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Epimerase Deficiency Galactosemia

Synonyms: GALE Deficiency, Galactose Epimerase Deficiency, Galactosemia Type III, UDP-Galactose-4'-Epimerase Deficiency

, PhD, , PhD, , PhD, and , MD.

Author Information
, PhD
Department of Human Genetics
Emory University School of Medicine
Atlanta, Georgia
, PhD
Division of Medical Genetics
Department of Human Genetics
Emory University School of Medicine
Atlanta, Georgia
, PhD
Department of Pathology and Laboratory Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
, MD
Greenwood Genetic Center
Greenwood, South Carolina

Initial Posting: ; Last Update: October 24, 2013.

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 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.

Diagnosis/testing. 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.

Management. 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.

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

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). As illustrated in Figure 1, GALE catalyzes an essential step in this pathway converting UDP-galactose to UDP-glucose. GALE is a reversible enzyme that also catalyzes the synthesis of UDP-galactose from UDP-glucose when other sources of UDP-galactose are limiting. Functioning outside of the Leloir pathway, GALE also interconverts UDP-N-acetyl galactosamine and UDP-N-acetylglucosamine. All four of these UDP-sugars are essential substrates for the biosynthesis of glycoproteins and glycolipids in humans.

Figure 1

Figure

Figure 1. Leloir pathway

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 apparent enzyme activity level 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 blood cells and circulating white blood cells, but normal or near normal in all other tissues tested.
  • Intermediate epimerase deficiency galactosemia. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested.

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 or 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

In states in which the newborn screening program includes galactosemia screening based on the measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see Galactosemia), epimerase deficiency galactosemia (GALE deficiency galactosemia) may be detected in infants who have consumed sufficient lactose. Such infants will have elevation of total galactose (sum of galactose and galactose-1-phosphate) in dried blood spot from newborns (e.g., >10 mg/dL; cut-off varies by state) but normal GALT enzyme activity. However, in states in which total galactose is only measured if GALT enzyme activity is low, these infants will not trigger a positive galactosemia screen. Infants with a positive screen should undergo confirmatory testing (see 2. below).

Patients who have clinical signs and symptoms of galactosemia generally first undergo confirmatory testing for GALT enzyme deficiency because of its greater prevalence. In these patients, if GALT enzyme activity is normal despite elevation of galactose or galactose-1-phosphate, confirmatory testing for epimerase deficiency galactosemia should also be performed.

Confirmatory testing for epimerase deficiency galactosemia is predicated upon the following:

1.

Measure GALE enzyme activity in red blood cells (RBCs) either directly or indirectly by spectrometry method or recently by LC-MS/MS method. GALE enzyme activity is usually reported as micromoles (μmol) UDP-glucose production per hour per mg of hemoglobin.

Typical ranges for GALE enzyme activity measured in RBC lysates:

  • Normal. 17.1-40.1 μmol/hr/g hemoglobin (Hb)
  • Affected. 0.0-8.0 μmol/hr/g Hb
2.

If GALE enzyme activity is decreased, perform molecular genetic testing to identify potentially causative GALE sequence variants (see Table 1) [Liu et al 2013].

a.

First perform sequence analysis.

b.

If two GALE sequence variants are not identified, deletion/duplication analysis may be warranted.

Table 1. Summary of Molecular Genetic Testing Used in Epimerase Deficiency Galactosemia

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
GALESequence analysisSequence variants 4Unknown 5
Deletion / duplication analysis 6Exonic or whole-gene deletions/duplicationsUnknown, none reported 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. While whole-gene sequencing has revealed ostensibly causal GALE variants in most persons with biochemically confirmed GALE deficiency who have been studied (e.g., Park et al [2005], Openo et al [2006], reviewed in Fridovich-Keil & Walter [2008]), the small number of alleles studied and the biochemical complexity of the diagnosis prevent accurate estimates of mutation detection frequency at this time.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. No deletions or duplications involving GALE have been reported to cause epimerase deficiency galactosemia.

Additional Testing Options

So far all the established clinically available tests measure RBC GALE activity only and, therefore, cannot accurately distinguish between the generalized, intermediate, and peripheral forms of epimerase deficiency galactosemia (see Genotype-Phenotype Correlations). GALE enzyme activity can be measured in lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms of epimerase deficiency galactose.

