Clinical characteristics.

Epimerase deficiency galactosemia (GALE deficiency galactosemia) is generally considered a continuum comprising several forms:

• Generalized. Enzyme activity is profoundly decreased in all tissues tested.
• Peripheral. Enzyme activity is deficient in red blood cells (RBC) 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); manifestations include 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. Longer-term features that may be seen in those with generalized epimerase deficiency include short stature, developmental delay, sensorineural hearing loss, and skeletal anomalies. 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.

Diagnosis/testing.

The diagnosis of epimerase deficiency galactosemia is established in a proband with impaired GALE activity in RBC or other cells and/or biallelic pathogenic variants in GALE identified on molecular genetic testing. The degree of GALE enzyme activity impairment in RBC does not distinguish between the clinically severe generalized and the milder intermediate or peripheral forms of epimerase deficiency; further enzymatic testing in other cell types such as stimulated leukocytes or EBV-transformed lymphoblasts is required to make that distinction.

Management.

Treatment of manifestations: The common acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-restricted diet. Note: Affected individuals may require trace environmental sources of galactose: infants should be fed a formula (e.g., soy formula) that contains 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. Standard treatment for developmental delay, skeletal anomalies, poor weight gain / failure to thrive, mature cataracts, and sensorineural hearing loss.

Prevention of primary manifestations: In generalized epimerase deficiency galactosemia, restriction of dietary galactose/lactose appears to correct or prevent the common 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 affected individuals. Because of the difficulty in distinguishing peripheral and intermediate forms of epimerase deficiency galactosemia, dietary restriction of galactose/lactose is recommended for all infants with GALE deficiency, relaxing the restriction, as warranted, once a more accurate diagnosis has been confirmed.

Surveillance: Hemolysate gal-1P (galactose-1-phosphate) or urinary galactitol is monitored, especially if the diet is to be normalized. Acceptable levels of RBC gal-1P are not known, but are estimated to be <3.5 mg/100 mL (normal ≤1.0 mg/100 mL) on data from classic galactosemia. Other parameters that warrant monitoring are growth and developmental milestones, vision, and hearing (particularly in those in whom hearing loss has been identified).

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: Each at-risk newborn sib should be treated with dietary restriction of galactose from birth while awaiting results of diagnostic testing for epimerase deficiency galactosemia; either molecular genetic testing (if the pathogenic variants in the family are known) or measurement of GALE enzyme activity in RBC (if the pathogenic variants in the family are not known) can be performed.

Genetic counseling.

Epimerase deficiency galactosemia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GALE pathogenic variant, 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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Suggestive Findings

Epimerase deficiency galactosemia should be suspected in individuals with the following newborn screening results, suggestive clinical features, and supportive laboratory findings while on a normal milk diet.

Newborn screening results

• In states in which the newborn screening program includes measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see Galactosemia):
  • Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
  • GALT enzyme activity is normal.
• In states in which total galactose is only measured if GALT enzyme activity is low, an infant with GALE deficiency will have a normal newborn screening result for galactosemia.

Suggestive clinical features

• Hypotonia
• Poor feeding
• Vomiting
• Weight loss
• Jaundice
• Hepatomegaly
• Liver dysfunction
• Cataracts
• No clinical findings (peripheral and intermediate forms of GALE deficiency)

Supportive laboratory findings in an infant drinking breast milk or a dairy milk formula

• Elevated RBC hemolysate gal-1P concentration (normal: 0-1.0 mg/100 mL RBC):
  • As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
  • >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
• Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL)
• Non-glucose reducing substance in the urine (which represents urinary galactose)
• Elevated urinary galactitol concentrations (normal: <94.7 mmol/mol creatinine for age <1 year, <45.3 mmol/mol creatinine for age 1-6 years, <18.4 mmol/mol creatinine for age >6 years)
• Generalized aminoaciduria
• Normal GALT, GALK, and GALM enzyme activities
• Note: If epimerase deficiency galactosemia is suspected, assessment of enzymatic activity for GALT, GALK, and GALM is not required prior to pursuing either measurement of GALE enzyme activity or molecular genetic testing for GALE (see Establishing the Diagnosis). If Gal-1P is elevated, GALT activity should be tested to rule out classic galactosemia, but GALT testing may be done concurrently with GALE. GALM activity testing may not be clinically available.

Establishing the Diagnosis

A diagnosis of epimerase deficiency galactosemia is established in a proband by ONE OR MORE of the following:

• 0.0-8.0 μmol/hr/g hemoglobin (Hb) GALE enzyme activity in red blood cells (RBC) (normal 17.1-40.1 μmol/hr/g Hb) as determined by the traditional spectrophotometric assay
• <0.5 μmol/hr/g Hb GALE enzyme activity in RBC using liquid chromatography/tandem mass spectrometry (normal 2.3-12.7 μmol/hr/g Hb) [Chen et al 2014]
• Identification of biallelic pathogenic (or likely pathogenic) variants in GALE on molecular genetic testing (See Table 1.)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic GALE variants of uncertain significance (or of one known GALE pathogenic variant and one GALE variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular testing approaches can include single-gene testing or a multigene panel:

• Single-gene testing. Sequence analysis of GALE is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes GALE and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

The clinical severity of epimerase deficiency galactosemia caused by reduced activity of the enzyme GALE [Berry et al 2020] 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 in specific cell types into the following three forms: generalized, peripheral, and intermediate (see Diagnosis) [Openo et al 2006]. Note: In all three forms, GALE enzyme activity is deficient in peripheral circulating red and white blood 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, while infants with peripheral or intermediate epimerase deficiency galactosemia remain clinically well, at least in the neonatal period.

