Galactosemia is a disorder that affects how the body processes a simple sugar called galactose. A small amount of galactose is present in many foods. It is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas. The signs and symptoms of galactosemia result from an inability to use galactose to produce energy.

Researchers have identified several types of galactosemia. These conditions are each caused by mutations in a particular gene and affect different enzymes involved in breaking down galactose.

Classic galactosemia, also known as type I, is the most common and most severe form of the condition. If infants with classic galactosemia are not treated promptly with a low-galactose diet, life-threatening complications appear within a few days after birth. Affected infants typically develop feeding difficulties, a lack of energy (lethargy), a failure to gain weight and grow as expected (failure to thrive), yellowing of the skin and whites of the eyes (jaundice), liver damage, and abnormal bleeding. Other serious complications of this condition can include overwhelming bacterial infections (sepsis) and shock. Affected children are also at increased risk of delayed development, clouding of the lens of the eye (cataract), speech difficulties, and intellectual disability. Females with classic galactosemia may develop reproductive problems caused by an early loss of function of the ovaries (premature ovarian insufficiency).

Galactosemia type II (also called galactokinase deficiency) and type III (also called galactose epimerase deficiency) cause different patterns of signs and symptoms. Galactosemia type II causes fewer medical problems than the classic type. Affected infants develop cataracts but otherwise experience few long-term complications. The signs and symptoms of galactosemia type III vary from mild to severe and can include cataracts, delayed growth and development, intellectual disability, liver disease, and kidney problems.

Galactosemia, which means “galactose in the blood,” refers to a group of inherited disorders that impair the body's ability to process and produce energy from a sugar called galactose. When people with galactosemia injest foods or liquids containing galactose, undigested sugars build up in the blood. Galactose is present in many foods, including all dairy products (milk and anything made from milk), many baby formulas, and some fruits and vegetables. The impaired ability to process galactose can be due to the deficiency of any of 3 enzymes, caused by mutations in different genes. There are 3 main types of galactosemia which are distinguished based on their genetic causes, signs and symptoms, and severity:

• Classic galactosemia (type 1) - the most common and severe type, caused by mutations in the GALT gene, and characterized by a complete deficiency of an enzyme called galactose-1-phosphate uridyl transferase (GALT). Early signs and symptoms include liver dysfunction, susceptibility to infections, failure to thrive, and cataracts. These can usually be prevented or improved by early diagnosis and treatment, but other progressive or long-term problems are common despite treatment. These include intellectual deficits, movement disorders, and premature ovarian failure (in females).
• Galactokinase deficiency (type 2) - caused by mutations in the GALK1 gene and characterized by a deficiency of the enzyme galactokinase 1. This type typically causes only the development of cataracts, which may be prevented or resolved with treatment. Rarely, this type causes pseudotumor cerebri (a condition which mimics the symptoms of a large brain tumor when no brain tumor is present).
• Galactose epimerase deficiency (type 3) - caused by mutations in the GALE gene and characterized by a deficiency of the enzyme UDP-galactose-4-epimerase. Symptoms and severity of this type depend on whether the deficiency is confined to certain types of blood cells or is present in all tissues. Some people with this type have no signs or symptoms, while others have symptoms similar to those with classic galactosemia. Like in classic galactosemia, many symptoms can be prevented or improved with treatment.

There is also a "variant" of classic galactosemia called Duarte variant galactosemia, in which a person has mutations in the GALT gene but has only partial deficiency of the enzyme. Infants with this form may have jaundice, which resolves when switched to a low-galactose formula. Some studies have found that people with this form are at increased risk for mild neurodevelopmental problems, but other studies have found there is no increased risk. The risk may depend on the extent of the deficiency.

Inheritance of all types of galactosemia is autosomal recessive. The diagnosis may be suspected based on symptoms or results of newborn screening tests, and can be confirmed by measuring enzyme activity and genetic testing. Depending on the type of galactosemia, treatment may involve removing galactose from the diet (as soon as the disorder is suspected), calcium supplementation, and individualized care for any additional symptoms. The long-term outlook for people with galactosemia varies depending on the type, symptoms present, and commitment to the diet.

Classic galactosemia is an inherited (genetic) condition that prevents the body from breaking down a sugar called galactose.

Your body gets energy from breaking down galactose in milk and other foods. Several enzymes break down galactose into other substances that your body can use or remove.

