Galactosemia types I, II and III (galactosemia) - Genes GALT, GALE and GALK1.

Galactosemia is an alteration that alters the way the body processes galactose. Galactose is a part of the lactose molecule found in all dairy products and many newborn prepared.

They have identified several types of galactosemia, each due to mutations in a particular gene, and thus affect different enzymes involved in galactose metabolism: Type I (classical) galactosemia, galactosemia type II (deficiency galactokinase), and type III (galactose epimerase deficiency). Each of the types has different signs and symptoms. Type I (classic) is the most common and most severe form of the disorder. If infants with classic galactosemia is not treated quickly with a diet low in galactose, potentially fatal within days of birth complications can occur. Children with galactosemia type I can manifest feeding difficulties, lethargy, growth retardation, jaundice, liver damage, hemorrhage, sepsis and shock. These children are also at risk of developmental delay, cataracts, speech difficulties and intellectual disabilities. Women with classic galactosemia may have reproductive problems due to ovarian failure. Type II galactosemia causes fewer medical problems than the classic type. Affected children develop cataracts but otherwise, suffer few long - term complications. Signs and symptoms of type III galactosemia range from mild to severe and can include cataracts, delayed growth and development, mental retardation, liver disease and kidney problems.

This disease is due to mutations in the GALT (galactose-1-phosphate uridylyltransferase), GALK1 (galactokinase 1) and GALE (UDP-galactose-4-epimerase) genes. These genes encode enzymes that are essential for processing of galactose. These enzymes convert galactose into another simple carbohydrate, glucose and other molecules that the body can store or use as energy.

GALT (galactose-1-phosphate uridylyltransferase) gene, located on the short arm of chromosome 9 (9p13), encoding galactose-1-phosphate uridylyltransferase enzyme. This enzyme allows the body to process the galactose. The uridylyltransferase galactose-1-phosphate is responsible for a step in a metabolic process that degrades galactose in other molecules that can be used by the body. Specifically, this enzyme converts a modified form of galactose (galactose-1-phosphate) glucose. This chemical reaction also produces another form of galactose (UDP-galactose) used to form proteins and fats containing galactose. These proteins and modified fats play a critical role in chemical signaling, the construction of cellular structures, the transport of molecules and energy production. They have identified more than 300 mutations in the GALT gene in people with the classic form of galactosemia. Mutations in the GALT gene are responsible for the classic galactosemia (type I). Most of these genetic changes almost completely eliminated the enzyme activity, altering the processing of galactose. The most frequent mutation replaces the amino acid glutamine for the amino acid arginine at position 188 of the enzyme (Gln188Arg). Another mutation replaces the amino acid leucine by the amino acid serine at position 135 (Ser135Leu). A gene mutation GALT, known as Duarte (Asn314Asp or N314D) variant, reduces but does not eliminate the activity of the enzyme. People with Duarte variant often have signs and symptoms of the much milder galactosemia because the enzyme retains from 5 to 20 percent of normal activity.

The GALK1 gene (galactokinase 1), located on the long arm of chromosome 17 (17q24), encoding galactokinase enzyme 1. This enzyme allows the body to process the galactose. Galactokinase 1 is responsible for a step in a metabolic process that converts galactose into other molecules that can be used by the body. Specifically, this enzyme modified galactose to generate galactose-1-phosphate. A number of additional steps convert galactose-1-phosphate to glucose, which is the main source of energy for most cells. Galactose-1-phosphate can also be converted into a form that is used to form molecules of proteins and fats containing galactose (glycoproteins and glycolipids). These proteins and modified fats play critical roles in chemical signaling, the construction of cellular structures, the transport of molecules and energy production. They have identified more than 30 mutations in the gene GALK1 in people with type II galactosemia. Most mutations in the amino acid change GALK1 galactokinase gene 1. Some mutations remove a small amount of genetic material GALK1 gene, resulting in an unstable or inactive version of this enzyme. Galactokinase deficiency alters one functional processing galactose. As a result, galactose and a related carbohydrate, called galactitol, can accumulate, particularly in the cells that make the lens. An accumulation of these substances damages the lens, causing cataracts.

GALE gene (UDP-galactose-4-epimerase), located on the short arm of chromosome 1 (1p36-p35) encoding the UDP-galactose 4-epimerase enzyme. This enzyme allows the body to process the galactose, which is present in small amounts in many foods. UDP-galactose-4-epimerase converts a modified form of the galactose (UDP-galactose) to another modified sugar (UDP-glucose). This enzyme also promotes reverse chemical reaction, the conversion of UDP-glucose to UDP-galactose. UDP-galactose is used to form proteins and fats containing galactose, which play a critical role in chemical signaling, the formation of cellular structures, the transport of molecules and energy production. There are more than 20 mutations in the GALE gene in people with type III galactosemia. Some mutations in the GALE gene, drastically reduce or eliminate the activity of the enzyme in all tissues of the body, leading to a severe form of type III galactosemia described as the generalized form. A loss of enzyme activity inhibits the processing of ingested galactose diet. Consequently, the compounds associated with the processing of galactose may accumulate to toxic levels in the body. The accumulation of these substances damages the tissues and organs, leading to serious complications such as cataracts, mental retardation and damage to the liver, kidneys and brain. Other mutations reduce the activity of the enzyme only in erythrocytes. These genetic changes underlie a much milder form of galactosemia type III, called peripheral. Affected individuals may not have any of the complications associated with galactosemia and often do not require treatment. It is not clear why the effects of some mutations GALE limited to blood cells, while other mutations affect all body tissues and cause serious medical problems.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with galactosemia, by complete PCR amplification of the exons of GALE, GALK1 and GALT genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).