Copyright © 1993-2013, University of Washington, Seattle. All rights reserved.
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
Bookshelf ID: NBK51671PMID: 21290786
Summary
Disease characteristics. 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 and white blood cells, but normal or near normal in all other tissues); and intermediate (enzyme activity is deficient in red and white blood cells and less than 50% of normal levels in all other cells). 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 form and the 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 lactose typically manifest hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose from their diet resolves or prevents these acute symptoms.
Diagnosis/testing. GALE enzyme activity can be measured in red blood cells (RBCs) either directly or indirectly. Molecular genetic testing of GALE, the only gene in which mutations are known to be associated with epimerase deficiency galactosemia, is available on a clinical basis.
Management. Treatment of manifestations: The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose-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 restriction, but this remains unclear.
Prevention of primary manifestations: In profound generalized epimerase deficiency galactosemia, restriction of dietary galactose 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 <3.5 mg/100 mL. Other parameters that warrant monitoring are growth and developmental milestones.
Agents/circumstances to avoid: dietary galactose in persons with generalized epimerase deficiency galactosemia, certainly as infants and perhaps for life.
Testing 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.
Genetic counseling. 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.
Diagnosis
Clinical Diagnosis
Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprising the enzymes galactokinase (GALK, EC 2.7.1.6), galactose 1-P uridylyltransferase (GALT, EC 2.7.7.12), and UDP-galactose 4'-epimerase (GALE, EC 5.1.3.2).
The clinical severity of epimerase deficiency galactosemia caused by reduced activity of the enzyme GALE [Fridovich-Keil & Walter 2008] ranges from potentially lethal [Holton et al 1981, Henderson et al 1983, Walter et al 1999, Sarkar et al 2010] to apparently benign [Gitzelmann 1972].
Epimerase deficiency galactosemia can be divided by enzyme activity into the following three forms [Openo et al 2006]. Note: In all three forms GALE enzyme activity is deficient in peripheral circulating red and white blood cells.
- Generalized epimerase deficiency galactosemia. Enzyme activity is profoundly decreased in all tissues tested.
- Peripheral epimerase deficiency galactosemia. Enzyme activity is deficient in red and white blood cells, but normal or near normal in all other tissues.
- Intermediate epimerase deficiency galactosemia. Enzyme activity is deficient in red and white blood cells and less than 50% of normal levels in all other cells.
A key difference between generalized epimerase deficiency galactosemia and intermediate or peripheral epimerase deficiency galactosemia is that individuals with generalized epimerase deficiency galactosemia develop clinical findings on a normal milk diet (see Clinical Description) while infants with peripheral epimerase deficiency galactosemia and intermediate epimerase deficiency galactosemia remain clinically well, at least in the neonatal period, and are usually only detected on biochemical testing, for example in newborn screening programs.
Testing
Urinary excretion of galactose. Galactosuria is most pronounced in infants with severe epimerase deficiency galactosemia who have consumed substantial quantities of galactose (usually as lactose, the disaccharide composed of galactose and glucose). Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL) have been reported [Holton et al 1981]; however, individuals with less severe enzyme deficiency or limited galactose exposure may show much lower levels.
Urinary galactose can also be detected as a non-glucose reducing substance in the urine [Naumova et al 2006].
Note: Measurement of hemolysate gal-1P (galactose-1-phosphate; see following) is more sensitive than measurement of urinary galactose and, therefore, is often used for confirmatory testing and follow-up.
Galactose (gal+gal-1P) concentration. Newborns with epimerase deficiency galactosemia may demonstrate elevated "total blood galactose" (gal + gal-1P) on newborn screening.
Follow-up should include testing of hemolysate gal-1P concentration.
- In epimerase deficiency galactosemia the increase in hemolysate gal-1P depends on the severity of GALE enzyme deficiency and quantity of galactose (lactose) consumed.
- The normal range for hemolysate gal-1P is 0-1.0 mg/100 mL red blood cells.
