Diagnosis
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| Galactosemic cataract | |
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| Specialty | Ophthalmology |
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. [1] :4
An impairment or deficiency in the enzyme, galactose-1-phosphate uridyltransferase (GALT), results in classic galactosemia, or Type I galactosemia. [2] 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. [3] :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. [1] :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. [4] 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. [1] :22 A 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). [5] 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". [6] 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. [7] 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. [8] :786
A cataract is an opacity that develops in the crystalline lens of the eye. [9] 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. [10] However, galactose concentration must be fairly high before the enzyme, aldose reductase, will convert significant amounts of the sugar to its galactitol form. [8] :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. [8] :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. [11] 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.
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 [galactitol] retention.
[8] :792 Galactosemic patients will also present with amino aciduria and galactitoluria (excessive levels of amino acids and galactitol in the urine).
Osmotic swelling of the lens is also responsible for a reduction in electrolyte concentration during the initial vacuolar stage of galactosemic cataract. The water that is osmotically flowing into the lens fibers is not accompanied by ions such as Na+, K+, and Cl−, and so the electrolyte concentration inside the lens is simply diluted by the influx of water. The net concentration of the individual ions does not change during the initial vacuolar stage however. In Fig. 7, note the decrease in electrolyte concentration due to osmotic swelling during the initial vacuolar stage of galactosemic cataract. But when comparing it to the dry weight of the ions, note that there is no change in individual ion concentration at this stage. However, Kinoshita's experiments showed a remarkable upswing in electrolyte concentration toward the latter stages of the galactosemic cataract and in the nuclear stage in particular. This observation seems to be explained by the continuous increase in lens permeability due to the osmotic swelling from galactitol accumulation. Cation and anion distribution becomes erratic, with N+ and Cl− concentrations increasing while K+ concentration decreases as seen in Figures 8 and 9. [8] :795–96 Researchers have postulated that as the cataractous lens loses its ability to maintain homeostasis, electrolyte concentration eventually increases within the lens, which further encourages osmotic movement of water into the lens fibers, increasing lens permeability even more so. This damaging cycle may play a pivotal role in accelerating the rupture of lens fibers during the most advanced, nuclear stage of the galactosemic cataract. [8] :797
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Galactosemic infants present clinical symptoms just days after the onset of a galactose diet. They include difficulty feeding, diarrhea, lethargy, hypotonia, jaundice, cataract, and hepatomegaly (enlarged liver). If not treated immediately, and many times even with treatment, severe mental deficiencies, verbal dyspraxia (difficulty), motor abnormalities, and reproductive complications may ensue. The most effective treatment for many of the initial symptoms is complete removal of galactose from the diet. Breast milk and cow's milk should be replaced with soy alternatives. Infant formula based on casein hydrolysates and dextrin maltose as a carbohydrate source can also be used for initial management, but are still high in galactose. [3] :519 The reason for long-term complications despite a discontinuation of the galactose diet is vaguely understood. However, it has been suggested that endogenous (internal) production of galactose may be the cause.
The treatment for galactosemic cataract is no different from general galactosemia treatment. In fact, galactosemic cataract is one of the few symptoms that is actually reversible. Infants should be immediately removed from a galactose diet when symptoms present, and the cataract should disappear and visibility should return to normal. [12] Aldose reductase inhibitors, such as sorbinil, have also proven promising in preventing and reversing galactosemic cataracts. [13] :49 AR inhibitors hinder aldose reductase from synthesizing galactitol in the lens, and thus restricts the osmotic swelling of the lens fibers. Other AR inhibitors include the acetic acid compounds zopolrestat, tolrestat, alrestatin, and epalrestat. Many of these compounds have not been successful in clinical trials due to adverse pharmokinetic properties, inadequate efficacy and efficiency, and toxic side effects. [14] Testing on such drug-treatments continues in order to determine potential long-term complications, and for a more detailed mechanism of how AR inhibitors prevent and reverse the galactosemic cataract.