Genotype-Phenotype Correlations

Because the numbers of individuals reported with molecularly confirmed epimerase deficiency galactosemia are currently limited, it is difficult to make strong genotype-phenotype correlations. However, some GALE variants have been associated with mild or severe outcomes in multiple affected individuals.

• Individuals who are homozygous for c.280G>A (p.Val94Met) are likely to have generalized epimerase deficiency galactosemia and have a more severe outcome [Wohlers et al 1999, Dias Costa et al 2017].
• Individuals who have biallelic GALE alleles that are each associated with higher residual GALE activity in non-peripheral cells, such as c.770A>G (p.Lys257Arg) and c.956G>A (p.Gly319Glu), are more likely to have asymptomatic peripheral epimerase deficiency [Alano et al 1997, Openo et al 2006]. However, too few individuals have been described to confirm or refute this prediction.

Nomenclature

Some authors refer to the different forms of galactosemia as type I, type II, type III, and type IV 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);
• Type IV galactosemia refers to GALM deficiency (galactose mutarotase deficiency) [Timson 2019].

Prevalence

True prevalence figures are unavailable at this time. Generalized 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 US infants of European ancestry [Openo et al 2006, Dias Costa et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with epimerase deficiency galactosemia that is not clearly peripheral, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Generalized epimerase deficiency galactosemia. The acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-restricted diet (see Table 4).

Intermediate epimerase deficiency galactosemia. Individuals with intermediate epimerase deficiency galactosemia are typically treated with dietary galactose/lactose restriction, at least in infancy (see Table 4). They may be at an (as-yet unknown) increased risk for 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.

Peripheral epimerase deficiency galactosemia. Individuals with peripheral epimerase deficiency galactosemia do not require any dietary restriction.

Prevention of Primary Manifestations

The challenge in treating an asymptomatic newborn with epimerase deficiency galactosemia is that it may take months to obtain the results of tests used to distinguish peripheral epimerase deficiency galactosemia from intermediate epimerase deficiency galactosemia (see Establishing the Diagnosis, Additional Testing); 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.

In generalized epimerase deficiency galactosemia restriction of dietary galactose/lactose appears to correct or prevent the common 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) or structural defects that likely originated in utero (e.g., cardiomyopathy).

In generalized epimerase deficiency galactosemia dietary restriction of galactose/lactose also prevents early feeding issues, vomiting, poor weight gain, hepatic dysfunction, and cataracts.

Surveillance

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 and/or urinary galactitol 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

If prenatal testing has not been performed (see Genetic Counseling), each at-risk newborn sib should be treated with dietary restriction of galactose from birth until results of diagnostic testing are available. Diagnostic evaluations can include the following:

• Molecular genetic testing if the pathogenic variants in the family are known
• Measurement of GALE enzyme activity in red blood cells if the pathogenic variants in the family are not known

Note: If there are concerns about the reliability of the prenatal testing, soy-based formula may be given while the diagnostic testing is being performed.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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 typically heterozygotes (i.e., carriers of a GALE pathogenic variant).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GALE pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in GALE.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.

Sibs of a proband

• If both parents are known to be heterozygous for a GALE pathogenic variant, 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.
• 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 also likely to have generalized epimerase deficiency galactosemia; if one sib has peripheral epimerase deficiency galactosemia, other sibs in that family are likely to have the same form.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.

Offspring of a proband. Unless an affected individual's reproductive partner also has epimerase deficiency galactosemia or is a carrier, offspring will be heterozygous for a pathogenic variant in GALE but will not be affected unless a second GALE pathogenic variant is acquired by an alternative genetic mechanism (e.g., a de novo pathogenic variant or uniparental isodisomy).

Other family members. Assuming no other family history of galactosemia, each full sib of the proband’s parents is at a 50% risk of being a carrier of the familial GALE pathogenic variant.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the GALE pathogenic variants in the family.

Note: 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.

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 and discussion of the availability of prenatal/preimplantation genetic 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, are carriers, or are at increased risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GALE pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Note: Theoretically, prenatal testing could be accomplished by enzymatic studies of amniocytes or CVS tissue; however, due to lack of a GALE reference range for the relevant sample type and appropriate controls, this testing is not typically offered on a clinical basis.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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). A fourth enzyme, galactose mutarotase (GALM, EC 5.1.3.3), catalyzes the epimerization of β-D-galactose, released from lactose, to α-D-galactose, which is a substrate for GALK. 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.

Leloir pathway

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 or aberrant production of glycoproteins and glycolipids including cerebrosides.

Mechanism of disease causation. Loss of function

No individuals with complete loss of GALE enzyme activity in non-peripheral cells have been reported [Kalckar 1965]. In addition, fruit fly [Sanders et al 2010, Daenzer et al 2012] and C elegans [Brokate-Llanos et al 2014] models for GALE impairment suggest that complete loss of GALE enzyme activity may be lethal.

The c.280G>A (p.Val94Met) pathogenic variant, which is associated with a severe presentation, 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].

Acknowledgments

The authors gratefully acknowledge the time and efforts of the many patients, families, health care professionals, and scientists who have brought our knowledge of epimerase deficiency galactosemia to its current state. JLFK also gratefully acknowledges funding from the National Institutes of Health and the Galactosemia Foundation.

Revision History

• 4 March 2021 (ma) Comprehensive update posted live
• 16 June 2016 (ma) Comprehensive update posted live
• 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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