Galacktokinase Deficiency

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Galacktokinase Deficiency


Galactokinase deficiency is a one of a set of three distinct autosomal recessive-inherited disorders that causes galactosemia , or build up of the dietary sugar galactose in the body as a result of inborn errors of metabolism. This relatively rare form of the galactosemia disorder can lead to toxic injury to the eyes unless all forms of galactose, found chiefly in dairy products, are eliminated from the diet early in life.


Lactose, the principle carbohydrate of human milk, commercial infant formulas, and other dairy products, is broken down in the human intestine into its component sugars: glucose and galactose. After absorption by the intestine, galactose is sequentially metabolized by three separate enzymes (galactokinase, galactose-1-phosphate uridyl transferase, and galactose-4-epimerase) to convert it to glucose, a usable form of fuel for individual cells.

The term, galactosemia, denotes the abnormally elevated level of galactose in the blood and body tissues that results when any of these three enzymes are missing or defective. Thus, inherited defects in any one of these three enzymes will result in galactosemia.

Classic galactosemia, the most common form of galactosemia, is due to the deficiency of the second enzyme in the pathway, galactose-1-phosphate uridyl transferase (GALT), and is typically associated with cataract formation, mental retardation, and liver damage. Galactokinase deficiency (also known as GALK deficiency, or Galactosemia Type II) is a rarer form of galactosemia caused by the absence of the enzyme, galactokinase, which is responsible for the first step of the conversion of galactose to glucose. However, unlike the more serious form of classic galactosemia, galactokinase deficiency mainly manifests as injury to the eyes without damage to other organ systems. The third and final form of galactosemia, uridine-diphosphate galactose-4-epimerase deficiency, is the rarest of the group; few cases have been described, and the symptoms of this form of galactosemia are variable, but usually mild.

Galactosemia may have been described in German medical publications as early as 1908, and in 1917, F. Goeppert noted symptoms of galactosemia in an infant and sibling, suggesting that the disorder could be inherited. In 1935, the American scientists H. H. Mason and M. F. Turner described a patient with a group of symptoms that could be prevented by removal of milk from the diet. In 1954, the individual steps in the metabolic pathway for the conversion of galactose to glucose was described by L. F. Leloir, who was later awarded a Nobel Prize in Chemistry for his efforts. Leloir's work made it possible for scientists, such as V. Schwatz and K. J. Isselbacher to demonstrate that defects in this metabolic pathway were responsible for galactosemia and its associated symptoms.

Genetic profile

Galactokinase deficiency, like other causes of galactosemia, is transmitted as an autosomal recessive trait. Individuals that are heterozygous for the defective allele have half the normal enzyme levels, which is still sufficient to convert all of their dietary galactose to glucose. Thus, heterozygotes experience neither galactosemia nor its symptoms.

Using advanced scientific techniques, the location of a gene that encodes for the galactokinase enzyme (GALK1) was localized to the human chromosome 17 (17p24) by D. Stambolian in 1995. At least 13 different types of mutations in the GALK1 gene have been identified that result in a nonfunctional galactokinase enzyme. A second human galactokinase gene (GK2), located on human chromosome 15, was also identified in 1992 by R. T. Lee. However, it is unclear whether this second gene plays an active role in galactose metabolism.


Galactokinase deficiency has an estimated incidence ranging from one in 500,000 to one in one million births and is much more rare than classic galactosemia. However, there is evidence that this trait may be unevenly distributed between various ethic and geographical groups. In 1967, R. Gitzelman characterized galactokinase deficiency in two related Romani (Gypsy) individuals. Later, in 1999, L. Kalaydijeva studied six Gypsy families from Bulgaria with galactokinase deficiency and found the same specific mutation in all cases. It was estimated that the carrier rate of the mutation in this population was as high as 5%, and Kalaydijeva suggested that this same mutation was likely responsible for the cases originally described by Gitzelman in 1967. As a result of the widespread prevalence of this mutation, incidence of galactokinase deficiency in Bulgaria has been reported to be one in 50,000 and among the Gypsy population, even higher, at one in 2,000.

The mutant galactokinase gene also shows higher prevalence in several other groups. In 1982, M. Magnani estimated the heterozygote frequency in Italy to be one in 310. In 1972, T. A. Tedesco presented evidence that African-Americans have an allele in high frequency that causes a decrease in red cell galactokinase activity that is likely different from the mutant allele that causes galactokinase deficiency. This finding was confirmed in 1988, when T. Soni found the same mutation in a group of African-Americans living in Philadelphia.

Signs and symptoms

Galactokinase deficiency is associated with galactosemia and cataracts (clouding of the lens of the eyes resulting in blurred vision), but without the systemic manifestations of liver disease and severe mental retardation that are commonly found in classic galactosemia. The cause of the cataract is an accumulation of galactitol (sugar alcohol derivative of galactose) within the lens of the eye. This galactitol accumulation attracts water, resulting in swelling and damage of the lens fiber.

