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Galactosemia

[Classic Galactosemia, GALT Deficiency, Galactose-1-Phosphate Uridyltransferase Deficiency. Includes: Variant Galactosemias]

Summary

Disease characteristics.  Galactosemia is a disorder of galactose metabolism that 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 ten days of life, the neonatal symptoms quickly resolve and the complications of liver failure, sepsis, neonatal death, and mental retardation can be prevented. Despite adequate treatment from an early age, children with galactosemia remain at increased risk for developmental delays, speech problems (termed "verbal dyspraxia"), and abnormalities of motor function. A female with galactosemia is at increased risk for premature ovarian failure.

Diagnosis/testing.   The diagnosis of galactosemia is established by measurement of erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity and isoelectric focusing of GALT. In classic (G/G) galactosemia, GALT enzyme activity is less than 5% of control values; in Duarte variant (D/G) galactosemia, GALT enzyme activity is between 5% and 20% of control values. Molecular genetic testing of GALT, the gene encoding galactose-1-phosphate uridyltransferase, is clinically available for individuals with biochemically confirmed galactosemia. Virtually 100% of affected infants can be detected in states that include testing for galactosemia in their newborn screening programs.

Management.  Prevention of primary manifestations: immediate dietary intervention in infants with GALT enzyme activity that is less than 10% of control activity and red blood cell (RBC) galactose-1-phoshpate that is greater than 10 mg/day; all milk products are replaced immediately with formulas (e.g., Isomil^® or Prosobee^®) containing sucrose, fructose, and non-galactose polycarbohydrates and no bioavailable lactose; management of the diet becomes less important after infancy and early childhood; it is debated whether galactose intake should be restricted in infants and children with 5% to 20% of control GALT enzyme activity. Prevention of secondary complications: calcium supplements at 750 mg/day in neonates and more than 1200 mg/day in children. Surveillance: routine monitoring for the accumulation of toxic analytes (e.g., RBC gal-1-P and urinary galactitol); routine ophthalmologic examination; developmental evaluation; assessment of speech development. Agents/circumstances to avoid: casein hydrolysates (Alimentum^®, Nutramigen^®, Pregestimil^®); medications with lactulose. Testing of relatives at risk: for at-risk sibs, either prenatal testing to anticipate necessary treatment of neonates or screening after delivery using galactose-1-phosphate uridyltransferase content of erythrocytes and molecular genetic testing; treat neonates with soy formula while awaiting diagnostic test results. Therapies under investigation: ways to lower endogenous production of galactose, because endogenous galactose production that can approach 2.0 g/day despite exogenous galactose restriction may result in "self-intoxication" with galactose.

Genetic counseling.  Galactosemia is inherited in an autosomal recessive manner. Couples who have had one affected child have a 25% chance of having an affected child in each subsequent pregnancy. Prenatal diagnosis is possible for pregnancies at 25% risk for classic galactosemia using both GALT enzyme activity and molecular genetic testing if the disease-causing GALT mutations in the family are known.

Diagnosis

Clinical Diagnosis

Classic galactosemia (G/G) presents in the neonatal period with poor suck, failure to thrive, bleeding diathesis, and jaundice. If classic galactosemia is not treated, hyperammonemia, sepsis, and shock are likely. In approximately 10% of individuals, cataracts are present. Most affected infants are detected through newborn screening programs as symptoms emerge. Clinicians need to be alert to early signs (poor feeding, prolonged neonatal jaundice) in order to initiate early biochemical diagnosis and dietary therapy.

Lactose should be removed from the diet of an infant suspected of having galactosemia while results of biochemical and molecular testing are pending.

Testing

For laboratories offering biochemical testing, see .

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) galactose-1 phosphate concentration and galactose. These are the most sensitive and specific diagnostic tests in a newborn.
• A second tier of molecular testing for specific GALT mutations should also be available.

