DiagnosisClinical DiagnosisClassic galactosemia (G/G) presents in the neonatal period with prolonged neonatal jaundice. By five days of age poor suck, failure to thrive, bleeding diathesis, and increasing jaundice occur. If classic galactosemia is not treated, hyperammonemia, sepsis, and shock are likely by six to ten days of age. Cataracts are present in approximately 10% of infants. Most affected infants are detected through newborn screening programs; however, clinicians need to be alert to early signs (poor feeding, prolonged neonatal jaundice) and remove lactose from the diet and initiate soy-based, dietary therapy while awaiting results of newborn screening and/or diagnostic tests. TestingSee Cuthbert et al [2008] for a detailed discussion of test methods and clinical interpretation of test results.Biochemical assays necessary for diagnosis and monitoring of therapy include the following: Erythrocyte galactose-1-phosphate concentration. Metabolism of this precursor is blocked in the GALT reaction sequence. Concentration of erythrocyte galactose-1-phosphate exceeds 2 mg/dL and can be used to monitor the effectiveness of therapy. In classic galactosemia, gal-1-P remains elevated between 2 and 5 mg/dL despite therapy. Galactitol. A product of an alternate pathway for galactose metabolism, galactitol can be measured in the urine. Urinary galactitol greater than 78 mmol/mol creatinine is abnormal. Correlation with other measures may not be perfect. Total body oxidation of 13C galactose to 13CO2. Elimination in breath of less than 5% of ¹³C galactose as ¹³CO₂ two hours after administration of ¹³C-D galactose defines a severe metabolite phenotype [Berry et al 2000]. Such testing is used in Phase II research protocols [Guerrero et al 2000, Webb et al 2003] and may become useful as an early screen for galactosemia before discharge from the nursery [Barbouth et al 2007]. GC/MS isotope dilution method. Experimental measurements of galactitol and galactonate in urine are made by the GC/MS isotope dilution method [Yager et al 2006]. Activity of galactose-1-phosphate uridyltransferase (GALT) enzyme (EC 2.7.712). The GALT enzyme has a bimolecular function. It first converts UDP-glucose to glucose-1-P. The intermediate UMP-GALT is formed and the second reaction binds galactose-1-phosphate (gal-1-P) and releases UDP-galactose (Figure 1). The overall reaction is rate-limiting in producing uryldylated hexoses for post-translational modification of glycoproteins and glycolipids. FigureFigure 1. Galactose metabolism, the Leloir pathway When GALT enzyme activity is deficient, gal-1-P, galactose, and galactitol accumulate. Gal-1-P competes with the UTP-dependent glucose-1-P pyrophosphorylase to reduce UDP-glucose production; thus, both UDP-glu and UDP-gal are reduced, resulting in abnormally glycosylated proteins and glycolipids (Figure 2). Galactose is converted to galactitol in cells and produces osmotic effects such as swelling of lens fibers that may result in cataracts and swelling of neurons that may produce pseudotumor cerebri. FigureFigure 2. Galactose metabolism, GALT deficiency Classic galactosemia Homozygotes for the classic galactosemia (G) allele (i.e., G/G) have GALT enzyme activity less than 5% of control values. Heterozygotes for the classic galactosemia allele and a normal (N) allele (i.e., G/N) have GALT enzyme activity of approximately 50% of control values. Duarte variant galactosemia The Los Angeles (LA) (D₁) (p.Asn314Asp) variant produces no change in GALT enzyme activity in the erythrocyte and has normal promoter activity. The Duarte (D₂) (p.Asn314Asp) allele produces bioinstability to the GALT enzyme complex and has reduced promoter expression [Langley et al 1997, Lai et al 1998, Elsas et al 2001]. Newborns who are G/D heterozygotes may have a positive newborn screen and require further clinical, biochemical, and molecular genetic testing. Note: (1) Both the D₁ and D₂ mutations have the same abnormal amino acid (p.Asn314Asp) in GALT. The Duarte (D₂ ) variant and LA variant (D₁ ) have the same biochemical isoelectric focusing pattern (i.e., they move toward the anode and lower pH) which differs from that of the G/G biochemical phenotype [Elsas et al 1994]. (2) Molecular analysis is needed to differentiate between the Duarte (D₂) and LA (D₁) variants [Elsas et al 2001]. See Molecular Genetic Testing.Newborn screening. Galactosemia can be detected in virtually 100% of affected infants in states that include testing for galactosemia in their newborn screening programs [National Newborn Screening Status Report (pdf)]. Newborn screening utilizes a small amount of blood obtained from a heel prick to assay galactose-1-phosphate uridyltransferase (GALT) enzyme activity and quantify total red blood cell (RBC) gal-1-P concentration and galactose. A second tier of molecular testing for specific GALT mutations should also be available, since this is the most sensitive and specific laboratory test.
