Epimerase-deficiency galactosemia was originally described as a benign condition in which GALE impairment is restricted to circulating red and white blood cells (Gitzelmann, 1972). Fibroblasts, liver, phytohemagglutinin-stimulated leukocyes, and Epstein Barr virus-transformed lymphoblasts from these patients all demonstrated ... Epimerase-deficiency galactosemia was originally described as a benign condition in which GALE impairment is restricted to circulating red and white blood cells (Gitzelmann, 1972). Fibroblasts, liver, phytohemagglutinin-stimulated leukocyes, and Epstein Barr virus-transformed lymphoblasts from these patients all demonstrated normal or near-normal levels of GALE, leading to the designation 'peripheral' (or 'isolated') epimerase deficiency. A second form of epimerase deficiency became apparent in which a patient, despite normal GALT activity, presented with symptoms reminiscent of classic galactosemia and demonstrated severely impaired GALE activity in both red blood cells and fibroblasts (Holton et al., 1981). This form was designated 'generalized' epimerase deficiency. Openo et al. (2006) demonstrated that epimerase deficiency is in fact not a binary condition but is, rather, a continuum disorder. GALE encodes the third enzyme in the Leloir pathway of galactose metabolism. Galactosemia I is classic galactosemia (230400), caused by deficiency of the second enzyme in the Leloir pathway, galactose-1-phosphate uridylyl-transferase (GALT; 606999). Galactosemia II (230200) is caused by deficiency of the first enzyme in the Leloir pathway, galactokinase (GALK; 604313).
Inherited deficiencies of galactose epimerase are detected by the finding of elevated galactose sugars in newborn screening programs designed to detect classic galactosemia but with normal levels of galactose-1-phosphate uridylyltransferase. Most of the mild cases have deficiency in ... Inherited deficiencies of galactose epimerase are detected by the finding of elevated galactose sugars in newborn screening programs designed to detect classic galactosemia but with normal levels of galactose-1-phosphate uridylyltransferase. Most of the mild cases have deficiency in red cells and uncultured white blood cells with presence of the enzyme in liver and cultured skin fibroblasts (Alano et al., 1998).
Kalckar (1965) predicted some of the consequences of galactose epimerase deficiency. Gitzelmann (1972) reported galactose epimerase deficiency in a healthy infant who had elevated blood galactose on a screening exam. The parents had an intermediate level of enzymatic ... Kalckar (1965) predicted some of the consequences of galactose epimerase deficiency. Gitzelmann (1972) reported galactose epimerase deficiency in a healthy infant who had elevated blood galactose on a screening exam. The parents had an intermediate level of enzymatic activity. The prognosis of the child was uncertain. Mitchell et al. (1975) reported that galactose epimerase deficiency had been identified in the peripheral blood of 7 persons in 3 families, and that no clinical abnormality was identified. Gitzelmann et al. (1976) reported 8 cases in 3 families. The probands were ascertained in newborn screening. Again, all were healthy. Galactose epimerase deficiency was limited to circulating blood cells, whereas epimerase activity in liver, cultured skin fibroblasts, and activated lymphocytes was normal. Heterozygotes had an intermediate level of enzyme. All 8 were of the cddee Rhesus genotype. This may merely reflect the high frequency of Rh-negativity in the population studied. However, linkage should be kept in mind. Gitzelmann and Hansen (1980) reported an Rh-positive case (1 out of 9) of epimerase deficiency, discovered in eastern Switzerland and Liechtenstein. Oyanagi et al. (1981) reported 3 Japanese families. Through newborn screening, Alano et al. (1998) identified a GALE-deficient patient of mixed Pakistani/European ancestry. He was clinically well in the neonatal period on a lactose-containing diet, and biochemical studies, including urine-reducing sugars and galactitol, were consistent with the diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he later showed significant developmental delays in both motor and language skills. Holton et al. (1981) reported a Pakistani baby with a severe form of galactosemia due to epimerase deficiency. The patient presented in the newborn period with clinical symptoms similar to classic galactosemia, including jaundice, vomiting, hypotonia, failure to thrive, hepatomegaly, moderate generalized amino aciduria and marked galactosuria. Henderson et al. (1983) provided further information on the patient at age 19 months. The spleen was then firmly enlarged. In a subsequent pregnancy of the couple, enzyme activity was in the heterozygous range and the newborn was healthy (Gillett et al., 1983). Sardharwalla et al. (1988) reported a case of the severe type in an Asian Muslim child. Despite early recognition and treatment and satisfactory biochemical control, clinical assessment at the age of 2 years and 9 months showed severe mental retardation and profound sensorineural deafness. The 2 patients reported by Holton et al. (1981) and Sardharwalla et al. (1988) were treated with a galactose-limited diet, which was successful in alleviating acute symptoms in both of these patients, but they subsequently experienced motor and intellectual delays. Deficient GALE activity was found not only in red blood cells but also in liver cells and cultured skin fibroblasts, suggesting that the severe clinical presentation is associated with a generalized deficiency of GALE activity. At least some patients with GALE deficiency may be at increased risk for cataracts (115660; Schulpis et al., 1993). Wohlers et al. (1999) stated that only 5 patients with generalized galactose epimerase deficiency had been reported (not including the patient reported by Quimby et al. (1997) and Alano et al. (1998); see 606953.0001).
