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Classic Galactosemia and Clinical Variant Galactosemia.

Authors

Berry GT.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2000 Feb 04 [updated 2014 Apr 03].

Excerpt

DISEASE CHARACTERISTICS:

The term galactosemia refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia. This GeneReview focuses on: Classic galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E. coli sepsis in untreated infants. If a lactose-restricted diet is provided during the first ten days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis, and neonatal death are prevented; however, despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for developmental delays, speech problems (termed childhood apraxia of speech and dysarthria), and abnormalities of motor function. Almost all females with classic galactosemia manifest premature ovarian insufficiency (POI). Clinical variant galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage including cirrhosis and bleeding in untreated infants. This is exemplified by the disease that occurs in African Americans and native Africans in South Africa. Persons with clinical variant galactosemia may be missed with newborn screening (NBS) as the hypergalactosemia is not as marked as in classic galactosemia and breath testing is normal. If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications are usually prevented. African Americans with clinical variant galactosemia and adequate early treatment do not appear to be at risk for long-term complications including POI.

DIAGNOSIS/TESTING:

The diagnosis of classic galactosemia and clinical variant galactosemia is established by detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity, and/or biallelic mutations in GALT, the gene encoding galactose-1-phosphate uridyltransferase. In classic galactosemia, erythrocyte galactose-1-phosphate is usually higher than 10 mg/dL and erythrocyte GALT enzyme activity is absent or barely detectable. In clinical variant galactosemia, erythrocyte GALT enzyme activity (which may be absent or barely detectable, as in African Americans) is much higher in brain and intestinal tissue (e.g., 10% of control values). Other individuals with clinical variant galactosemia may have erythrocyte GALT enzyme activity close to or above 1% of control values but probably never above 10%-15%. Virtually 100% of infants with classic galactosemia or clinical variant galactosemia can be detected in newborn screening programs that include testing for galactosemia in their panel. However, infants with clinical variant galactosemia may be missed if the program only measures blood total galactose level and not erythrocyte GALT enzyme activity.

MANAGEMENT:

Prevention of primary manifestations: Standard of care in any newborn who is “screen-positive” for galactosemia is immediate dietary intervention while diagnostic testing is underway. If erythrocyte galactose-1-phosphate concentration is >10 mg/dL and erythrocyte GALT enzyme activity is ≤10% of control activity (i.e., the child has classic galactosemia or clinical variant galactosemia), restriction of galactose intake is continued and all milk products are replaced with lactose-free formulas (e.g., Isomil® or Prosobee®) containing non-galactose carbohydrates; management of the diet becomes less important after infancy and early childhood. Treatment of manifestations: In rare instances cataract surgery may be needed in the first year of life. Childhood apraxia of speech and dysarthria require expert speech therapy. Developmental assessment at age one year by a psychologist is recommended in order to formulate a treatment plan with the speech therapist and treating physician. For school age children, an individual education plan and/or professional help with learning skills and special classrooms as needed. Hormone replacement therapy as needed for delayed pubertal development and/or primary or secondary amenorrhea. Prevention of secondary complications: Recommended calcium and vitamin intake to help prevent decreased bone mineralization. Surveillance: Routine monitoring for: the accumulation of toxic analytes (e.g., erythrocyte galactose-1-phosphate and urinary galactitol); cataracts; speech and development; POI; and osteoporosis. Agents/circumstances to avoid: Breast milk, proprietary infant formulas containing lactose, cow’s milk, dairy products, and casein or whey-containing foods; medications with lactose and galactose. Evaluation of relatives at risk: To allow for earliest possible diagnosis and treatment of at-risk sibs: Perform prenatal diagnosis when the disease-causing GALT mutations in the family are known; or If prenatal testing has not been performed, test the newborn for either the family-specific GALT mutations or erythrocyte GALT enzyme activity.

GENETIC COUNSELING:

Classic galactosemia and clinical variant galactosemia are inherited in an autosomal recessive manner. Couples who have had one affected child have a 25% chance of having an affected child in each subsequent pregnancy. Carrier testing for at-risk sibs and prenatal diagnosis for pregnancies at increased risk are an option if the disease-causing GALT mutations in the family are known. If the disease-causing GALT mutations in a family are not known, prenatal testing can rely on assay of GALT enzyme activity in cultured amniotic fluid cells.

Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

PMID:
20301691
[PubMed]
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