Note: The newborn with questionable results on newborn screening should continue to be treated with soy-based formula pending definitive results of confirmatory testing.Newborn Screening under investigation: Total body oxidation of ¹³C-D galactose to ¹³CO₂ in expired air (“the breath test”) remains a research endeavor; however, it may be used in the future before discharge of the neonate from the nursery [Berry et al 2000, Barbouth et al 2007]. Molecular Genetic TestingGene. GALT is the only gene in which mutation is known to be associated with the classic signs of galactosemia. Clinical testing Classic (G/G) galactosemiaTargeted mutation analysis identifies the eight common GALT galactosemia (G) mutations (p.Gln188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, 5kbdel, c.253-2A>G).Laboratories may offer all, a subset, or an expanded panel of these mutations [Elsas & Lai 1998].
Note: The 5kbdel allele is a complex deletion that involves a 3163-nt deletion of the GALT promoter and a 5' gene region along with a 2295-bp deletion of the 3' gene; only segments of exon 8 and intron 8 are retained [Coffee et al 2006]. The 5kbdel complex deletion is detectable by any of a variety of methods that detect deletions (e.g., Southern blot analysis, deletion-specific PCR, quantitative PCR, MLPA). Misdiagnoses are made when typical GALT primers are used [Barbouth et al 2006, Coffee et al 2006].Sequence analysis. Sequence analysis indentifies the common mutations identified by targeted mutation analysis as well sequence variants such as small intragenic deletions/insertions, missense, nonsense, and splice site mutations.Deletion/duplication analysis. Deletion of GALT exons and multi-exons has been detected in affected individuals.Duarte variant (D/G) galactosemiaTargeted mutation analysis. For individuals with Duarte variant (D/G) galactosemia identified by biochemical testing of the individual and both parents, the Duarte allele (p.Asn314Asp) can be identified by targeted mutation analysis.