UDP-galactose 4’- epimerase (GALE) enzyme activity
- GALE enzyme activity can be measured in red blood cells (RBCs) either directly or indirectly. GALE enzyme activity is usually reported as micromoles (μmol) UDP-glucose production per hour per mg of hemoglobin.
Clinical laboratories often perform a two-step coupled spectrophotometric assay in which 0.4 μmol UDP-galactose (the substrate) is mixed with RBC lysate in the presence of 1 μmol NAD and incubated to allow for the conversion of UDP-galactose to UDP-glucose. The amount of UDP-glucose is then measured by a coupled reaction involving UDP-glucose dehydrogenase and NAD: one molecule of NAD is converted to NADH for each molecule of UDP-glucose that is converted to UDP-glucuronate.
Typical ranges for GALE activity measured in RBC lysates are:- Normal range: 17.1-40.1 μmol/hr/g hemoglobin (Hb)
- Affected range: 0.0-8.0 μmol/hr/g Hb
- GALE enzyme activity can also be measured in lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms of epimerase deficiency galactosemia (see Molecular Genetic Testing). Such testing is available on a research basis only.
Molecular Genetic Testing
Gene. GALE is the only gene in which mutations are known to be associated with epimerase deficiency galactosemia.
Clinical testing
- Sequence analysis. Full-gene sequencing for GALE is clinically available. The number of samples analyzed to date is small but the results have been consistent with published reports (e.g., Park et al [2005], Openo et al [2006]; reviewed in Fridovich-Keil & Walter [2008]). Most individuals with significant GALE enzyme deficiency have:
- Two recognized GALE mutations
OR - Two GALE sequence variants of unknown significance
- Deletion/duplication analysis. For the small number of individuals with epimerase deficiency galactosemia who have undergone molecular genetic testing [Park et al 2005, Openo et al 2006], testing to detect whole-exon or whole-gene deletions or duplications has not been performed; therefore, no GALE deletions or duplications have been reported to date.
Table 1. Summary of Molecular Genetic Testing Used in Epimerase Deficiency Galactosemia
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method 1 | Test Availability |
|---|---|---|---|---|
| GALE | Sequence analysis | Sequence variants 2 | Unknown 3 | Clinical |
| Deletion/duplication analysis 4 | Exonic or whole-gene deletions | Unknown 3 |
Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.
1. The ability of the test method used to detect a mutation that is present in the indicated gene
2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.
3. While whole-gene sequencing has revealed ostensibly causal GALE genetic variants in most persons with biochemically confirmed GALE deficiency who have been studied (e.g., Park et al [2005], Openo et al [2006]), the small numbers of alleles studied and the biochemical complexity of the diagnosis prevent accurate estimates of mutation detection frequency at this time.
4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Testing Strategy
To confirm/establish the diagnosis in a proband. In the presence of clinical and/or biochemical suspicion of galactosemia and apparently normal GALT enzyme activity:
- 1.
Measure UDP-galactose 4’- epimerase (GALE) enzyme activity in RBC; if it is deficient then
- 2.
Perform GALE sequence analysis
Note: (1) If GALE enzyme activity is deficient in RBCs and if sequence analysis does not identify two GALE sequence variants, deletion/duplication analysis may be warranted. (2) None of the established clinically available tests can accurately distinguish between the generalized, intermediate, and peripheral forms of epimerase deficiency galactosemia. GALE sequence analysis may reveal previously recognized mutations, but many affected individuals have variants of unknown significance. Because insufficient numbers of individuals with molecularly confirmed epimerase deficiency galactosemia have been followed clinically to identify genotype/phenotype correlations, studies of transformed lymphoblasts or other "non-peripheral" cell types are the only way to distinguish biochemically between the different forms of epimerase deficiency galactosemia [Mitchell et al 1975, Openo et al 2006]; such testing is available on a research basis only.