In patients with epimerase deficiency galactosemia, elevation of RBC hemolysate gal-1P concentration is expected, and can further support the diagnosis; however, it is not by itself confirmatory. 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.
  • Hemolysate gal-1P levels in patients with generalized epimerase deficiency can be as higher than 170 mg/100 mL packed RBC [Walter et al 1999].
  • Hemolysate gal-1P levels in patients with intermediate or peripheral epimerase deficiency can be higher than 30 mg/100 mL packed RBC [Openo et al 2006].

Urinary excretion of galactose or galactitol. Measurement of hemolysate gal-1P is more sensitive than measurement of urinary galactose or galactitol and, therefore, is often used for confirmatory testing and follow up. However, if needed urinary galactose or galactitol can be measured. Galactosuria is most pronounced in infants with severe epimerase deficiency galactosemia who have consumed substantial quantities of galactose/lactose. 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], but this is not a specific test.

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/lactose typically present with symptoms reminiscent of classic galactosemia: hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction (e.g., markedly elevated serum transaminases), aminoaciduria, and cataracts. Prompt removal of galactose/lactose 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. Those few patients with generalized epimerase deficiency who have been followed long-term demonstrate apparently normal puberty with no apparent evidence of premature ovarian insufficiency [Walter et al 1999].

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/lactose 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/lactose 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 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].

Nomenclature

Some authors refer to the different forms of galactosemia as 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

Galactose-1P uridylyltransferase (GALT) deficiency, a disorder of galactose metabolism caused by deficient GALT activity, can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and sepsis in untreated infants. If a galactose/lactose-restricted diet is provided during the first days of life, the neonatal symptoms are prevented or quickly resolve and the acute 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) [Spencer et al 2013].

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 galactosemia, GALT enzyme activity is often less than 1%-5% of control values and erythrocyte gal-1P is >>1 mg/100 mL blood following consumption of milk. Virtually 100% of infants with classic galactosemia should be detected in states that include testing for galactosemia in their newborn screening programs.
  • In Duarte variant galactosemia, GALT enzyme activity usually approximates 25% of control values and gal-1P is also >1 mg/ 100 mL blood following consumption of milk. Duarte variant galactosemia may or may not be detected by newborn screening, depending on the GALT cut-off used.

Galactokinase (GALK) deficiency should be considered in otherwise healthy individuals with cataracts, increased plasma concentration of galactose, and increased urinary excretion of galactitol. These individuals have normal GALT enzyme activity and do NOT accumulate gal-1P. The cataracts are caused by accumulation of the galactose metabolite, galactitol, in the lens. Galactitol is 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 Image SimulConsult.jpg, 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
  • Medical genetics consultation

Treatment of Manifestations

The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-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/lactose involves continued restriction of dairy products.

Note: Some, but not all, physicians recommend that their patients with classic galactosemia also abstain from those fruits and vegetables that contain more than trace levels of galactose/lactose (e.g., tomatoes or legumes); as above, this more rigorous dietary restriction may not be advisable for persons with generalized epimerase deficiency galactosemia. Furthermore, many nutritionists are also beginning to allow more fruits and vegetables in the diets of older children and adults with classic galactosemia.

In 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. Presumably, as in classic galactosemia, dietary treatment would not correct profound tissue damage resulting from prolonged galactose exposure (e.g., hepatic cirrhosis or mature cataracts). Mature cataracts that do not resolve with dietary restriction of galactose/lactose may require surgical removal.

Prevention of Primary Manifestations

In profound generalized epimerase deficiency galactosemia dietary restriction of galactose/lactose prevents early feeding problems, vomiting, poor weight gain, hepatic dysfunction, and cataracts, but not the developmental delay or learning difficulties reported for some of these children who may also have had other genetic risk factors beyond impairment of epimerase [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 containing high levels of galactose/lactose may therefore be inadvisable for these infants; however, insufficient data exist to make firm recommendations.

The challenge in treating an asymptomatic newborn with epimerase deficiency galactosemia is that it takes months to obtain the results of tests used to distinguish peripheral epimerase deficiency galactosemia from intermediate epimerase deficiency galactosemia; furthermore, such tests may not be available. The most conservative approach, therefore, is to advise dietary restriction of galactose/lactose 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/lactose-restricted diet, certainly as infants and perhaps for life.

Persons with intermediate epimerase deficiency galactosemia may be placed on a galactose/lactose-restricted diet, either transiently or long-term. Assessment of hemolysate gal-1P following a galactose challenge (e.g., 2 weeks on a normal diet) may help determine if an individual should remain on a galactose/lactose-restricted diet for longer periods of time.

