Alternative titles; symbols
SNOMEDCT: 8849004; ORPHA: 308473, 308487, 352, 79238; DO: 0111458;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11 | Galactose epimerase deficiency | 230350 | Autosomal recessive | 3 | GALE | 606953 |
A number sign (#) is used with this entry because galactosemia III (GALAC3), or galactose epimerase deficiency, is caused by homozygous or compound heterozygous mutation in the UDP-galactose-4-epimerase gene (GALE; 606953) on chromosome 1p36.
Galactosemia III (GALAC3), or 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 leukocytes, 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.
For a discussion of genetic heterogeneity of galactosemia, see GALAC1 (230400).
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. (1977) 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).
Mitchell et al. (1975) found that phytohemagglutinin stimulation of lymphocytes from patients with GALE deficiency resulted in the appearance of epimerase activity in cultured cells. The authors hypothesized that there may be a degradatory mechanism in vivo which is absent in vitro, that the results may represent production of an isoenzyme, or that transformation of the cells in culture may lead to derepression of a genetic locus.
Mitchell et al. (1975) noted that the stimulation of blood cells with phytohemagglutinin resulted in levels of galactose epimerase activity close to those observed in controls. Furthermore, transformation of the patients' cells to create long-term lymphoblastoid lines also resulted in essentially normal galactose epimerase activity.
Openo et al. (2006) studied 10 patients who, in the neonatal period, received a diagnosis of hemolysate epimerase deficiency. They characterized these patients with regard to 3 parameters: (1) GALE activity in transformed lymphoblasts (considered to represent a 'nonperipheral' tissue), (2) metabolic sensitivity of those lymphoblasts to galactose challenge in culture, and (3) evidence of normal versus abnormal galactose metabolism in the patients themselves. Two important points were demonstrated by the results: first, whereas some of the patients studied exhibited near-normal levels of GALE activity in lymphoblasts, consistent with a diagnosis of peripheral epimerase deficiency, many did not. GALE activity levels ranged from 15 to 64% of control levels, demonstrating that epimerase deficiency is not a binary condition; it is a continuum disorder. Second, lymphoblasts demonstrating the most severe reduction in GALE activity also demonstrated abnormal metabolite levels in the presence of external galactose and, in some cases, also in the absence of galactose. Moreover, some of the patients themselves demonstrated metabolic abnormalities, both on and off galactose-restricted diet. Openo et al. (2006) suggested that long-term follow-up studies of these and other patients will be required to elucidate the clinical significance of these biochemical abnormalities and the potential impact of dietary intervention on outcome.
UDP-galactose-4-epimerase deficiency is an autosomal recessive disorder. The patient described by Holton et al. (1981) was the offspring of Pakistani half first cousins. The patient reported by Sardharwalla et al. (1988) was a child born of first-cousin parents.
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).
Although a galactose-free diet is recommended in galactokinase deficiency (GALAC2; 230200) and in classic galactosemia (GALAC1; 230400), patients with galactose epimerase deficiency cannot utilize the endogenous pathway for synthesis of UDP-galactose, making them dependent on exogenous galactose; thus, a galactose-restricted rather than a galactose-free diet is recommended in the management of this disorder (Walter et al., 1999). The clear dual function of this enzyme suggests that dietary supplements with both galactose and N-acetylgalactosamine should be considered for galactose epimerase-deficient patients (Kingsley et al., 1986).
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).
Glucose-1-phosphate and UDP-galactose are formed by the gal-1-P uridyltransferase reaction deficient in classic galactosemia. The interconversion of UDP-galactose and UDP-glucose is catalyzed by UDP-galactose-4-epimerase. The latter reaction is important to infants, in whom galactose is a significant energy source. Also, since the reaction produces galactose from glucose, galactose is not an essential component of food in man (Holton et al., 2001).