The Duarte and LA alleles have the same p.Asn314Asp missense mutation:The Duarte variant p.Asn314Asp missense mutation has a GTCA deletion in cis configuration in the promoter region (c.-116_-119delGTCA) that impairs a positive regulatory domain. Identification of the Duarte variant requires detecting both cis sequence abnormalities.The LA variant allele contains the identical p.Asn314Asp missense mutation but does not have the GTCA promoter deletion [Langley et al 1997, Elsas et al 2002]. Sequence analysis and deletion/duplication analysis described above apply for detection of the non-Duarte allele in D/G galactosemia.Table 1. Summary of Molecular Genetic Testing Used in Classic (G/G) GalactosemiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency ^{1, 2Test AvailabilityTwo mutationsOne common/ one private mutationGALTTargeted mutation analysisEight common GALT G mutations 3, 4, 580% 3, 5 10%Clinical Sequence analysisPrivate 6 and common GALT G mutations99% 7Deletion/ duplication analysis 8Partial- or whole-gene deletionsSee footnote 91. The ability of the test method used to detect a mutation that is present in the indicated gene2. In individuals with biochemically confirmed G/G galactosemia 3. Common alleles identified by targeted mutation analysis (p.Gly188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, c.253-2A>G, 5kbdel) 4. The c.253-2A>G allele is common in Hispanics; the 5kbdel allele is common in Ashkenazim.5. Mutations included in targeted mutation panels may vary by laboratory; detection rates will vary accordingly.6. Examples of “private” mutations detected by sequence analysis include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.7. Includes detection of the common mutations identified by targeted mutation analysis3. 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.9. Detection rates may vary among testing laboratories.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandQuantitative measurement of erythrocyte concentration of gal-1-P and erythrocyte GALT enzyme activity establishes the diagnosis of galactosemia. Note: Infants who have a positive newborn screening test or symptoms, or older children with a positive Clinitest® reaction (copper-oxidizing aldehyde) and a negative Glucostix® reaction (glucose oxidase-impregnated strip) warrant measurement of GALT enzyme activity. Molecular genetic testing is used to confirm the diagnosis of galactosemia and to distinguish the Duarte variant allele from the LA variant allele. The Duarte allele and the LA allele have the same p.Asn314Asp missense mutation. They are differentiated by molecular analysis of the GALT promoter region: the true Duarte allele (D₂) has a c.-116_-119GTCAdel in a positive regulatory region on the same allele as p.Asn314Asp. (The LA variant [D₁] does not have this mutation.)
If biochemical testing has confirmed the diagnosis of galactosemia and if neither or only one disease-causing mutation is detected by targeted mutation analysis, sequence analysis followed by deletion/duplication analysis, if necessary, can be used to detect mutations not included in the targeted mutation analysis panel.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes and are not at risk of developing the disorder.Prognosis. Molecular genetic testing defines the genotype and enables prognosis [Guerrero et al 2000, Webb et al 2003]. 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) DisordersNo other phenotypes are associated with GALT mutations.}

Natural HistoryClassic Galactosemia (G/G)Infants with classic galactosemia (G/G) have no GALT enzyme activity and are unable to oxidize galactose to CO₂. Within days of ingesting breast milk or lactose-containing formulas, affected infants develop life-threatening complications including feeding problems, failure to thrive, hypoglycemia, hepatocellular damage,bleeding diathesis, jaundice, and hyperammonemia (see Table 2). If classic galactosemia is not treated, sepsis with Escherichia coli, shock, and death may occur. Infants who survive the neonatal period and who continue to drink milk that contains galactose develop intellectual disability and other cortical and cerebellar tract signs.Table 2. Frequency of Specific Findings in Symptomatic Neonates with Classic GalactosemiaView in own windowFinding Percent Additional Details Hepatocellular damage 89% Jaundice (74%)
Hepatomegaly (43%)
Abnormal liver function tests (10%)
Coagulation disorders (9%)
Ascites (4%) Food intolerance 76% Vomiting (47%)
Diarrhea (12%)
Poor feeding (23%) Failure to thrive 29% Lethargy 16% Seizures 1% Sepsis 10% Escherichia coli (26 cases)
Klebsiella (3)
Enterobacter (2)
Staphylococcus (1)
Beta-streptococcus (1)
Streptococcus faecalis (1) From a survey reporting findings in 270 symptomatic neonates [Waggoner et al 1990] If a lactose-/galactose-restricted diet is provided during the first three to ten days of life, the symptoms resolve quickly and prognosis is good for prevention of liver failure, Escherichia coli sepsis, neonatal death, and intellectual disability. If the diagnosis of galactosemia is not established, the infant who is partially treated with intravenous antibiotics and self-restricted lactose intake demonstrates relapsing and episodic jaundice and bleeding from altered hemostasis concomitant with the introduction of lactose. If treatment is delayed, complications such as intellectual disability and growth retardation are likely. Even with early and adequate therapy, the long-term outcome in older children and adults with classic (G/G) galactosemia can include cataracts, speech defects, poor growth, poor intellectual function, neurologic deficits (predominantly