Newborn screening programs that measure
- Both total galactose (gal+gal-1P) concentration and GALT enzyme activity in all samples may detect epimerase deficiency galactosemia because infants with epimerase deficiency galactosemia who have consumed sufficient lactose have elevated total galactose despite normal GALT enzyme activity.
- GALT enzyme activity first and total galactose only if GALT enzyme activity is low do not identify children with either epimerase deficiency galactosemia or galactokinase deficiency.
Carrier testing for at-risk relatives using molecular genetic testing requires prior identification of the disease-causing mutations in the family. Although biochemical testing to detect carriers is also a possibility, the ranges for control and carrier GALE enzyme activity overlap, thus making molecular genetic testing the preferred method for carrier detection.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in GALE.
Clinical Description
Natural History
Information on the natural history of profound generalized epimerase deficiency galactosemia is based on very few patients; information on the natural history of peripheral and intermediate epimerase deficiency galactosemia is limited by under-ascertainment and incomplete follow-up of affected individuals.
Infants with profound generalized epimerase deficiency galactosemia who are on a diet containing galactose (commonly as lactose) typically present with hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction (e.g., markedly elevated serum transaminases), aminoaciduria, and cataracts. Prompt removal of galactose from the diet resolves or prevents these acute symptoms [Walter et al 1999, Sarkar et al 2010] (see Management).
Long-term outcome information for persons with generalized epimerase deficiency galactosemia is limited: fewer than ten persons with generalized epimerase deficiency galactosemia have been reported [Walter et al 1999, Sarkar et al 2010]. Some have demonstrated long-term complications that became evident by early childhood, including sensorineural hearing impairment and physical and cognitive developmental delay and/or learning difficulties, while others have not. Of note, a majority of the individuals reported were born to consanguineous parents, raising the concern that homozygosity for other autosomal recessive alleles, independent of GALE, may underlie some if not most of the long-term complications reported.
Neonates with the peripheral or intermediate forms of epimerase deficiency galactosemia are usually asymptomatic even on a regular milk diet; these infants are only identified following biochemical detection of elevated total galactose on newborn screening.
Children with peripheral epimerase deficiency galactosemia appear to remain asymptomatic even if maintained on a normal milk diet.
The long-term outcome of children with intermediate epimerase deficiency galactosemia remains unclear. Long-term outcome information is available for only one affected individual who was not treated with dietary restriction of galactose as an infant; this child experienced delays in both motor and cognitive development that became evident by early childhood [Alano et al 1998, Openo et al 2006]. All other individuals known to have intermediate epimerase deficiency galactosemia have been treated by dietary galactose restriction, at least in infancy, and thus far those who have been followed appear to remain clinically well.
Pathophysiology. As in classic galactosemia, the cataracts associated with epimerase deficiency galactosemia are believed to be caused by galactitol accumulation in the ocular lens; it is possible, but not proven, that other acute findings may be caused by tissue accumulation of gal-1P (galactose-1-phosphate) or other metabolites. Persons with epimerase deficiency galactosemia who are exposed to galactose demonstrate abnormal accumulation of UDP-galactose (UDP-gal). However, because GALE is required in humans for the endogenous biosynthesis of UDP-gal and also UDP-N-acetylgalactosamine (UDP-galNAc), at least part of the pathophysiology of epimerase deficiency galactosemia may result from inadequate production of these compounds, especially in utero, ostensibly leading to deficient production of galactoproteins and galactolipids including cerebrosides.
Genotype-Phenotype Correlations
Because of the small number of affected individuals reported and the fact that most are compound heterozygotes, accurate genotype-phenotype correlations are not yet available.
Nomenclature
Some authors refer to the different forms of galactosemia using the nomenclature: type I, type II, and type III galactosemia in which:
- Type I galactosemia refers to GALT deficiency
- Type II galactosemia refers to GALK deficiency
- Type III galactosemia refers to GALE deficiency (epimerase deficiency galactosemia)
Prevalence
True prevalence figures are unavailable at this time. Generalized profound epimerase deficiency galactosemia is very rare; however, epimerase deficiency galactosemia detected by newborn screening may be as frequent as about 1:6,700 among African American infants and about 1:70,000 among American infants of European ancestry [Alano et al 1997, Fridovich-Keil & Walter 2008].
