NORD gratefully acknowledges Madeline Zupan, NORD Editorial Intern from the University of Notre Dame, and Gerard T. Berry, MD, Harvey Levy Chair in Metabolism, Director, Metabolism Program, Division of Genetics and Genomics, Boston Children's Hospital and Professor of Pediatrics, Harvard Medical School, for assistance in the preparation of this report.
Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body’s ability to convert galactose (a sugar contained in milk, including human mother’s milk) to glucose (a different type of sugar). The disorder is caused by a deficiency of an enzyme galactose-1-phosphate uridylyl transferase (GALT) which is vital to this process. Early diagnosis and treatment with a lactose-restricted (dairy-free) diet is absolutely essential to avoid profound intellectual disability, liver failure and death in the newborn period. Galactosemia is inherited as an autosomal recessive genetic condition. Classic galactosemia and clinical variant galactosemia can both result in life-threatening health problems unless treatment is started shortly after birth. A biochemical variant form of galactosemia termed Duarte is not thought to cause clinical disease due to lactose consumption.
An infant with galactosemia appears normal at birth, but within a few days or weeks loses his or her appetite (anorexia) and starts vomiting excessively. Yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), enlargement of the liver (hepatomegaly), appearance of amino acids and protein in the urine, growth failure, and, ultimately, accumulation of fluid in the abdominal cavity (ascites) with abdominal swelling (edema) may also occur. Diarrhea, irritability, lethargy and a bacterial infection may also be early signs of galactosemia. In time, wasting of body tissues, marked weakness, and extreme weight loss occur unless lactose is removed from the diet.
Children with galactosemia who have not received early treatment may show arrested physical and mental development and are particularly susceptible to cataracts in infancy or childhood. In severe cases, overwhelming infection in the newborn period can cause life-threatening complications, but mild cases present few signs and no serious impairment(s).
In order to avoid the consequences of galactosemia, which may include liver failure and kidney dysfunction, brain damage and/or cataracts, infants must be treated promptly by removing lactose from the diet. Children treated with this special diet usually show satisfactory general health and growth. They can make reasonable, though often not optimal, intellectual progress. Speech and learning difficulties and some behavioral problems are still likely to occur. Ovarian impairment is almost always seen in girls with classic galactosemia and is associated with an increase in the blood level of the gonadotropin hormone, follicle-stimulating hormone (FSH); males with galactosemia do not usually exhibit abnormalities in gonadal function.
The above-mentioned complications associated with classic galactosemia and clinical variant galactosemia have not occurred in individuals with Duarte variant galactosemia, which is the best example of the biochemical variant galactosemia subdivision. However, in a minority of subjects, developmental delay and/or a speech abnormality has occurred but it is unclear whether this is related to accumulation of galactose and its metabolites. Individuals with Duarte variant galactosemia do not need to maintain a special diet.
Galactosemia occurs due to disruptions or changes (mutations) in the GALT gene resulting in deficiency of the GALT enzyme. This leads to abnormal accumulation of galactose-related chemicals in various organs of the body causes the signs and symptoms and physical findings of galactosemia.
The galactose-1-phosphate uridyl transferase (GALT) enzyme is needed for the breakdown of the milk sugar, galactose. Deficiency of this enzyme results in the accumulation of toxic products: galactose-1-phosphate (a derivative of galactose), and galactitol (an alcohol derivative of galactose). Galactitol accumulates in the lens of the eye where it causes lens swelling and protein precipitation and, subsequently, cataracts. Accumulation of galactose-1-phosphate is thought to cause the other signs and symptoms of disease.
Galactosemia is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Classic galactosemia is diagnosed in the range of 1/16,000 to 1/48,000 births through newborn screening programs around the world, depending on the diagnostic criteria used by the program. The disorder has been reported in all ethnic groups. An increased frequency of galactosemia occurs in individuals of Irish ancestry. Clinical variant galactosemia occurs most often in African Americans and native Africans in South Africa who have a specific GALT gene mutation.
Classic galactosemia and clinical variant galactosemia are diagnosed when galactose-1-phosphate is elevated in red blood cells and GALT enzyme activity is reduced. Molecular genetic testing is also available to identify mutations in the GALT gene.
Nearly 100% of infants with galactosemia can be diagnosed in newborn screening programs using a blood sample from the heel stick. Infants with clinical variant galactosemia can be missed at newborn screening if GALT enzyme activity is not measured.
Infants and children with galactosemia should have a lactose-restricted (dairy-free) diet that contains lactose-free milk substitutes and other foods such as soy bean products.
A lactose tolerance test should NOT be administered to children with galactosemia. Fortunately, the body of an infant with galactosemia can synthesize galactolipids and other essential galactose-containing compounds without the presence of galactose in food. Therefore, satisfactory physical development is largely possible if a strict diet is followed.
Speech therapy may be necessary for children with childhood apraxia of speech or dysarthria. For school age children, individual education plans and/or professional help with learning skills may be necessary for some individuals, depending on psychological developmental assessments. Hormone replacement therapies may also be used in cases of delayed puberty, and later in adolescence for the secondary loss of menstrual periods, termed premature ovarian insufficiency (POI).
Appropriate treatment (i.e., antibiotic drugs) may be used to control infection in the newborn period. The emotional effects of the strict diet may require attention and supportive measures throughout childhood. Genetic counseling is recommended for families with children who have galactosemia.
Following several conferences, a consensus on the treatment and follow-up of patients with galactosemia was published in 2017.
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