extrapyramidal findings with ataxia), and premature ovarian insufficiency (POI) [Schweitzer-Krantz 2003]. Outcome and the "disease burden" can be predicted based on the level of GALT enzyme activity, GALT genotype, age at which successful therapeutic control was achieved, and compliance with lactose restrictions. Formal outcome analysis for POI and for verbal dyspraxia found the ¹³CO₂ breath test to be the most sensitive and specific prognostic parameter [Guerrero et al 2000, Webb et al 2003, Barbouth et al 2006]. The following details on long-term outcome were reported by Waggoner et al [1990] as the result of a retrospective, cross-sectional survey of 270 individuals with classic galactosemia. Intellectual development. Of 177 individuals who were at least age six years and had no obvious medical causes for developmental delay other than galactosemia, 45% were described as developmentally delayed. The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age. Studies of Dutch individuals at various ages using a quality of life questionnaire indicated subnormal cognitive outcomes [Bosch et al 2004b]. Speech problems were reported in 56% (136/243) of individuals age three years or older. More than 90% of the individuals with speech problems were described as having delayed vocabulary and articulation problems, also called "verbal dyspraxia." The speech problem resolved in only 24%. A recent, more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis of developmental verbal dyspraxia [Robertson & Singh 2000, Webb et al 2003]. The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech; however, some individuals with speech problems tested in the average range. Motor function. Among individuals older than age five years, 18% had fine-motor tremors and problems with coordination, gait, and balance. Severe ataxia was observed in two teenagers. Gonadal function. Of 47 girls and women, 81% had signs of premature ovarian insufficiency (POI). POI may be manifest as cutaneous rashes in estrogen-depleted children. The mean age at menarche was 14 years with a range from ten to 18 years. Eight out of 34 women over age 17 years (including two with "streak gonads") had primary amenorrhea. Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche. Only five out of 17 women over age 22 years had normal menstruation. Two, who gave birth at age 18 and 26 years, had never experienced normal menstrual periods. Guerrero et al [2000] determined that the development of POI in females with galactosemia is more likely if the following are true: The individual is homozygous for p.Gln188Arg,The mean erythrocyte gal-1-P concentration is greater than 3.5 mg/dL during therapy, andThe recovery of ¹³CO₂ from whole-body ¹³C galactose oxidation is reduced below 5% of administered ¹³C galactose. Normal serum concentrations of testosterone and/or follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were reported for males. Growth. In many individuals, growth was severely delayed during childhood and early adolescence; when puberty was delayed and growth continued through the late teens, final adult heights were within the normal range. Decreased height over mean parental height was related to decreased IGF-I [Panis et al 2007]. Cataracts were reported in 30% of 314 individuals. Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically. Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth. Relationship between treatment and outcome. No significant associations were found except for a greater incidence of developmental delay among individuals who were not treated until after age two months. However, IQ scores were not highly correlated with the age at which treatment began. The effect of early treatment on outcome was also studied in 27 sibships, three of which had three affected sibs. The older sibs were diagnosed and treated after clinical symptoms occurred or newborn screening results had been reported, whereas the younger sibs were treated within two days of birth. Although the younger sibs were treated early and only one developed neonatal symptoms, the differences in IQ scores among the sibs were not statistically significant, and the speech and ovarian function of the younger sibs were no better than those of their older sibs. Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy. No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for their age. Individuals with/without neurologic complications. No differences were observed in treatment or biochemical factors between the 56 individuals who had normal intellect, speech, and motor function and the 25 individuals who were developmentally delayed and had speech and motor problems. Relationships of complications. Developmental delay and low IQ scores were associated with speech problems, motor problems, and delayed growth, but not with abnormal ovarian function. Gender differences. Females had lower mean IQ scores after age ten years (p <0.05) and had lower mean heights for age at five to 12 years (p <0.05), but did not differ in frequency of speech or motor problems or in the treatment variables, including age treatment began, neonatal illness, or gal-1-P erythrocyte concentration. However, the association of problems with intellectual development, speech, and motor function could also indicate a specific neurologic abnormality in some cases of galactosemia. Variant GalactosemiaIndividuals with variant forms of galactosemia have some aspects of classic galactosemia, including early cataracts, mild intellectual disability with ataxia, and growth retardation. In addition they may have dyspraxic speech, and females may have amenorrhea or early menopause.