Differential Diagnosis
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Galactose-1P uridylyltransferase (GALT) deficiency, a disorder of galactose metabolism caused by deficient galactose-1-phosphate uridylyltransferase (GALT) enzyme activity, can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and sepsis in untreated infants. If a lactose/galactose-restricted diet is provided during the first days of life, the neonatal symptoms quickly resolve and the complications of liver failure, sepsis, and neonatal death can be prevented. Despite adequate treatment from an early age, however, children with classic GALT-deficient galactosemia remain at increased risk for developmental and cognitive delays, speech problems (termed "verbal dyspraxia"), and abnormalities of motor function, among other complications. Females with classic galactosemia very often have primary or premature ovarian insufficiency (POI).
The diagnosis of galactosemia is established by measurement of erythrocyte GALT enzyme activity, erythrocyte galactose-1-phosphate (gal-1P) concentration, and molecular genetic testing of GALT, the only gene in which mutations are known to cause classic galactosemia. In classic (G/G) galactosemia, GALT enzyme activity is often less than 1% of control values and erythrocyte gal-1P is >>1 mg/ 100 mL blood following consumption of milk; in Duarte variant (D/G) galactosemia, GALT enzyme activity usually approximates 25% of control values and gal-1P is also >1 mg/ 100 mL blood following consumption of milk. Virtually 100% of affected infants can be detected in states that include testing for galactosemia in their newborn screening programs.
Galactokinase (GALK) deficiency should be considered in individuals who have cataracts, increased plasma concentration of galactose, and increased urinary excretion of galactitol, but are otherwise healthy. These individuals have normal GALT enzyme activity and do NOT accumulate gal-1P. The cataracts are caused by accumulation of galactose in lens fibers and its reduction to galactitol, an impermeant alcohol which results in increased intracellular osmolality and swelling with loss of plasma membrane redox potential and consequent cell death. Detection of reduced GALK enzyme activity in hemolysates is diagnostic. Mutations in GALK1 are causative [Kolosha et al 2000, Hunter et al 2001]. The prevalence of GALK deficiency in most populations is unknown, but is probably less than 1:100,000.
Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to 
, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with epimerase deficiency galactosemia the following evaluations are recommended:
- Measurement of height, weight, and head circumference
- Nutrition and feeding assessments
- Neurologic examination
- Developmental assessment
- Liver function testing
- Ophthalmology consult to check for cataracts
Treatment of Manifestations
The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose-restricted diet. This means switching infants from breast milk or a milk-based formula to a formula with only trace levels of galactose or lactose, such as soy formula. Of note, some infants with classic galactosemia are prescribed elemental formula, which has even lower galactose content than soy formula. Elemental formula should not be prescribed for infants with generalized epimerase deficiency galactosemia because the GALE enzyme is required for the endogenous biosynthesis of UDP-galactose; that is, persons with epimerase deficiency galactosemia may require trace environmental sources of galactose. However, the galactose intake needed for optimum outcome remains unknown.
For older children with generalized epimerase deficiency galactosemia, dietary restriction of galactose involves continued restriction of dairy products. Some, but not all, physicians recommend that their patients with classic galactosemia also abstain from fruits and vegetables that contain more than trace levels of galactose (e.g., tomatoes or legumes); as above, this more rigorous dietary restriction may not be advisable for persons with generalized epimerase deficiency galactosemia.
In generalized epimerase deficiency galactosemia restriction of dietary galactose appears to correct or prevent the acute signs and symptoms of the disorder: hepatic dysfunction, renal dysfunction, and mild cataracts. Presumably, as in classic galactosemia, dietary treatment would not correct profound tissue damage resulting from prolonged galactose exposure, for example, hepatic cirrhosis or mature cataracts. Mature cataracts that do not resolve with dietary restriction of galactose may require surgical removal.