Although advancement has been slow to come during the decades of research dedicated to the galactosemic cataract, some notable additions have been made. In 2006, Michael L. Mulhern and colleagues further investigated the effects of the osmotic swelling on galactosemic cataract development. Experiments were based on systematic observation of rats fed a 50% galactose diet. [11] According to Mulhern, 7 to 9 days after the onset of the galactose diet, lenses appeared hydrated and highly vacuolated. Lens fibers became liquefied after nine days of the diet, and nuclear cataract formation appeared after 15 days of the diet.
The experiment concluded that
Apoptosis in lens epithelial cells (LEC) is linked to cataract formation.
[11] Essentially, the study suggested that the mechanism outlined by Friedenwald and Kinoshita, which centers on osmotic swelling of the lens fibers, is just the beginning in a cascade of events that causes and progresses the galactosemic cataract. Mulhern determined that osmotic swelling is actually a cataractogenic stressor that leads to LEC apoptosis. This is because osmotic swelling of lens fibers considerably strains LEC endoplasmic reticula. As the endoplasmic reticulum is the principal site of protein synthesis, stressors on the ER can cause proteins to become misfolded. The subsequent accumulation of misfolded proteins in the ER activates the unfolded protein response (UPR) in LECs. In agreement, it was later observed on galactosemic yeast models, the activation of UPR upon galactose treatment. [15] UPR initiates apoptosis, or cell death, by various mechanisms, one of which is the release of reactive oxygen species (ROS). [11] Thus, according to recent findings, osmotic swelling, UPR, oxidative damage, and the resultant LEC apoptosis all play key roles in the onset and progression of the galactosemic cataract. Other studies claim that the oxidative damage in LECs is less a result of the release of ROS and more because of the competition between aldose reductase and glutathione reductase for nicotinamide adenine dinucleotide phosphate (NADPH). [13] :48 Aldose reductase requires NADPH for the reduction of galactose to galactitol, while glutathione reductase utilizes NADPH to reduce glutathione disulfide (GSSG) to its sulfhydryl form, GSH. GSH is an important cellular antioxidant. Therefore, what exactly the key roles are for these cataractogenic factors is not yet fully understood or agreed upon by researchers. Recently, it has been shown that the intake of milk (lactose and galactose) in human diet does not seem to be a cause of cataract. [16]
Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.
Sorbitol, less commonly known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alcohol group (−CH2OH). Most sorbitol is made from potato starch, but it is also found in nature, for example in apples, pears, peaches, and prunes. It is converted to fructose by sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2. While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.
Galactose sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molecule linked with a glucose molecule forms a lactose molecule.
Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.
Galactokinase is an enzyme (phosphotransferase) that facilitates the phosphorylation of α-D-galactose to galactose 1-phosphate at the expense of one molecule of ATP. Galactokinase catalyzes the second step of the Leloir pathway, a metabolic pathway found in most organisms for the catabolism of β-D-galactose to glucose 1-phosphate. First isolated from mammalian liver, galactokinase has been studied extensively in yeast, archaea, plants, and humans.
Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.
Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, fluid balance, oxygen delivery, acid–base balance and much more. Electrolyte imbalances can develop by consuming too little or too much electrolyte as well as excreting too little or too much electrolyte.
Galactose-1-phosphate uridylyltransferase is an enzyme responsible for converting ingested galactose to glucose.
Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.
The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.
In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.
Galactokinase deficiency, is an autosomal recessive metabolic disorder marked by an accumulation of galactose and galactitol secondary to the decreased conversion of galactose to galactose-1-phosphate by galactokinase. The disorder is caused by mutations in the GALK1 gene, located on chromosome 17q24. Galactokinase catalyzes the first step of galactose phosphorylation in the Leloir pathway of intermediate metabolism. Galactokinase deficiency is one of the three inborn errors of metabolism that lead to hypergalactosemia. The disorder is inherited as an autosomal recessive trait. Unlike classic galactosemia, which is caused by deficiency of galactose-1-phosphate uridyltransferase, galactokinase deficiency does not present with severe manifestations in early infancy. Its major clinical symptom is the development of cataracts during the first weeks or months of life, as a result of the accumulation, in the lens, of galactitol, a product of an alternative route of galactose utilization. The development of early cataracts in homozygous affected infants is fully preventable through early diagnosis and treatment with a galactose-restricted diet. Some studies have suggested that, depending on milk consumption later in life, heterozygous carriers of galactokinase deficiency may be prone to presenile cataracts at 20–50 years of age.