Differential DiagnosisInfectious diseases, obstructive biliary disease including Alagille syndrome, progressive familial intrahepatic cholestasis (Byler disease) and citrin deficiency and other metabolic diseases including Neimann-Pick Disease, Type C and Wilson disease are in the differential diagnosis for neonatal hepatotoxicity.Establishing the diagnosis of sepsis does not exclude the possibility of galactosemia, as sepsis, particularly E. coli sepsis, occurs commonly in infants with galactosemia. 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-1-P. The cataracts are caused by accumulation of galactose in lens fibers and its reduction to galactitol, an impermeant alcohol. This results in increased intracellular osmolality and swelling with loss of plasma membrane redox potential and consequent cell death. Detection of reduced GALK enzyme activity is diagnostic. Mutations in GALK1 are causative [Kolosha et al 2000, Hunter et al 2001]. The prevalence of GALK deficiency is unknown, but is probably less than 1:100,000. UDP-galactose 4-epimerase (GALE) deficiency should be considered in individuals who have liver disease, sensorineural deafness, failure to thrive, and elevated RBC galactose-1-phosphate (gal-1-P) but normal GALT enzyme activity. Increased RBC gal-1-P and normal GALT enzyme activity in healthy newborns is also associated with GALE deficiency. Detection of reduced GALE enzyme activity is diagnostic. Mutations in GALE are causative. GALE deficiency has an estimated prevalence of 1:23,000 in Japan and an unknown prevalence in other populations.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with galactosemia, measurement of RBC gal-1-P concentration and urinary galactitol is recommended as a baseline in monitoring the effect of treatment (see Surveillance).Treatment of ManifestationsLactose restriction reverses liver disease in newborns who already have hepatocellular disease. Infertility. Because FSH as a glycoprotein may be abnormal, stimulation with FSH may be useful in producing ovulation in some women. One female with premature ovarian insufficiency (POI) conceived following FSH therapy, and subsequently delivered a normal child [Menezo et al 2004]. Others have found that POI in classic galactosemia may be caused by reduced number or maturation of ovarian follicles and is potentially treatable by exogenous pharmacologic stimulation by gonadotropic hormones [Rubio-Gozalbo et al 2010]. Prevention of Primary ManifestationsClassic GalactosemiaDietary intervention. Immediate dietary intervention is indicated in infants whose GALT enzyme activity is less than 10% of control activity and whose RBC galactose-1-phosphate is greater than 10 mg/dL. Because 90% of the newborn’s carbohydrate source is lactose and human milk contains 6%-8% lactose, cows' milk 3%-4% lactose, and most proprietary infant formulas 7% lactose, all of these milk products must be replaced immediately by a formula that is free of bioavailable lactose (e.g., Isomil^® or Prosobee^®). Such soy formulas contain sucrose, fructose, and non-galactose polycarbohydrates. Continued treatment with soy-based formula depends on the response of elevated erythrocyte gal-1-P: concentrations lower than 5 mg/dL are considered within the therapeutic range. Some have advocated for the use of elemental formulas that contain small amounts of bioavailable galactose. Since endogenous galactose production is measured in grams per day, the elimination of a few milligrams may not be advantageous [Zlatunich & Packman 2005]. Monitoring the decline of erythrocyte gal-1-P production would be an appropriate parameter of therapy.Dietary restrictions on all lactose-containing foods (dairy products, tomato sauces, and candies) and medicines (tablets, capsules, sweetened elixirs that contain lactulose) should continue throughout life; however, managing the diet becomes less important after infancy and early childhood, when milk and dairy products are no longer the primary source of energy. It is debated how stringent the diet should be after the first year of life [Berry et al 2004, Bosch et al 2004a, Schadewaldt et al 