Prevention of Primary Manifestations
In profound generalized epimerase deficiency galactosemia dietary restriction of galactose prevents early feeding problems, vomiting, poor weight gain, hepatic dysfunction, and cataracts, but not the developmental delay or learning impairment reported for some of these children [Walter et al 1999].
At this time the risk, if any, for long-term complications in epimerase deficiency galactosemia detected in asymptomatic newborns is unknown.
- Newborns with documented peripheral epimerase deficiency galactosemia appear to remain asymptomatic regardless of diet and therefore do not seem to require treatment.
- Newborns with documented intermediate epimerase deficiency galactosemia may have an as-yet unknown increased risk of long-term complications including learning impairment and/or cataracts. Continued breastfeeding or exposure to a milk-based formula may therefore be inadvisable for these infants.
The challenge in treating an asymptomatic newborn with epimerase deficiency galactosemia is that it takes months to obtain the result of tests used to distinguish peripheral epimerase deficiency galactosemia from intermediate epimerase deficiency galactosemia; furthermore, such tests are available on a research basis only. The most conservative approach, therefore, is to advise dietary restriction of galactose for all infants with epimerase deficiency galactosemia, relaxing the restriction, as warranted, once a more accurate diagnosis has been confirmed.
Prevention of Secondary Complications
Because GALE enzyme activity is required for the endogenous biosynthesis of UDP-gal and UDP-galNAc, key substrates for the biosynthesis of glycoproteins and glycolipids, persons with epimerase deficiency galactosemia may require trace environmental sources of galactose if endogenous biosynthesis is inadequate. However, the galactose intake needed for optimum outcome remains unknown. Further, the underlying basis of the long-term complications reported for some individuals with generalized epimerase deficiency galactosemia [Walter et al 1999] or with intermediate epimerase deficiency galactosemia [Quimby et al 1997, Alano et al 1998] remains unclear. Therefore, while careful long-term dietary management is recommended, there is no guarantee that long-term complications will be entirely prevented by dietary intervention.
Surveillance
The following are appropriate:
- Monitor hemolysate gal-1P, especially if the diet is to be normalized. Acceptable levels of gal-1P in GALE deficiency are not known but are estimated from experience with classic galactosemia to be <3.5 mg/100 mL in red blood cells.
- Follow growth.
- Monitor developmental milestones; propose supportive intervention as needed.
Agents/Circumstances to Avoid
Persons with generalized epimerase deficiency galactosemia should be on a galactose-restricted diet, certainly as infants and perhaps for life.
Persons with intermediate epimerase deficiency galactosemia may be placed on a galactose-restricted diet, either transiently or long-term. Assessment of hemolysate gal-1P following a galactose challenge (e.g., two weeks on a normal diet) may help delineate whether an individual should remain on a galactose-restricted diet for longer periods of time.
Testing 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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Other
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Mode of Inheritance
Epimerase deficiency galactosemia is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
- Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
- 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 also not a carrier.
- Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
- Heterozygotes (carriers) are asymptomatic.
- Current data [Walter et al 1999] suggest that the subtype of epimerase deficiency galactosemia identified in a given family should “run true,” meaning that if one sib has generalized epimerase deficiency galactosemia, other affected sibs in that family are likely to have generalized epimerase deficiency galactosemia; if one sib has peripheral epimerase deficiency galactosemia, other sibs in that family are likely to have peripheral epimerase deficiency galactosemia.
Offspring of a proband. All of the offspring conceived by an affected individual with an unaffected, non-carrier partner are obligate heterozygotes (carriers) for a disease-causing mutation in GALE.
Other family members. Each full sib of the proband’s parents is at a 50% risk of being a carrier.
Carrier Detection
Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.
Related Genetic Counseling Issues
See Management, Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
- The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.