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 UMPGALT is formed and the second reaction binds galactose-1-P (gal-1P) and releases UDP-galactose (Figure 1). The overall reaction is rate-limiting in producing uryldylated hexoses for post-translational modification of glycoproteins and glycolipids.

When GALT enzyme activity is deficient, gal-1P and galactose accumulate. Gal-1P competes with the UTP-dependent glucose-1-P pyrophosphorylase to reduce UDP-glucose production (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. Other analytical methods are under study [Jeong et al 2007].

Classic galactosemia

• Homozygotes for the classic galactosemia (G) allele (i.e., G/G) have GALT enzyme activity that accounts for 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 that accounts for approximately 50% of control values.

Duarte variant galactosemia

• The Los Angeles (LA) (D₁) variant produces no change in GALT enzyme activity in the erythrocyte and has normal promotor activity.
• The Duarte (D₂) 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) As GALT isoforms that express stronger activity bands, the Duarte variant and LA variant have the same biochemical isoelectric focusing pattern (i.e., they move toward the anode and lower pH) [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 .

Biochemical assays also necessary for diagnosis and as therapeutic parameters 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-1P 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 2006].

• 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].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   GALT is the only gene known to be associated with the classic signs of galactosemia.

Clinical testing

• Classic (G/G) galactosemia

  Targeted mutation analysis.  Mutation analysis for the eight common GALT galactosemia (G) mutations (p.Gln188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, Δ5kb, IVS2-2A>G) is available on a clinical basis (laboratories may offer all or a subset of these mutations in their testing panels) [Elsas & Lai 1998].

  Note: The Δ5kb 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 Δ5-kb complex deletion is detectable by southern blot analysis or by PCR with deletion-specific primers that detect the deletion junction fragment. Misdiagnoses are made when typical GALT primers are used [Barbouth et al 2006 , Coffee et al 2006].

  Sequence analysis.  If both disease-causing mutations are not detected by targeted mutation  analysis and if biochemical testing has confirmed the diagnosis of galactosemia, GALT sequence  analysis can be used to detect private  mutations .

• Duarte variant (D/G) galactosemia

  Targeted 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 its promoter region(c.-116_-119delGTCA) that impairs a positive regulatory domain.
  • 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].

Table 1. Testing Used in Classic (G/G) Galactosemia Test Method Mutations Detected Mutation Detection Frequency 1,2 Test Availability Two mutations One common/ one private mutation Targeted mutation analysis Eight common GALT G mutations 3,4 80% 3 10% Clinical Sequence analysis Private and common GALT G mutations 19%

1. Proportion of affected individuals with a mutation(s) as classified by test method 2. 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, IVS2-2A>G, Δ5kb) 4. The IVS2 allele is common in Hispanics; the Δ5kb allele is common in Ashkenazim.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• 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.
• The diagnosis of galactosemia is established by quantitative measurement of erythrocyte GALT enzyme activity and erythrocyte concentration of galactose-1-phosphate.

• The true Duarte allele (D₂) has a c.-116-119 del GTCA in a positive regulatory region.
• The LA variant (D₁) does not have this mutation.

Prognostication.   Molecular genetic testing defines the genotype and enables prognosis [Guerrero et al 2000 , Webb et al 2003].

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.

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 other phenotypes are associated with GALT mutations.

Clinical Description

Natural History

Classic 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 mental retardation and other cortical and cerebellar tract signs.

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 mental retardation. 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 mental retardation 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 ovarian failure [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 ovarian failure 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 results of a retrospective, cross-sectional survey of 270 individuals with classic galactosemia.

• Mental 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, Grootenhuis et al 2004].

• 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 ovarian failure. Ovarian failure 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 primary ovarian failure in females with galactosemia is more likely if: (1) the individual's genotype is p.Gln188Arg/p.Gln188Arg, (2) the mean erythrocyte gal-1-P concentration is greater than 3.5 mg/dL during therapy, and (3) the 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 had been diagnosed and treated after clinical symptoms occurred or newborn screening results had been reported, whereas the younger sibs had been 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 mental development, speech, and motor function could also indicate a specific neurologic abnormality in some cases of galactosemia.