2004], as endogenous galactose production is an order of magnitude higher than that ingested from foods other than milk. Despite exogenous galactose restriction the endogenous production of galactose results in a continual increase in cellular gal-1-P that is greater than normal (e.g., 2-5 mg/dL compared to <1 mg/dL). The following criteria have been used to assess dietary compliance: Strict compliance: careful avoidance of all lactose-containing foods Fair compliance: avoidance of all milk products Poor compliance: ingestion of some milk products Parents should be educated about the lifelong need for some dietary restriction. Variant GalactosemiaAgreement has not been reached on whether individuals with variant forms of galactosemia with residual GALT enzyme activity in the range of 5%-20% of control activity should be restricted from galactose intake during infancy and early childhood. Continued gal-1-P accumulation may cause sequelae such as cataracts, ataxia, dyspraxic speech, cognitive deficits, and POI. Prevention of Secondary ComplicationsCalcium supplements are indicated in the neonatal period (750 mg/day) and in childhood (>1200 mg/day) [Elsas & Acosta 1998, Elsas & Acosta 2012]. Because bone mineral content may be diminished in children with galactosemia, supplements of vitamin D to more than 1000 IU/day and vitamin K have also been advocated [Panis et al 2006b]. SurveillanceAffected individuals should be monitored routinely for the accumulation of toxic analytes such as RBC gal-1-P (levels <5 mg/dL are considered within the therapeutic range) and urinary galactitol. If sudden increases are detected, dietary sources of excess galactose should be sought or evaluation undertaken for other causes, including infection. Ophthalmologic examination, developmental evaluation, and focus on speech development with appropriate interventions are recommended. Agents/Circumstances to AvoidLactose-containing drug preparations should be avoided. Casein hydrolysates (Alimentum^®, Nutramigen^®, Pregestimil^®) are not recommended for dietary treatment because they contain small amounts of bioavailable lactose. Medications with lactulose should not be used to treat hyperammonemia associated with liver disease, as lactulose contains free lactose [Elsas & Acosta 2006]. Evaluation of Relatives at RiskPrenatal testing is advised for at-risk sibs so that the parents can be prepared for treatment of the newborn [Elsas 2001]. If prenatal testing is not performed, each at-risk newborn should be screened for galactosemia using the GALT enzyme activity of erythrocytes as well as molecular genetic testing of buffy coat DNA immediately after delivery. Note: Treatment with soy formula should be implemented while diagnostic tests are underway. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationResearch suggests that despite exogenous galactose restriction, endogenous galactose production may approach 2.0 g/day [Berry et al 2004, Schadewaldt et al 2004]. If this is true, "self-intoxication" with galactose may be more of a problem than restriction of galactose from exogenous sources in the management of older children and adults who no longer depend on milk as their primary source of energy. Approaches to lowering endogenous production of gal-1-P are under investigation using small inhibitors of the GALK enzyme [Tang et al 2010]. Although in vitro studies of GALT enzyme-deficient human fibroblasts demonstrated proof of concept, a GALT enzyme-deficient mouse model is needed that expresses an ARHI signal. Note that GALT knockout mice do not express the human phenotype of galactosemia and have lost ARHI (DIRAS3) during evolution [Lai et al 2008, Rubio-Gozalbo et al 2010, Tang et al 2010].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherSome have considered ovarian biopsy with egg preservation for future use if serum concentrations of FSH and LH rise, indicating premature ovarian insufficiency. The efficacy of restricting lactose in the diets of pregnant women who are at risk of having a child with galactosemia is unknown but probably not significant. Uridine supplements have not been of value.