Prenatal Testing
Molecular genetic testing. If the pathogenic mutations have been identified in the family, prenatal diagnosis for pregnancies at risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at 15 to 18 weeks’ gestation or chorionic villus (CVS) sampling at approximately ten to 12 weeks’ gestation.
Biochemical genetic testing. Prenatal diagnosis of generalized epimerase deficiency galactosemia may be possible by assay of GALE enzyme activity in amniocytes if the separation between the affected and the carrier enzyme activities is sufficient; however, data currently available are insufficient to recommend this approach.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .
Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- Save Babies Through Screening Foundation, Inc.P. O. Box 42197Cincinnati OH 45242Phone: 888-454-3383Email: email@savebabies.org
- Association for Neuro-Metabolic Disorders (ANMD)5223 Brookfield LaneSylvania OH 43560-1809Phone: 419-885-1809; 419-885-1497Email: volk4olks@aol.com
- Children Living with Inherited Metabolic Diseases (CLIMB)Climb Building176 Nantwich RoadCrewe CW2 6BGUnited KingdomPhone: 0800-652-3181 (toll free); 0845-241-2172Fax: 0845-241-2174Email: info.svcs@climb.org.uk
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A. Epimerase Deficiency Galactosemia: Genes and Databases
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| GALE | 1p36 | UDP galactose 4'-epimerase | GALE homepage - Mendelian genes | GALE |
Table B. OMIM Entries for Epimerase Deficiency Galactosemia (View All in OMIM)
Normal allelic variants. GALE is just over 4 kb in length and has 11 coding exons that together encode a protein of 348 amino acids. Multiple alternatively spliced transcripts encoding the same protein have been identified. Transcript NM_000403.3 represents the longest transcript with 1647 nucleotides and 12 exons.
Pathologic allelic variants. For the purposes of this review, variants are considered pathologic if they have been shown to reduce GALE expression, stability, or catalytic function in any cell type or assay system, whether or not they are known to cause clinical signs. Most individuals identified with epimerase deficiency galactosemia are clinically asymptomatic, but do have GALE sequence variants that explain, or may explain, their biochemical findings.
One mutation, c.280G>A (p.Val94Met), has been identified in the homozygous state in persons with the severe, generalized form of epimerase deficiency galactosemia [Wohlers et al 1999]. This mutation leaves approximately 5% residual enzyme activity with regard to UDP-gal metabolism and close to 25% residual enzyme activity with regard to UDP-galNAc metabolism [Wohlers et al 1999, Wohlers & Fridovich-Keil 2000].
Other mutations have been shown to cause moderate to severe reduction in GALE enzyme activity in vitro or in model systems (e.g., c.269G>A [p.Gly90Glu] or c.548T>C [p.Leu183Pro]) [Quimby et al 1997, Wohlers et al 1999, Timson 2005], but to date these alleles have been identified only in persons who are heterozygotes or compound heterozygotes.
The in vivo consequence of homozygosity for apparently severe mutations other than p.Val94Met is unknown. Of note, no individuals reported with GALE enzyme deficiency have been completely null for GALE enzyme activity in non-peripheral cells: both biochemical reasoning [Kalckar 1965] and a fly model for GALE impairment [Sanders et al 2010] suggest that complete loss of GALE enzyme activity may be incompatible with life for humans and other metazoa.
The potential for interaction between two GALE alleles must also be considered. For example, a partial dominant negative effect has been described in a yeast model system for the c.548T>C (p.Leu183Pro) mutation, which demonstrates low GALE enzyme activity, and the c.101A>G (p.Asn34Ser) mutation, which demonstrates slightly reduced GALE enzyme activity when expressed alone [Quimby et al 1997].
GALE variant alleles that are common in specific populations include the following:
- c.505C>T (p.Arg169Trp), c.715C>T (p.Arg239Trp), and c.905G>A (p.Gly302Asp) together account for 67% of alleles reported in a cohort of asymptomatic Koreans with peripheral epimerase deficiency galactosemia [Park et al 2005].
