endogenous (internal) production of galactose can cause symptoms such as long-term morbidity, presenile development of cataract, renal failure, cirrhosis, and cognitive, neurologic, and female reproductive complications. Galactosemia used to be confused with diabetes due to the presence of sugar in a patient's urine. However, screening advancements have allowed the exact identity of those sugars to be determined, thereby distinguishing galactosemia from diabetes.:786 A cataract is an opacity that develops in the crystalline lens of the eye. The word cataract literally means, 'curtain of water' or 'waterfall' as rapidly running water turns white, so the term may have been used metaphorically to describe the similar appearance between mature ocular opacities and water fall. The mechanism by which galactosemia causes cataract is not well understood, but the topic has been approached by researchers for decades, notably by the ophthalmologists, Jonas S. Friedenwald and Jin H. Kinoshita. Through this collective effort, a general mechanism for galactosemia's causation of presenile cataract has come into form. In galactosemic cataracts, osmotic swelling of the lens epithelial cells (LEC) occurs. Osmosis is the movement of water from areas of low particle concentration to areas of high particle concentration, to establish equilibrium. Researchers concluded that this osmotic swelling must be the result of an accumulation of abnormal metabolites or electrolytes in the lens. Ruth Van Heyningen was the first to discover that the lens's retention of dulcitol, synonymous for galactitol, induces this osmotic swelling in the galactosemic cataract. However, galactose concentration must be fairly high before the enzyme, aldose reductase, will convert significant amounts of the sugar to its galactitol form.:789 As it turns out, the lens is a favorable site for galactose accumulation. The lens phosphorylates galactose at a relatively slow pace in comparison to other tissues. This factor, in combination with the low activity of galactose-metabolizing enzymes in galactosemic patients, allows for the accumulation of galactose in the lens. Aldose reductase is able to dip into this galactose reservoir and synthesize significant amounts of galactitol. As is mentioned above, galactitol is not a suitable substrate for the enzyme, polyol dehydrogenase, which catalyzes the next step in the carbohydrate metabolic cycle. Thus, the sugar alcohol idly begins to accumulate in the lens. As galactitol concentration increases in the lens, a hypertonic environment is created. Osmosis favors the movement of water into the lens fibers to reduce the high osmolarity.:789–90 Figures 2 and 3 show how water concentration increases as galactitol concentration increases inside the lens of galactosemic animals sustained on a galactose diet. This osmotic movement ultimately results in the swelling of lens fibers until they rupture. Vacuoles appear where a significant amount of osmotic dissolution of fiber has taken place. What are left are interfibrillar clefts filled with precipitated proteins: the manifestation of a cataract. Friedenwald was able to show that periphery lens fibers always dissolve before fibers at the equatorial region of the lens. This observation has been confirmed by more recent experiments as well, but is still unexplained. The progression of galactosemic cataract is generally divided into three stages; initial vacuolar, late vacuolar, and nuclear cataract. The formation of a mature, nuclear, cloudy galactosemic cataract typically surfaces 14 to 15 days after the onset of the galactose diet. Fig. 6 depicts the three stages of galactosemic cataract with their respective changes in lens hydration. As cataract formation progresses due to galactitol synthesis and subsequent osmotic swelling, changes occur in the lens epithelial cells. For instance, when rabbit lenses are placed in high-galactose mediums, a nearly 40% reduction in lens amino acid levels is observed, along with significant ATP reduction as well. Researchers theorized that this reduction in amino acid and ATP levels during cataract formation is a result of osmotic swelling. To test this theory, Kinoshita placed rabbit lenses in a high-galactose environment, but inhibited the osmotic swelling by constantly regulating galactose and galactitol concentrations. The results show that amino acid levels remained relatively constant and in some cases even increased.