Evaluation of Relatives at Risk

Molecular genetic testing (if the family-specific causal 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.

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. —ED.

Mode of Inheritance

Epimerase deficiency galactosemia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele) unless they are also affected (homozygotes).
  • Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.

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.
  • Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
  • 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 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 symptoms of generalized epimerase deficiency galactosemia.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating 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 increased 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.

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 ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 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 an option for some families in which the disease-causing mutations have been identified.

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 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: 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 SymbolChromosomal LocusProtein NameLocus SpecificHGMD
GALE1p36​.11UDP galactose 4'-epimeraseGALE databaseGALE

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Epimerase Deficiency Galactosemia (View All in OMIM)

230350GALACTOSE EPIMERASE DEFICIENCY
606953UDP-GALACTOSE-4-EPIMERASE; GALE

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 pathogenic 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, Daenzer et al 2012)] 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:

  • The c.505C>T (p.Arg169Trp), c.715C>T (p.Arg239Trp), and c.905G>A (p.Gly302Asp) mutations together account for 67% of alleles reported in a cohort of asymptomatic Koreans with peripheral epimerase deficiency galactosemia [Park et al 2005].
  • The 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 AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Peripheralc.505C>Tp.Arg169TrpNM_000403​.3
NP_000394​.2
c.715C>Tp.Arg239Trp
c.770A>Gp.Lys257Arg
c.905G>Ap.Gly302Asp
c.956G>Ap.Gly319Glu
Suspected intermediatec.101A>Gp.Asn34Ser 1
Reported or suspected generalizedc.269G>Ap.Gly90Glu
c.280G>Ap.Val94Met
c.548T>Cp.Leu183Pro 1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Observed in trans in an individual with intermediate GALE deficiency; however, expression studies in a yeast model system demonstrated that p.Leu183Pro causes profound loss of GALE activity. The individual in whom this allele was identified may have had intermediate GALE deficiency because the other allele was mild (p.Asn34Ser). Evidence for a potential dominant negative effect between p.Asn34Ser and p.Leu183Pro has also 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

Literature Cited

  1. 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;21:341–50. [PubMed: 9700591]
  2. 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.
  3. Daenzer JM, Sanders RD, Hang D, Fridovich-Keil JL. UDP-galactose 4'-epimerase activities toward UDP-Gal and UDP-GalNAc play different roles in the development of Drosophila melanogaster. PLoS Genet. 2012;8:e1002721. [PMC free article: PMC3359975] [PubMed: 22654673]
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  7. 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;56:885–7. [PMC free article: PMC1627389] [PubMed: 7305435]
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  9. Kalckar HM. Galactose metabolism and cell "sociology". Science. 1965;150:305–13. [PubMed: 5319435]
  10. 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;15:447–53. [PubMed: 10790206]
  11. Liu Y, Bentler K, Coffee B, Chhay JS, Sarafoglou K, Fridovich-Keil JL. A case study of monozygotic twins apparently homozygous for a novel variant of UDP-galactose 4'-epimerase (GALE): a complex case of variant GALE. JIMD Rep. 2013;7:89–98. [PMC free article: PMC3575048] [PubMed: 23430501]
  12. 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;72:5026–30. [PMC free article: PMC388868] [PubMed: 1748]
  13. Naumova NN, Schappert J, Kaplan LA. Commentary: reducing substances in urine: a paradigm for changes in a standard test. Ann Clin Lab Sci. 2006;36:447–8. [PubMed: 17127733]
  14. 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;78:89–102. [PMC free article: PMC1380226] [PubMed: 16385452]
  15. 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;7:646–9. [PubMed: 16301867]
  16. 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;61:590–8. [PMC free article: PMC1715948] [PubMed: 9326324]
  17. 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]
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  19. Spencer JB, Badik JR, Ryan EL, Gleason TJ, Broadaway KA, Epstein MP, Fridovich-Keil JL. Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab. 2013;98:e1257–65. [PMC free article: PMC3701263] [PubMed: 23690308]
  20. Timson DJ. Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase. FEBS J. 2005;272:6170–7. [PubMed: 16302980]
  21. 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;80:374–6. [PMC free article: PMC1717903] [PubMed: 10086948]
  22. 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]
  23. 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 prior funding from the National Institutes of Health.

Revision History

  • 24 October 2013 (me) Comprehensive update posted live
  • 25 January 2011 (me) Review posted live
  • 31 August 2010 (jfk) Original submission
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