Galactosemia is an inborn error of metabolism. Because of energy barriers, essentially none of the chemical reactions that take place in living things could occur at any measurable rate without the presence of a catalyst. Most catalysts in living things are enzymes that depend on their structure to be able to function. Their structure is determined by their coding on DNA. Inborn errors of metabolism, like the one seen in galactosemia, are caused by defective genes.
Galactosemia is an inherited metabolic disorder in which the transformation of galactose to glucose is blocked, allowing galactose to increase to toxic levels in the body (Chung 1997). Galactose epimerase, the enzyme in the liver that is required to break down galactose, is deficient in galactosemia patients (Galactosemia 1995 and Wohlers, Christacos, and Harreman 1999). This enzyme works as a catalyst to speed up the breakdown of galactose. When there is a deficiency of this enzyme, the body cannot metabolize galactose as quickly as needed, causing a toxic buildup (Olendore, Jenyan, and Bayden 1999).
This disease is inherited in an autosomal recessive manner, this means that galactosemia is only present in individuals with two defective copies of any one of the three genes that causes it (Chung 1997). These genes are the genes that code for the three enzymes, galactosemia-1-phosphate-uridyl transferase (GALT), galactokinase (GALK), and uridyl disphosphogalactose-4-epimerase (Olendore, Jenyan, and Bayden 1999). Although carriers have less than normal enzyme activity, carriers of the disease are unaware that they are carrying a defective gene since no symptoms are evident (Chung 1997). If two carriers of the same defective gene have children, the chance of their child getting galactosemia by having two copies of the same defective gene is 25% for each pregnancy (Elsas 1999). Every cell nucleus has two copies of each gene, therefore, if only one of the two copies is defective, enough of the enzyme is made and the pathway of galactose metabolism is not blocked (Olendore, Jenyan, and Bayden 1999).
Most states have now included testing for galactosemia in newborn screening programs (Galactosemia 1995). However, if galactosemia is not found in a screening program, some symptoms appear within the first couple of days of the newborns life (Elsas 1999). Symptoms usually begin to appear quickly in newborns because their entire diet is made up of milk, which is made of 20% galactose (Olendore, Jenyan, and Bayden 1999). High levels of galactose cause vomiting diarrhea, lethargy, low blood sugar, brain damage, jaundice, liver enlargement, cataracts, malnutrition, rapid organ damage, susceptibility to infection especially to gram negative bacteria, and even death (Olendare, Jenyan, and Bayden 1999 and Chung 1997). Infants may also exhibit poor growth, feeding difficulties, encephalopathy, and renal tubular dysfunction (Berry et al. 1995).
The Human Genome Project has had a great impact on what is known about galactosemia. They have identified what causes the disease and on which chromosome the mutation occurs. Three enzymes are required to completely convert galactose to glucose-1-phosphate, which is able to enter the metabolic pathway and turn into energy. A separate gene encodes each of these three enzymes. If any of these enzymes fail to function galactose builds up and galactosemia result (Olendore, Jenyan, and Bayden 1999).
The first type of galactosemia is called galactosemia I or classic galactosemia. This form has been discovered to be caused by defects in both copies of the gene that codes the enzyme galactosemia-1-phosphate-uridyl transferase (GALT) (Olendore, Jenyan, and Bayden 1999). This enzyme is responsible for the second phase of galactose metabolism. Without this enzyme, the body cannot convert galactose to UDP galactose, which eventually leads to glucose formation causing hypoglycemia. Since this cannot occur, the galactose metabolite, galactose-1-phosphate remains unconverted and accumulates causing rapid damage to vital organs (Chung 1997). There are thirty known mutations in this gene that cause GALT to malfunction. The frequency of this form is relatively high, occurring in 1 in 50,000 to 70,000 births (Olendore, Jenyan, and Bayden 1999).
The second type of galactosemia is called galactosemia II. This form is caused by defect in the gene that codes for the enzyme galactokinase (GALK). Galactokinase normally acts as a catalyst that converts galactose-1-phosphate to glucose-1-phosphate using a series of reactions requiring uridine triphosphate (UTP) as a coenzyme. Without galactokinase, the reaction occurs too slowly and galactose-1-phosphate is not converted to glucose-1-phosphate (Oldenore, Jenyan, and Bayden 1999). A deficiency in galactokinase causes some physical problems such as nuclear cataracts before or shortly after birth. It also causes mental retardation in some. Biochemically, it results in the increased secretion of galactose and corresponding sugar alcohol, galactitol, following galactose. This results in the elevation of blood galactose levels (Galactokinase Deficiency 1996). Galactosemia II is less harmful than galactosemia I and only occurs in about 1 in every 100,000 150,000 births (Oldendore, Jenyan, and Bayden 1999).
The third form is galactosemia III. It is a benign form, usually asymptomatic, and does not require a special diet. This form is caused by defects on the gene that codes for the enzyme uridyl diphosphogalactose-4-epimerase (GALE). Uridyl diphosphogalactose-4-epimerase assists in the conversion of galactose-1-phosphate by catalyzing the conversion of UDP-glucose to UDP-galactose. In the benign form, the enzyme deficiency is only found in the blood cells (leukocytes, lymphocytes, and erythrocytes). However, in the severe form, the enzyme deficiency is in the blood cells and in the fibroblasts and is usually less than 10% of normal (Galactosemia III 1994). This very rare, severe form of galactosemia III has been found to have similar symptoms to galactosemia I but with more severe neurological problems (Oldendore, Jenyan, and Bayden 1999). For example, Fanconi Syndrome appears which causes episodes of vomiting, dehydration, weakness, anorexia, constipation, polydipsia, polyuria, and rickets (Galactosemia III 1994).
A number of different types of mutations on these genes have been found in galactosemia patients. These include nucleotide substitutions, small deletions, small insertions, small indles, gross deletions, gross insertions and duplications, and repeat variations (Galactose-1-phosphate 1990). In fact, over 172 different mutations are known to cause galactosemia (Elsas 1999).
Although galactosemia can lead to death if not found immediately after birth, many precautions can be taken to lessen the chances of this occurring. First of all, adults who want to start a family can be tested for having a defective gene. If a defective gene is found in both parents, the child should be tested immediately after birth for galactosemia (Olendre, Jenyan, and Bayden 1999). Also, most states have added tests for galactosemia in with their newborn screening process to eliminate the potential of death (Galactosemia 1995).
Unfortunately, many children are born each year with galactosemia and there is no medication that can treat it (Chung 1997). However, galactosemia is manageable and the symptoms can be greatly reduced by taking a few precautions. First of all, babies whose GALT activity is less than 10% need to have all their milk products replaced by formula such as Isomil or Prosobee, which are free of lactose. Soy products contain other sugars such as sucrose, fructose, and non-galactose polycarbohydrates, which supply the needed energy to the baby. All lactose containing foods such as dairy products, tomato sauces, candies, and medicines should be avoided fro the remainder of the patients life (Elsas 1999). Finally, legumes, organ meats, and processed meats also contain galactose and should be avoided (Olendore, Jenyan, and Bayden 1999). Management of the diet becomes less important after infancy and early childhood because milk products are no longer the primary source of energy (Elsas 1999). So, although galactosemia can be fatal, it is highly treatable and a patient can live a normal life with only a few changes in their diet.
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