- c.770A>G (p.Lys257Arg) and c.956G>A (p.Gly319Glu) mutations are associated with asymptomatic peripheral epimerase deficiency galactosemia in African Americans [Alano et al 1997, Fridovich-Keil & Walter 2008].
Table 2. Selected GALE Allelic Variants
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|---|
| Peripheral | c.505C>T | p.Arg169Trp | NM_000403 NP_000394 |
| c.715C>T | p.Arg239Trp | ||
| c.770A>G | p.Lys257Arg | ||
| c.905G>A | p.Gly302Asp | ||
| c.956G>A | p.Gly319Glu | ||
| Suspected intermediate | c.101A>G | p.Asn34Ser 1 | |
| c.548T>C | p.Leu183Pro 1 | ||
| Reported or suspected generalized | c.269G>A | p.Gly90Glu | |
| c.280G>A | p.Val94Met |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Observed in trans in an individual with intermediate GALE deficiency. Evidence for a dominant negative effect has been reported.
Normal gene product. The UDP-galactose 4'-epimerase (known in Swiss-Prot as UDP-glucose 4-epimerase) protein encoded by GALE has 348 amino acids.
Abnormal gene product. See Pathologic allelic variants.
References
Medical Genetic Searches A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page 
Literature
- Alano A, Almashanu S, Chinsky JM, Costeas P, Blitzer MG, Wulfsberg EA, Cowan TM. Molecular characterization of a unique patient with epimerase-deficiency galactosaemia. J Inherit Metab Dis. 1998;21(4):341–50. [PubMed: 9700591]
- Alano A, Almashanu S, Maceratesi P, Reichardt J, Panny S, Cowan TM. UDP-galactose-4-epimerase deficiency among African-Americans: evidence for multiple alleles. J Invest Med. 1997;45:191A.
- Fridovich-Keil J, Walter J. In: Valle D, Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 72. Available at www
.ommbid.com. 2008. Accessed 1-20-11. - Gitzelmann R. Deficiency of uridine diphosphate galactose 4-epimerase in blood cells of an apparently healthy infant. Preliminary communication. Helv Paediatr Acta. 1972;27(2):125–30. [PubMed: 4644860]
- Henderson MJ, Holton JB, MacFaul R. Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation. J Inherit Metab Dis. 1983;6(1):17–20. [PubMed: 6408303]
- Holton JB, Gillett MG, MacFaul R, Young R. Galactosaemia: a new severe variant due to uridine diphosphate galactose-4-epimerase deficiency. Arch Dis Child. 1981;56(11):885–7. [PMC free article: PMC1627389] [PubMed: 7305435]
- Hunter M, Angelicheva D, Levy HL, Pueschel SM, Kalaydjieva L. Novel mutations in the GALK1 gene in patients with galactokinase deficiency. Hum Mutat. 2001;17(1):77–8. [PubMed: 11139256]
- Kalckar HM. Galactose metabolism and cell "sociology". Science. 1965;150(3694):305–13. [PubMed: 5319435]
- Kolosha V, Anoia E, de Cespedes C, Gitzelmann R, Shih L, Casco T, Saborio M, Trejos R, Buist N, Tedesco T, Skach W, Mitelmann O, Ledee D, Huang K, Stambolian D. Novel mutations in 13 probands with galactokinase deficiency. Hum Mutat. 2000;15(5):447–53. [PubMed: 10790206]
- Mitchell B, Haigis E, Steinmann B, Gitzelmann R. Reversal of UDP-galactose 4-epimerase deficiency of human leukocytes in culture. Proc Natl Acad Sci U S A. 1975;72(12):5026–30. [PMC free article: PMC388868] [PubMed: 1748]
- Naumova NN, Schappert J, Kaplan LA. Commentary: Reducing Substances in Urine: a Paradigm for Changes in a Standard Test. Annals of Clinical & Laboratory Science. 2006;36(4):447–448. [PubMed: 17127733]