Galactose epimerase deficiency, also known as GALE deficiency, Galactosemia III and UDP-galactose-4-epimerase deficiency, is a rare, autosomal recessive form of galactosemia associated with a deficiency of the enzyme galactose epimerase.
D-Galactose-1-phosphate is an intermediate in the intraconversion of glucose and uridine diphosphate galactose. It is formed from galactose by galactokinase.The improper metabolism of galactose-1-phosphate is a characteristic of galactosemia. The Leloir pathway is responsible for such metabolism of galactose and its intermediate, galactose-1-phosphate. Deficiency of enzymes found in this pathway can result in galactosemia; therefore, diagnosis of this genetic disorder occasionally involves measuring the concentration of these enzymes. One of such enzymes is galactose-1-phosphate uridylytransferase (GALT). The enzyme catalyzes the transfer of a UDP-activator group from UDP-glucose to galactose-1-phosphate. Although the cause of enzyme deficiency in the Leloir pathway is still disputed amongst researchers, some studies suggest that protein misfolding of GALT, which may lead to an unfavorable conformational change that impacts its thermal stability and substrate-binding affinity, may play a role in the deficiency of GALT in Type 1 galactosemia. Increase in galactitol concentration can be seen in patients with galactosemia; putting patients at higher risk for presenile cataract.
Galactose-1-phosphate uridylyltransferase deficiency(classic galactosemia), is the most common type of galactosemia, an inborn error of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridylyltransferase. It is an autosomal recessive metabolic disorder that can cause liver disease and death if untreated. Treatment of galactosemia is most successful if initiated early and includes dietary restriction of lactose intake. Because early intervention is key, galactosemia is included in newborn screening programs in many areas. On initial screening, which often involves measuring the concentration of galactose in blood, classic galactosemia may be indistinguishable from other inborn errors of galactose metabolism, including galactokinase deficiency and galactose epimerase deficiency. Further analysis of metabolites and enzyme activities are needed to identify the specific metabolic error.
The enzyme UDP-glucose 4-epimerase, also known as UDP-galactose 4-epimerase or GALE, is a homodimeric epimerase found in bacterial, fungal, plant, and mammalian cells. This enzyme performs the final step in the Leloir pathway of galactose metabolism, catalyzing the reversible conversion of UDP-galactose to UDP-glucose. GALE tightly binds nicotinamide adenine dinucleotide (NAD+), a co-factor required for catalytic activity.
Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.
Galactitol (dulcitol) is a sugar alcohol, the reduction product of galactose. It has a slightly sweet taste. In people with galactokinase deficiency, a form of galactosemia, excess dulcitol forms in the lens of the eye leading to cataracts.
Sorbinil (INN) is an aldose reductase inhibitor being investigated for treatment of diabetic complications including neuropathy and retinopathy. Aldose reductase is an enzyme present in lens and brain that gets rid of excess glucose by converting it to sorbitol. Sorbitol accumulation can lead to the development of cataracts in the lens and neuropathy in peripheral nerves. Sorbinil has been shown to inhibit aldose reductase in human brain and placenta and calf and rat lens. Sorbinil reduced sorbitol accumulation in rat lens and sciatic nerve of diabetic rats orally administered 0.25 mg/kg sorbinil.
Duarte galactosemia is an inherited condition associated with diminished ability to metabolize galactose due to a partial deficiency of the enzyme galactose-1-phosphate uridylyltransferase. DG differs from classic galactosemia in that patients with Duarte galactosemia have partial GALT deficiency whereas patients with classic galactosemia have complete, or almost complete, GALT deficiency. Duarte galactosemia (DG) is much more common than classic galactosemia, and is estimated to affect close to one in 4,000 infants born in the United States. Historically, most healthcare professionals have considered DG to be clinically mild based on pilot studies and anecdotal experience, and in 2019 a large study confirmed that children with DG are not at increased risk for developmental problems relative to children who do not have DG. Due to regional variations in newborn screening (NBS) protocols, some infants with DG are identified by NBS but others are not.
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