The galactose epimerase enzyme catalyzes 2 distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose as described here, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. (Piller et al., 1983, Kingsley et al., 1986). The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine. Studies of the mutant cells have shown broad defects in synthesis of N-linked, O-linked, and lipid-linked carbohydrate chains when cells are grown only in glucose. For example, the cells are unable to synthesize normal LDL receptors (LDLR; 606945) under these conditions and have an LDL receptor-deficient phenotype. Adding galactose and N-acetylgalactosamine back into the medium restores normal posttranslational processing of LDL receptors and other glycoproteins and restores normal receptor function. Fibroblasts from one of the patients with severe galactose epimerase deficiency were shown also to be deficient in both epimerase activities (Kingsley et al., 1986). However, the enzyme deficiency was not as severe as that seen in the CHO cell mutant, and the cells did not show defects in LDL receptors.
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.
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.
Although Garibaldi et al. (1983) reported a patient with galactosemia due to generalized galactose epimerase deficiency, Garibaldi et al. (1986) found that in fact the defect in this patient was that of classic galactosemia. A blood transfusion may have obscured the basic transferase defect, and an error in determination of epimerase activity may have occurred as well.
Alano, A., Almashanu, S., Chinsky, J. M., Costeas, P., Blitzer, M. G., Wulfsberg, E. A., Cowan, T. M. Molecular characterization of a unique patient with epimerase-deficiency galactosaemia. J. Inherit. Metab. Dis. 21: 341-350, 1998. [PubMed: 9700591] [Full Text: https://doi.org/10.1023/a:1005342306080]
Daude, N., Gallaher, T. K., Zeschnigk, M., Starzinski-Powitz, A., Petry, K. G., Haworth, I. S., Reichardt, J. K. V. Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4-prime-epimerase. Biochem. Molec. Med. 56: 1-7, 1995. [PubMed: 8593531] [Full Text: https://doi.org/10.1006/bmme.1995.1048]
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Kingsley, D. M., Kozarsky, K. F., Hobbie, L., Krieger, M. Reversible defects in O-linked glycosylation and LDL receptor expression in a UDP-Gal/UDP-GalNAc 4-epimerase deficient mutant. Cell 44: 749-759, 1986. [PubMed: 3948246] [Full Text: https://doi.org/10.1016/0092-8674(86)90841-x]
Kingsley, D. M., Krieger, M., Holton, J. B. Structure and function of low-density-lipoprotein receptors in epimerase-deficient galactosemia. (Letter) New Eng. J. Med. 314: 1257-1258, 1993.
Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia. Molec. Genet. Metab. 63: 26-30, 1998. [PubMed: 9538513] [Full Text: https://doi.org/10.1006/mgme.1997.2645]
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Openo, K. K., Schulz, J. M., Vargas, C. A., Orton, C. S., Epstein, M. P., Schnur, R. E., Scaglia, F., Berry, G. T., Gottesman, G. S., Ficicioglu, C., Slonim, A. E., Schroer, R. J., Yu, C., Rangel, V. E., Keenan, J., Lamance, K., Fridovich-Keil, J. L. Epimerase-deficiency galactosemia is not a binary condition. Am. J. Hum. Genet. 78: 89-102, 2006. [PubMed: 16385452] [Full Text: https://doi.org/10.1086/498985]
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Quimby, B. B., Alano, A., Almashanu, S., DeSandro, A. M., Cowan, T. M., Fridovich-Keil, J. L. 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. 61: 590-598, 1997. [PubMed: 9326324] [Full Text: https://doi.org/10.1086/515517]
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Schulpis, K. H., Papaconstantinou, E. D., Koidou, A., Michelakakis, H., Tzamouranis, J., Patsouras, A., Shin, Y. UDP galactose-4-epimerase deficiency in a 5.5-year-old girl with a unilateral cataract. J. Inherit. Metab. Dis. 16: 903-904, 1993. [PubMed: 8295413] [Full Text: https://doi.org/10.1007/BF00714292]
Thoden, J. B., Wohlers, T. M., Fridovich-Keil, J. L., Holden, H. M. Molecular basis for severe epimerase deficiency galactosemia: x-ray structure of the human V94M-substituted UDP-galactose 4-epimerase. J. Biol. Chem. 276: 20617-20623, 2001. [PubMed: 11279193] [Full Text: https://doi.org/10.1074/jbc.M101304200]
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Wohlers, T. M., Christacos, N. C., Harreman, M. T., Fridovich-Keil, J. L. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia. Am. J. Hum. Genet. 64: 462-470, 1999. [PubMed: 9973283] [Full Text: https://doi.org/10.1086/302263]