- Openo KK, Schulz JM, Vargas CA, Orton CS, Epstein MP, Schnur RE, Scaglia F, Berry GT, Gottesman GS, Ficicioglu C, Slonim AE, Schroer RJ, Yu C, Rangel VE, Keenan J, Lamance K, Fridovich-Keil JL. Epimerase-deficiency galactosemia is not a binary condition. Am J Hum Genet. 2006;78(1):89–102. [PMC free article: PMC1380226] [PubMed: 16385452]
- Park HD, Park KU, Kim JQ, Shin CH, Yang SW, Lee DH, Song YH, Song J. The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients. Genet Med. 2005;7(9):646–9. [PubMed: 16301867]
- Quimby BB, Alano A, Almashanu S, DeSandro AM, Cowan TM, Fridovich-Keil JL. Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase. Am J Hum Genet. 1997;61(3):590–8. [PMC free article: PMC1715948] [PubMed: 9326324]
- Sanders RD, Sefton JM, Moberg KH, Fridovich-Keil JL. UDP-galactose 4' epimerase (GALE) is essential for development of Drosophila melanogaster. Dis Model Mech. 2010;3:628–38. [PMC free article: PMC2931539] [PubMed: 20519568]
- Sarkar M, Bose SS, Mondal G, Chatterjee S. Generalized Epimerase Deficiency Galactosemia. Indian J Pediatr. 2010 [PubMed: 20725869]
- Timson DJ. Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase. FEBS J. 2005;272(23):6170–7. [PubMed: 16302980]
- Walter JH, Roberts RE, Besley GT, Wraith JE, Cleary MA, Holton JB, MacFaul R. Generalised uridine diphosphate galactose-4-epimerase deficiency. Arch Dis Child. 1999;80(4):374–6. [PMC free article: PMC1717903] [PubMed: 10086948]
- Wohlers TM, Christacos NC, Harreman MT, Fridovich-Keil JL. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia. Am J Hum Genet. 1999;64:462–70. [PMC free article: PMC1377755] [PubMed: 9973283]
- Wohlers TM, Fridovich-Keil JL. Studies of the V94M-substituted human UDPgalactose-4-epimerase enzyme associated with generalized epimerase-deficiency galactosaemia. J Inherit Metab Dis. 2000;23:713–29. [PubMed: 11117433]
Chapter Notes
Acknowledgments
The authors gratefully acknowledge the time and efforts of the many patients, families, health care professionals, and scientists who have brought our knowledge of epimerase deficiency galactosemia to its current state. JLFK also gratefully acknowledges funding from the National Institutes of Health.
Revision History
- 25 January 2011 (me) Review posted live
- 31 August 2010 (jfk) Original submission
GeneReviews™ [Internet].
Pagon RA, Bird TD, Dolan CR, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-.
- Galactosemia[GeneReviews™. 1993]Elsas LJ. GeneReviews™. 1993
- Phosphorylase Kinase Deficiency[GeneReviews™. 1993]Goldstein JAustin S, Kishnani P, Bali D, . GeneReviews™. 1993
- Methylmalonic Acidemia[GeneReviews™. 1993]Manoli IVenditti CP, . GeneReviews™. 1993
- Review Galactosemia: when is it a newborn screening emergency?[Mol Genet Metab. 2012]Berry GT. Mol Genet Metab. 2012 May; 106(1):7-11. Epub 2012 Mar 21.
- Review Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management.[Orphanet J Rare Dis. 2012]Review Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management.Magoulas PLEl-Hattab AW, . Orphanet J Rare Dis. 2012 Sep 18; 7:68. Epub 2012 Sep 18.
- Epimerase Deficiency Galactosemia - GeneReviews™Epimerase Deficiency Galactosemia - GeneReviews™Bookself
Your browsing activity is empty.
Activity recording is turned off.
See more...