There are different types of galactosemia:

• Classic galactosemia (galactosemia type I)
• Galactokinase deficiency (galactosemia type II)
• Galactoepimerase deficiency (galactosemia type III)

The type your baby has depends on which enzyme is not working properly to break down galactose.

Classic galactosemia is the most common type of galactosemia and results when an enzyme called GALT, which processes galactose, does not work correctly.

Milder forms of classic galactosemia include:

• Clinical variant galactosemia: People with this form have a small amount of working GALT enzyme, and can process some galactose, but not enough to avoid symptoms.
• Duarte galactosemia: People with this form have enough working GALT enzyme to experience either mild symptoms or no symptoms at all.

When you cannot break down galactose, undigested sugars build up in the body and can cause damage. If untreated, this damage can cause the signs and symptoms of the condition.

Mutations in the GALT, GALK1, and GALE genes cause galactosemia. These genes provide instructions for making enzymes that are essential for processing galactose obtained from the diet. These enzymes break down galactose into another simple sugar, glucose, and other molecules that the body can store or use for energy.

Mutations in the GALT gene cause classic galactosemia (type I). Most of these genetic changes almost completely eliminate the activity of the enzyme produced from the GALT gene, preventing the normal processing of galactose and resulting in the life-threatening signs and symptoms of this disorder. Another GALT gene mutation, known as the Duarte variant, reduces but does not eliminate the activity of the enzyme. People with the Duarte variant tend to have much milder features of galactosemia.

Galactosemia type II results from mutations in the GALK1 gene, while mutations in the GALE gene underlie galactosemia type III. Like the enzyme produced from the GALT gene, the enzymes made from the GALK1 and GALE genes play important roles in processing galactose. A shortage of any of these critical enzymes allows galactose and related compounds to build up to toxic levels in the body. The accumulation of these substances damages tissues and organs, leading to the characteristic features of galactosemia.

Normal Function

The GALT gene provides instructions for making an enzyme called galactose-1-phosphate uridylyltransferase. This enzyme enables the body to process a simple sugar called galactose, which is present in small amounts in many foods. Galactose is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas.

Galactose-1-phosphate uridylyltransferase is responsible for one step in a chemical process that breaks down 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, which is another simple sugar. Glucose is the main energy source for most cells. This chemical reaction also produces another form of galactose (UDP-galactose) that is used to build galactose-containing proteins and fats. These modified proteins and fats play critical roles in chemical signaling, building cellular structures, transporting molecules, and producing energy.

Health Conditions Related to Genetic Changes

Galactosemia

More than 300 mutations in the GALT gene have been identified in people with the classic form of galactosemia, a condition that causes life-threatening signs and symptoms beginning shortly after birth. Most of these mutations severely reduce or eliminate the activity of galactose-1-phosphate uridylyltransferase. A shortage of this enzyme prevents cells from processing galactose obtained from the diet. As a result, galactose-1-phosphate and related compounds can build up to toxic levels in the body. The accumulation of these substances damages tissues and organs, leading to the serious medical problems associated with classic galactosemia.

Most changes in the GALT gene alter single protein building blocks (amino acids) in galactose-1-phosphate uridylyltransferase. The most common GALT mutation in white Europeans and North Americans replaces the amino acid glutamine with the amino acid arginine at position 188 in the enzyme (written as Gln188Arg or Q188R). Another mutation occurs almost exclusively in people of African descent. This genetic change substitutes the amino acid leucine for the amino acid serine at position 135 (written as Ser135Leu or S135L).

A particular GALT mutation called the Duarte variant results in a form of galactosemia with less serious complications than the classic type. This mutation replaces the amino acid asparagine with the amino acid aspartic acid at protein position 314 (written as Asn314Asp or N314D). The Duarte variant reduces but does not eliminate the activity of galactose-1-phosphate uridylyltransferase. The signs and symptoms associated with this variant tend to be milder because the enzyme retains 5 percent to 20 percent of its normal activity.

Other Names for This Gene

• Gal-1-P uridylyltransferase
• Galactosephosphate Uridylyltransferase
• GALT_HUMAN
• UDP Galactose Pyrophosphorylase
• UTP-Hexose-1-Phosphate Uridylyltransferase
• UTP:alpha-D-hexose-1-phosphate uridylyltransferase

Genomic Location

Normal Function

The GALK1 gene provides instructions for making an enzyme called galactokinase 1. This enzyme enables the body to process a simple sugar called galactose, which is present in small amounts in many foods. Galactose is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas.