Wohlers et al. (1999) reported a V94M (606953.0008) missense mutation in both GALE alleles of a patient with the generalized form of galactose epimerase deficiency. The same mutation was found in homozygous state in 2 other patients with ... Wohlers et al. (1999) reported a V94M (606953.0008) missense mutation in both GALE alleles of a patient with the generalized form of galactose epimerase deficiency. The same mutation was found in homozygous state in 2 other patients with the same clinical picture. The specific activity of the mutant protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-actetylgalactosamine. In contrast, 2 GALE-variant proteins associated with peripheral epimerase deficiency, L313M (606953.0006) and D103G (606953.0004), demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E (606953.0003), demonstrated little if any detectable activity, despite near-normal abundance. Thermal lability and protease sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes. Two clinically relevant questions remained unanswered after this study: first, whether epimerase-deficient galactosemia is clinically a binary disorder or a continuum, and second, whether a genotype-phenotype pattern was emerging. - Yeast Studies To enable structural and functional studies of both wildtype and patient-derived alleles of the GALE gene, Quimby et al. (1997) developed and applied a null-background yeast expression system for analysis of the human enzyme. They demonstrated that human wildtype GALE sequences phenotypically complemented a yeast gal10 deletion, and they characterized the wildtype human enzyme isolated from these cells. Furthermore, they expressed and characterized 2 mutant alleles, leu183 to pro (L183P; 606953.0001) and asn34 to ser (N34S; 606953.0002), derived from a patient with no detectable GALE activity in red blood cells but with approximately 14% activity in cultured lymphoblasts. Analyses of crude extracts of yeast expressing the L183P mutant form of human GALE demonstrated 4% wildtype activity and 6% wildtype abundance. Extracts of yeast expressing the other human mutation, N34S, demonstrated approximately 70% wildtype activity and normal abundance. However, yeast coexpressing both mutations exhibited only approximately 7% wildtype levels of activity, thereby confirming the functional impact of both substitutions and suggesting that dominant-negative interaction may exist between the mutant alleles found in this patient.
Southern blot analysis in patients with GALE deficiency showed that the GALE gene was structurally intact, suggesting that the disorder is not due to gross gene deletions or rearrangements (Daude et al., 1995). Daude et al. (1995) hypothesized ... Southern blot analysis in patients with GALE deficiency showed that the GALE gene was structurally intact, suggesting that the disorder is not due to gross gene deletions or rearrangements (Daude et al., 1995). Daude et al. (1995) hypothesized that the difference between the so-called generalized and isolated forms may lie in the nature of the specific point mutations affecting the expression and/or physical properties of the GALE protein. In the patient reported by Alano et al. (1998), mutation analysis of the GALE gene showed compound heterozygous state for the N34S (606953.0002) and L183P (606953.0001) mutations. The same patient was reported by Quimby et al. (1997). Maceratesi et al. (1998) screened for mutations in galactose epimerase-deficient individuals and identified 5 mutations in the GALE gene. The patients were either homozygotes or compound heterozygotes for the mutations.
In Japan, Misumi et al. (1981) found the incidence of complete absence of galactose epimerase activity to be 1 in 23,000. They stated that reports of galactose epimerase deficiency had come only from Switzerland and Japan. However, nearly ... In Japan, Misumi et al. (1981) found the incidence of complete absence of galactose epimerase activity to be 1 in 23,000. They stated that reports of galactose epimerase deficiency had come only from Switzerland and Japan. However, nearly simultaneously, from England Holton et al. (1981) reported a baby with a severe form of galactosemia due to epimerase deficiency. The benign form of GALE deficiency appears to be relatively common among African Americans, with an estimated frequency in the Maryland newborn screening population of 1 in 6,200 as compared to 1 in 64,800 among non-blacks (Alano et al., 1998).
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)....
DiagnosisClinical 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.TestingUrinary 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 HbGALE 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).Molecular Genetic Testing Gene. GALE is the only gene in which mutations are known to be associated with epimerase deficiency galactosemia.Clinical testingSequence analysis: full-gene sequencing for GALE. 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 One recognized GALE mutation plus one sequence variant of unknown significance 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 GalactosemiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGALESequence analysisSequence variants 2Unknown 3ClinicalDeletion/duplication analysis 4Exonic or whole-gene deletionsUnknown 31. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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]. 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.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in GALE.
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....
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.
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. ...
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.
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). ...
Differential DiagnosisGalactose-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).Generalized epimerase deficiency galactosemiaPeripheral epimerase deficiency galactosemia
To establish the extent of disease and needs of an individual diagnosed with epimerase deficiency galactosemia the following evaluations are recommended:...
ManagementEvaluations 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 circumferenceNutrition and feeding assessmentsNeurologic examinationDevelopmental assessmentLiver function testingOphthalmology consult to check for cataractsTreatment of ManifestationsThe 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 ManifestationsIn 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 may not be available. 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 ComplicationsBecause 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.SurveillanceThe 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 AvoidPersons 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.Evaluation of Relatives at RiskMolecular 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 InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGALE1p36.11UDP galactose 4'-epimeraseGALE homepage - Mendelian genesGALEData 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) View in own window 230350GALACTOSE EPIMERASE DEFICIENCY 606953UDP-GALACTOSE-4-EPIMERASE; GALENormal 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 VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesPeripheralc.505C>Tp.Arg169TrpNM_000403.3 NP_000394.2c.715C>Tp.Arg239Trpc.770A>Gp.Lys257Argc.905G>Ap.Gly302Aspc.956G>Ap.Gly319GluSuspected intermediatec.101A>Gp.Asn34Ser 1c.548T>Cp.Leu183Pro 1Reported or suspected generalizedc.269G>Ap.Gly90Gluc.280G>Ap.Val94MetSee 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.