There are infrequent reports of mild mental retardation in people with galactokinase deficiency, but the overwhelming majority of people have been shown to have normal intelligence. The rare finding of pseudotumor cerebri (a syndrome of raised pressure within the skull) has also been reported. Several investigators have reported premature development of cataracts (between the ages of 20 and 40 years old), even in individuals who are heterozygous for the galactokinase deficiency mutation.


Newborn screening is the act of testing all infants for a specific disease shortly after birth for the purpose of preventing disease progression through prompt medical treatment. When newborn screening for the inherited disease phenylketonuria (PKU) began in 1962, it quickly became clear that many infants with PKU were being identified for early treatment and that the mental retardation caused by the disease was being prevented.

This success encouraged R. Guthrie and others to consider additional metabolic disorders that might benefit from newborn screening. Since restricting dietary galactose early in life would prevent the development of irreversible symptoms, galactosemia appeared to be an ideal candidate for newborn screening. In 1963, Guthrie and his colleague, K. Paigen, developed a method to detect galactosemia that could be applied to the newborn blood specimen, and screening for galactosemia in the newborn became practical.

When trying to establish a diagnosis of galactokinase deficiency, an initial test is performed to detect galactosuria, or high levels of galactose in the urine that is seen with galactosemia. If that test proves positive, the next step is to determine which of the three enzymes needed to convert galactose to glucose is defective. When looking for galactokinase deficiency, blood samples are taken, and galactokinase activity is measured from red blood cells. If galactokinase activity is low, then the person has galactokinase deficiency. Thus, the diagnosis is made by demonstrating the deficiency of galactokinase in red blood cells and can be further confirmed by showing normal levels of the other two enzymes involved in this pathway using other tests. The disease can also be diagnosed before birth by testing fluid surrounding the unborn fetus for high levels of galactose, but this is rarely done.

Before widespread institution of newborn screening, these diagnostic tests were performed in infants with symptoms consistent with any form of galactosemia. As of the year 2000, newborn screening was mandated by law in every U.S. state except Louisiana, Pennsylvania, and Washington state.

Treatment and management

The galactosemia syndromes are effectively treated by rigid dietary exclusion of all lactose and galactose, primarily involving the elimination of milk and its products. A galactose-free diet should be initiated as early as possible, particularly because cataract formation may be reversed in early stages. Non-lactose milk substitutes are often used. Although soybean preparations contain bound galactose, they appear to be well-tolerated because the bound galactose is not readily absorbed by the intestine.

This galactose-free diet must be followed for life and requires close supervision, normally overseen by a team of health care professionals including a primary care provider, specialist physician, and a nutritionist. Periodic blood or urine measurements of galactose can be performed to monitor compliance with the restricted diet. Even with early diagnosis and strict dietary restrictions, people with galactosemia are at increased risk for cataract development in adulthood and should have regular eye examinations.

One detrimental effect of eliminating milk and milk products from the diet is the loss of adequate intake of vital nutrients such as protein, calcium, phosphorus, and riboflavin. As a result, nutritional deficiencies may develop, resulting in poor growth. Great care must be taken to achieve adequate daily supplementation with these nutrients after an infant is weaned from the enriched non-dairy formula. However, studies have demonstrated that children, adolescents, and adults often fail to routinely take prescribed supplements.

It also should be noted that exclusion of milk and milk products alone does not constitute a galactose-restricted diet, as galactose is found in other foods as well. Some fruits and vegetables with higher galactose content must also be avoided. Education of parents and children regarding galactose content of specific foods is important, and lists of foods can be obtained from nutritionists that prove useful in management.


Abundant experience with early treatment supports the concept that effective treatment instituted in the initial weeks of life can prevent all symptoms of the disease. In the rare event that some degree of mild retardation results, it is likely irreversible. Cataracts appear to be reversible if treatment is started within the initial three months of life.



Chen, Y. "Defects in Metabolism of Carbohydrates." In Nelson Textbook of Pediatrics, edited by R.E. Behrman. Philadelphia: W.B. Saunders, 2000, pp. 413-414.

Isselbacher, K. J. "Galactosemia, Galactokinase Deficiency, and Other Rare Disorders of Carbohydrate Metabolism." In Harrison's Principles of Internal Medicine, edited by A. S. Fauci. New York: McGraw-Hill, 1998, pp.2131-2132.

Naviaux, R. K. "Galactosemia." In Cecil Textbook of Medicine, edited by R. E. Behrman, Philadelphia: W.B. Saunders, 2000, pp, 413-414.

Nyhan, W.E. "Galactosemia." In Atlas of Metabolic Disease. London: Chapman & Hall, 1998, pp. 322-329.


National Newborn Screening and Genetics Resource Center. 1912 W. Anderson Lane, Suite 210, Austin, TX 78757. Fax: (512) 454-6419. <>.

Parents of Galactosemic Children, Inc. 1100 West 49th St., Austin, TX 78756-3199. (512) 458-7111. <>.


Roberts, R. and Meyer, B. Living with Galactosemia: A Handbook for Families. 1993. University School of Medicine Department of Pediatrics, 702 Barnhill Dr., Indianapolis, Indiana 46202-5225.

Oren Traub, MD, PhD