Galactokinase 1 is responsible for one step in a chemical process that converts galactose into other molecules that can be used by the body. Specifically, this enzyme modifies galactose to create a similar molecule called galactose-1-phosphate. A series of additional steps converts galactose-1-phosphate to another simple sugar called glucose, which is the main energy source for most cells. Galactose-1-phosphate can also be converted to a form that is used to build galactose-containing proteins and fats. These modified proteins and fats play critical roles in chemical signaling, building cellular structures, transporting molecules, and producing energy.

Health Conditions Related to Genetic Changes

Galactosemia

More than 30 mutations in the GALK1 gene have been identified in people with a form of galactosemia called type II or galactokinase deficiency. Affected infants develop clouding of the lens of the eye (cataracts) but otherwise experience few of the long-term complications associated with classic galactosemia. Most of these mutations change single protein building blocks (amino acids) in galactokinase 1. A few mutations delete a small amount of genetic material from the GALK1 gene, resulting in an unstable or inactive version of this enzyme.

A shortage of functional galactokinase 1 prevents cells from processing galactose obtained from the diet. As a result, galactose and a related sugar called galactitol can build up, particularly in cells that make up the lens of the eye. An accumulation of these substances damages the lens, causing it to become cloudy and leading to blurred vision.

Other Names for This Gene

• ATP:D-galactose 1-phosphotransferase
• galactokinase
• GALK
• GALK1_HUMAN
• GK1

Genomic Location

Normal Function

The GALE gene provides instructions for making an enzyme called UDP-galactose-4-epimerase. This enzyme enables the body to process a simple sugar called galactose, which is present in small amounts in many foods. Galactose is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas.

UDP-galactose-4-epimerase converts a modified form of galactose (UDP-galactose) to another modified sugar (UDP-glucose). Glucose is a simple sugar that is the main energy source for most cells. This enzyme also promotes the reverse chemical reaction, the conversion of UDP-glucose to UDP-galactose. UDP-galactose is used to build galactose-containing proteins and fats, which play critical roles in chemical signaling, building cellular structures, transporting molecules, and producing energy.

Health Conditions Related to Genetic Changes

Galactosemia

More than 20 mutations in the GALE gene have been identified in people with a form of galactosemia known as type III or galactose epimerase deficiency. The signs and symptoms of this condition begin shortly after birth and can vary from mild to severe. Most of the genetic changes alter a single protein building block (amino acid) in UDP-galactose-4-epimerase, which makes the enzyme unstable or impairs its usual function.

Some GALE gene mutations severely reduce or eliminate the activity of UDP-galactose-4-epimerase in all of the body's tissues. These genetic changes lead to a severe form of galactosemia type III described as the generalized form. A loss of enzyme activity prevents cells from processing galactose obtained from the diet. As a result, compounds associated with galactose processing can build up to toxic levels in the body. The accumulation of these substances damages tissues and organs, leading to serious complications such as clouding of the lens of the eye (cataract), intellectual disability, and damage to the liver, kidneys, and brain.

Other mutations in the GALE gene reduce the activity of UDP-galactose-4-epimerase in red blood cells only. These genetic changes underlie a much milder form of galactosemia type III described as the peripheral form. Affected individuals may not have any of the complications typically associated with galactosemia and often do not require treatment. Researchers are unclear why the effects of some GALE mutations are restricted to blood cells, while other mutations affect all of the body's tissues and cause severe health problems.

Other Names for This Gene

• galactowaldenase
• GALE_HUMAN
• SDR1E1
• UDP - Uridyl diphosphate galactose-4-epimerase
• UDP Galactose Epimerase
• UDP-Glucose 4-Epimerase
• Uridine diphosphate galactose-4-epimerase
• Uridine Diphosphate Glucose Epimerase

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Avoidance of foods that contain galactose and lactose
• Avoidance of all dairy products
• Special foods and formulas
• Vitamin supplements (calcium, vitamin K, vitamin D)

Children who receive early and ongoing treatment for classic galactosemia can have healthy growth and development. Some children with classic galactosemia who receive treatment early still show delays in learning, development, speech/language, and motor skills.

Classic galactosemia occurs in 1 in 30,000 to 60,000 newborns. Galactosemia type II and type III are less common; type II probably affects fewer than 1 in 100,000 newborns and type III appears to be very rare.