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. Galactosemia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGALT9p13​.3Galactose-1-phosphate uridylyltransferaseARUP Laboratories GALT Mutation Database
GALT homepage - Mendelian genesGALTData 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 Galactosemia (View All in OMIM) View in own window 230400GALACTOSEMIA 606999GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE; GALTNormal allelic variants. The gene is approximately 4 kb in length and has 11 exons and ten introns. The promoter is GC rich as in a "housekeeping gene." There is high sequence homology with E. coli, yeast, rodent, and human [Flach et al 1990, Leslie et al 1992]. Pathologic allelic variants. More than 180 mutations in the 4.2-kb gene and its 1.1-kb cDNA are known [Elsas & Lai 1998, Tyfield et al 1999, Bosch et al 2005, Calderon et al 2007]. Disease-causing mutations that are most prevalent in the United States are shown in Table 3. The frequency of the five most common GALT mutations in diverse ethnic groups was reported by Suzuki et al [2001]. A 5-kb deletion of GALT is common in persons of Ashkenazi Jewish background [Coffee et al 2006].Table 3. Prevalence of Mutant Alleles in 284 (568 alleles) Individuals from the US with G/G GalactosemiaView in own windowMutationNumber of AllelesPercent of Totalp.Gln188Arg28049%p.Ser135Leu407%p.Lys285Asn204%p.Leu195Pro112%p.Tyr209Cys51%5-kb deletion71%p.Asn314Asp14125%Other6411%TOTAL568100%1. Adapted from Elsas & Lai [1998]Table 4. Selected GALT Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change Reference Sequencesc.-116_-119delGTCA--NM_000155​.2
NP_000146​.2c.404C>Tp.Ser135Leuc.512T>Cp.Phe171Serc.563A>Gp.Gln188Argc.584T>Cp.Leu195Proc.607G>Ap.Glu203Lysc.626A>Gp.Tyr209Cysc.652C>T
(1721C>T)p.= ^{2c.855G>Tp.Lys285Asnc.940A>Gp.Asn314Aspc.997CC>Gp.Arg333Glyc.253-2A>G
(IVS2-2A>G) 3--(Δ5kb) or (5kbdel) 4,5--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. p.= designates that protein has not been analyzed, but no change is expected3. Seen in persons of Hispanic heritage4. A complex deletion that involves a 3163-bp deletion of the GALT promoter and a 5' gene region along with a 2295-bp deletion at the 3' end of the gene; only segments of exon 8 and intron 8 are retained [Barbouth et al 2006, Coffee et al 2006]. Standard HGVS nomenclature of this deletion mutation is equally complex and may be best described as c.[-1039_753del; 820+50_*789delinsGAATAGACCCCA.]5. Seen in persons of Ashkenazic Jewish ethnicityNormal gene product. The GALT protein functions as a dimer and demonstrates unique bimolecular ping pong kinetics. The GALT enzyme first binds UDP-glucose, then releases glucose-1-phosphate. A stable GALT-UMP complex is required for the second displacement reaction, which involves binding of galactose-1-phosphate with release of UDP-galactose and the free GALT enzyme. Abnormal gene productThe mutation p.Gln188Arg prevents formation of a stable GALT-UMP intermediate [Lai et al 1999]. The p.Asn314Asp mutation destabilizes the dimer while a second G-allele, p.Glu203Lys, acts as a revertant when in cis configuration with p.Asn314Asp and stabilizes the protein. The LA variant (D₁) involves increased rates of translation caused at least in part by a nucleotide change in the codon for leucine at residue 218 from common to rare (c.652C>T), thereby obviating the bioinstability produced by the p.Asn314Asp mutation. A combination of "codon preference" and increased gene expression resulting from a GALT promoter polymorphism accounts for increased activity in the LA variant [Langley et al 1997]. This variant in codon 218 is known as p.Leu218Leu (c.652C>T). The true Duarte or D₂ variant is a deletion in the E-box, a carbohydrate response element that reduces GALT gene expression [Elsas et al 2001].}