Variant galactosemia.   Individuals with variant forms of galactosemia have some aspects of classic galactosemia, including early cataracts, mild mental retardation with ataxia, and growth retardation. In addition they may have dyspraxic speech, and females may have amenorrhea or early menopause.

Genotype-Phenotype Correlations

Significant correlations are emerging [Shield et al 2000 , Tyfield 2000].

Substitution of an arginine for a glutamine at amino acid position 188 (p.Gln188Arg) accounts for approximately 70% of the G alleles in the Caucasian population of northern European ethnicity. In the homozygous state, the mutation destabilizes the GALT UMP complex and ablates the second disassociation reaction [Lai et al 1999]. It is associated with increased risks for ovarian failure and dyspraxic speech [Robertson & Singh 2000]. In one cross-sectional retrospective study correlating genotype with outcome in individuals with classic galactosemia, a greater proportion of individuals with a poor outcome were homozygous for the p.Gln188Arg mutation, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg mutation. An adult male homozygous for the p.Gln188Arg mutation began normal lactose intake at age three years and had no known clinical deficits [Panis, Bakker et al 2006].

The Duarte variant is the allele in which an aspartate substituted for asparagine at residue 314 (p.Asn314Asp) imparts bioinstability to the GALT enzyme. In the homozygous state (D/D or p.Asn314Asp/p.Asn314Asp), erythrocyte GALT enzyme activity is reduced by only 50%. Compound heterozygotes with the mutation (i.e., D/G or p.Asn314Asp/p.Asn314Asp) have good prognoses [Langley et al 1997 , Lai et al 1998]. However, two D alleles, D₂ (Duarte) and D₁ (LA variant), are now known. The D₂ allele is defined by a deletion in a positive response element and mayhave more effect on the outcome than the D₁ allele.

The p.Ser135Leu allele, in which a leucine is substituted for serine at amino acid 135, is prevalent in Africa. If therapy is initiated in the neonatal period, African Americans with galactosemia who have this allele in either the homozygous state or compound heterozygous state have a good prognosis. Generally, these individuals do not have neonatal hepatotoxicity or chronic problems (i.e., dyspraxia, ovarian failure, and mental retardation) when treated from infancy [Lai et al 1996].

Substitution of an asparagine for a lysine at position 285 (p.Lys285Asn) is prevalent in southern Germany, Austria, and Croatia and has a poor prognosis for neurologic and cognitive dysfunction in either the homozygous state or compound heterozygous state with p.Gln188Arg.

Other compound heterozygotes, such as p.Gln188Arg/p.Arg333Gly, have a good long-term outcome [Ng et al 2003].

Penetrance

Although the range of clinical expression for GALT mutations is wide, most G alleles are fully penetrant in the homozygous state.

Prevalence

Based on the results of newborn screening programs, the prevalence of classic galactosemia (G/G) is approximately 1:30,000. However, when GALT enzyme activity below 5% and erythrocyte galactose-1-phosphate concentration above 2 mg/dL are used as diagnostic criteria, some newborn screening programs record a prevalence of 1:10,000 [Bosch et al 2005].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Infectious diseases, obstructive biliary disease such as Alagille syndrome , progressive familial intrahepatic cholestasis (Byler disease), citrin deficiency, and other metabolic diseases such as Niemann-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. 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 activity is diagnostic. Mutations in the GALK1 gene 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, but normal GALT enzyme activity. Detection of reduced GALE activity is diagnostic. Mutations in the GALE gene are causative. GALE deficiency has an estimated prevalence of 1:23,000 in Japan and an unknown prevalence in other populations.

