Galactosemia types I, II and III - GALT, GALE and GALK1 genes
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 preparations for newborns.
Several types of galactosemia have been identified, each due to mutations in a particular gene, and therefore affecting different enzymes involved in galactose metabolism: Galactosemia type I (classical), galactosemia type II (deficiency of galactokinase), and type III (galactose epimerase deficiency). Each type has different signs and symptoms. Type I (classic), is the most frequent and most serious form of the alteration. If newborns with classical galactosemia are not treated quickly with a low galactose diet, potentially fatal complications may appear within a few days after birth. Children with type I galactosemia may manifest feeding difficulties, lethargy, growth retardation, jaundice, liver damage, bleeding, sepsis and shock. These children are also at risk of developmental delay, cataracts, speech difficulties and intellectual disability. Women with classical galactosemia may have reproductive problems due to ovarian insufficiency. Type II galactosemia causes fewer medical problems than the classic type. Affected children develop cataracts, but otherwise, they suffer few long-term complications. Signs and symptoms of type III galactosemia vary from mild to severe and may include cataracts, stunted growth and development, intellectual disability, 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 galactose processing. These enzymes transform galactose into another simple carbohydrate, glucose and other molecules that the body can store or use as energy.
The GALT (galactose-1-phosphate uridylyltransferase) gene, located on the short arm of chromosome 9 (9p13), encodes the enzyme uridylyltransferase galactose-1-phosphate. This enzyme allows the body to process galactose. Uridylyltransferase galactose-1-phosphate is responsible for a step in a metabolic process that degrades galactose into other molecules that can be used by the body. Specifically, this enzyme converts a modified form of galactose (galactose-1-phosphate) to glucose. This chemical reaction also produces another form of galactose (UDP-galactose) that is used to constitute proteins and fats that contain galactose. These proteins and modified fats play a critical role in chemical signaling, the construction of cellular structures, the transport of molecules and the production of energy. More than 300 mutations in the GALT gene have been identified in people with the classic form of galactosemia. Mutations in the GALT gene are responsible for classical galactosemia (type I). Most of these genetic changes almost completely eliminate enzyme activity, altering galactose processing. The most frequent mutation replaces the amino acid glutamine with the amino acid arginine at position 188 of the enzyme (Gln188Arg). Another mutation replaces the amino acid leucine with the amino acid serine at position 135 (Ser135Leu). A mutation of the GALT gene, known as the Duarte variant (Asn314Asp or N314D), reduces, but does not eliminate the activity of the enzyme. People with the Duarte variant usually have much milder signs and symptoms of galactosemia because the enzyme retains 5 to 20 percent of its normal activity.
The GALK1 (galactokinase 1) gene, located on the long arm of chromosome 17 (17q24), encodes the enzyme galactokinase 1. This enzyme allows the body to process 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 modifies galactose to generate galactose-1-phosphate. A series 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 to a form that is used to constitute protein and fat molecules that contain 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 the production of energy. More than 30 mutations in the GALK1 gene have been identified in people with type II galactosemia. Most mutations in the GALK1 gene change amino acids in galactokinase 1. Some mutations remove a small amount of genetic material from the GALK1 gene, which results in an unstable or inactive version of this enzyme. Functional galactokinase 1 deficiency disrupts galactose processing. As a consequence, galactose and a related carbohydrate, called galactitol, can accumulate, particularly in the cells that make up the lens. An accumulation of these substances damages the lens, which causes the appearance of cataracts.
The GALE (UDP-galactose-4-epimerase) gene, located on the short arm of chromosome 1 (1p36-p35), encodes the enzyme UDP-galactose-4-epimerase. This enzyme allows the body to process galactose, which is present in small amounts in many foods. UDP-galactose-4-epimerase converts a modified form of galactose (UDP-galactose) to another modified sugar (UDP-glucose). This enzyme also promotes the reverse chemical reaction, the conversion of UDP-glucose to UDP-galactose. UDP-galactose is used to constitute proteins that contain galactose and fats, which play a critical role in chemical signaling, the constitution of cellular structures, the transport of molecules and the production of energy. More than 20 mutations in the GALE gene have been identified in people with type III galactosemia. Some mutations in the GALE gene, dramatically reduce or eliminate the activity of the enzyme in all tissues of the body, resulting in a severe form of galactosemia type III described as the generalized form. A loss of enzyme activity inhibits the processing of galactose ingested with the diet. As a consequence, the compounds associated with galactose processing can accumulate to toxic concentrations in the body. The accumulation of these substances damages tissues and organs, leading to serious complications such as cataracts, intellectual disability and, damage to the liver, kidneys and brain. Other mutations reduce the activity of the enzyme only in erythrocytes. These genetic changes are the basis of 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 GALE mutations are limited to blood cells, while other mutations affect all body tissues and cause serious medical problems.
This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with galactosemia, by means of the complete PCR amplification of the exons of the GALE, GALK1 and GALT genes, respectively, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).