Galacktokinase Deficiency Health Article

Definition

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.

Description

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.

Demographics

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.