Management

Evaluations Following Initial Diagnosis

To 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 Manifestations

Lactose 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 ovarian failure conceived following FSH therapy, and subsequently delivered a normal child [Menezo et al 2004].

Prevention of Primary Manifestations

Classic Galactosemia

Dietary intervention.  Immediate dietary intervention is indicated in infants whose GALT enzyme activity is less than 10% of control activity and when RBC galactose-1-phoshpate is greater than 10 mg/day. Because 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.

Some have advocated for the use of elemental formulas; however, endogenous galactose production is measured in grams per day; thus, the elimination of a few milligrams does not appear advantageous [Zlatunich & Packman 2005].

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, Bakker et al 2004 ; Schadewaldt et al 2004], as endogenous galactose production is an order of magnitude higher than that ingested from foods other than milk.

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 Galactosemia

Agreement 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. Galactose restriction may prevent sequelae such as cataracts, ataxia, dyspraxic speech, and cognitive deficits.

Prevention of Secondary Complications

Calcium supplements at 750 mg/day are recommended in the neonatal period and greater than 1200 mg/day in childhood [Elsas & Acosta 1998]. Bone mineral content may be diminished in children with galactosemia and supplements of vitamin D and vitamin K have also been advocated [Panis, Vermeer et al 2006].

Surveillance

Affected individuals should be monitored routinely for the accumulation of toxic analytes such as RBC gal-1-P 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 Avoid

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 2005].

Lactose-containing drug preparations should be avoided.

Testing of Relatives at Risk

Prenatal testing is advised for at-risk sibs at risk to prepare the parents for the treatment of the newborn [Elsas 2001].

If prenatal testing is not performed, each at-risk sib should be screened for galactosemia using the GALT content of erythrocytes as well as molecular genetic testing of buffy coat DNA immediately after delivery. Treatment with soy formula should be implemented while diagnostic tests are underway. In the future, the breath test may become available before discharge from the nursery [Barbouth et al 2007].

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

Therapies Under Investigation

Recent research 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 galactose are under investigation.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Some have considered ovarian biopsy with egg preservation for future use if serum concentrations of FSH and LH rise, thus providing evidence of gonadal failure.

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.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Genetic Counseling

Mode of Inheritance

Galactosemia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.

Sibs of a proband

• At conception, each sib of a proband with G/G galactosemia has a 25% chance of being affected, a 50% chance of being a carrier (heterozygote) of a disease-causing allele, and a 25% chance of having two normal alleles.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3 chance. Older asymptomatic sibs of a proband should be offered carrier testing using molecular genetic testing when they are of reproductive age.
• At conception, each sib of a proband with D/G galactosemia is at a 25% risk for D/G galactosemia if the parents are D/N and G/N and a 25% risk for G/G galactosemia if the parents are D/G and G/N. Thus, molecular genetic testing of the parents is recommended.

Offspring of a proband

• Affected females are at increased risk for premature ovarian failure, but may have children.
• Offspring of one parent with (G/G) galactosemia and one parent with two normal alleles (N/N) are obligate heterozygotes (G/N).
• If one parent is affected (G/G) and the other parent is a carrier for a G allele (G/N or D/G), each child has a 50% chance of being a heterozygote and a 50% chance of having G/G galactosemia.

Other family members of a proband.  Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Biochemical testing.  Carrier testing is done by measuring GALT enzyme activity, which is approximately 50% of control values in carriers.

Molecular genetic testing.  Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the family.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible for fetuses at 25% risk for classic (G/G) galactosemia using either GALT enzyme activity or molecular genetic testing if the two disease-causing GALT mutations in the family are known [Elsas 2001]. Analysis of GALT enzyme activity and molecular diagnosis rely on cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Other issues to consider.  Prenatal diagnosis of a treatable condition may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. Although most centers would consider this to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Normal allelic variants: The gene is approximately 4 kb in length and has 11 exons and 10 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 the GALT gene is common in persons of Ashkenazi Jewish