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Epimerase Deficiency Galactosemia.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2011 Jan 25 [updated 2013 Oct 24].



Epimerase deficiency galactosemia (GALE deficiency galactosemia) is a continuum comprising three forms: Generalized. Enzyme activity is profoundly decreased in all tissues tested. Peripheral. Enzyme activity is deficient in red blood cells and circulating white blood cells, but normal or near normal in all other tissues. Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested. Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); in contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs. Because of the limited number of affected individuals reported to date, information on the natural history of all forms of epimerase deficiency galactosemia is limited. Infants with the profound generalized form who are on a diet containing galactose/lactose manifest hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms.


UDP-galactose 4’-epimerase (GALE) enzyme activity can be measured in red blood cells (RBCs) either directly or indirectly. GALE is the only gene in which mutations are known to be associated with epimerase deficiency galactosemia. Of note, finding impaired GALE activity in RBC does not distinguish between the clinically severe generalized and milder intermediate or peripheral forms of epimerase deficiency. Further testing in other cell types such as stimulated leukocytes or EBV-transformed lymphoblasts is required to make that distinction.


Treatment of manifestations: The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-restricted diet. Infants should be fed a formula (e.g., soy formula) that contains only trace levels of galactose or lactose. Continued dietary restriction of dairy products in older children is recommended. In contrast, infants with peripheral epimerase deficiency galactosemia are believed to remain asymptomatic regardless of diet; infants with intermediate epimerase deficiency galactosemia may benefit in the long term from early dietary galactose/lactose restriction, but this remains unclear. Prevention of primary manifestations: In profound generalized epimerase deficiency galactosemia, restriction of dietary galactose/lactose appears to correct or prevent the acute signs and symptoms of the disorder (hepatic dysfunction, renal dysfunction, and mild cataracts), but not the developmental delay or learning impairment observed in some children with generalized epimerase deficiency galactosemia. Infants with peripheral or intermediate epimerase deficiency galactosemia do not exhibit acute sequelae regardless of diet. Surveillance: Hemolysate gal-1P (galactose-1-phosphate) is monitored, especially if the diet is to be normalized. Acceptable levels of RBC gal-1P are not known, but are estimated to be less than 3.5 mg/100 mL based on data from classic galactosemia. Other parameters that warrant monitoring are growth and developmental milestones. Agents/circumstances to avoid: Dietary galactose/lactose in persons with generalized epimerase deficiency galactosemia, certainly as infants and perhaps for life. Evaluation of relatives at risk: Molecular genetic testing (if the family-specific mutations are known) and/or evaluation by a physician specializing in treatment of metabolic disorders shortly after birth (if the family-specific mutations are not known) allows early diagnosis and treatment of sibs at risk for epimerase deficiency galactosemia.


Epimerase deficiency galactosemia is inherited in an autosomal recessive manner. At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

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