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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Classic Galactosemia and Clinical Variant Galactosemia

Synonyms: GALT Deficiency, Galactose-1-Phosphate Uridyltransferase Deficiency
, MD, FFACMG
Boston Children’s Hospital
Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Update: April 3, 2014.

Summary

Disease characteristics. The term galactosemia refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia. This GeneReview focuses on:

  • Classic galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E. coli sepsis in untreated infants. If a lactose-restricted diet is provided during the first ten days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis, and neonatal death are prevented; however, despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for developmental delays, speech problems (termed childhood apraxia of speech and dysarthria), and abnormalities of motor function. Almost all females with classic galactosemia manifest premature ovarian insufficiency (POI).
  • Clinical variant galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage including cirrhosis and bleeding in untreated infants. This is exemplified by the disease that occurs in African Americans and native Africans in South Africa. Persons with clinical variant galactosemia may be missed with newborn screening (NBS) as the hypergalactosemia is not as marked as in classic galactosemia and breath testing is normal. If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications are usually prevented. African Americans with clinical variant galactosemia and adequate early treatment do not appear to be at risk for long-term complications including POI.

Diagnosis/testing. The diagnosis of classic galactosemia and clinical variant galactosemia is established by detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity, and/or biallelic mutations in GALT, the gene encoding galactose-1-phosphate uridyltransferase.

In classic galactosemia, erythrocyte galactose-1-phosphate is usually higher than 10 mg/dL and erythrocyte GALT enzyme activity is absent or barely detectable. In clinical variant galactosemia, erythrocyte GALT enzyme activity (which may be absent or barely detectable, as in African Americans) is much higher in brain and intestinal tissue (e.g., 10% of control values). Other individuals with clinical variant galactosemia may have erythrocyte GALT enzyme activity close to or above 1% of control values but probably never above 10%-15%.

Virtually 100% of infants with classic galactosemia or clinical variant galactosemia can be detected in newborn screening programs that include testing for galactosemia in their panel. However, infants with clinical variant galactosemia may be missed if the program only measures blood total galactose level and not erythrocyte GALT enzyme activity.

Management. Prevention of primary manifestations: Standard of care in any newborn who is “screen-positive” for galactosemia is immediate dietary intervention while diagnostic testing is underway. If erythrocyte galactose-1-phosphate concentration is >10 mg/dL and erythrocyte GALT enzyme activity is ≤10% of control activity (i.e., the child has classic galactosemia or clinical variant galactosemia), restriction of galactose intake is continued and all milk products are replaced with lactose-free formulas (e.g., Isomil® or Prosobee®) containing non-galactose carbohydrates; management of the diet becomes less important after infancy and early childhood.

Treatment of manifestations: In rare instances cataract surgery may be needed in the first year of life. Childhood apraxia of speech and dysarthria require expert speech therapy. Developmental assessment at age one year by a psychologist is recommended in order to formulate a treatment plan with the speech therapist and treating physician. For school age children, an individual education plan and/or professional help with learning skills and special classrooms as needed. Hormone replacement therapy as needed for delayed pubertal development and/or primary or secondary amenorrhea.

Prevention of secondary complications: Recommended calcium and vitamin intake to help prevent decreased bone mineralization.

Surveillance: Routine monitoring for: the accumulation of toxic analytes (e.g., erythrocyte galactose-1-phosphate and urinary galactitol); cataracts; speech and development; POI; and osteoporosis.

Agents/circumstances to avoid: Breast milk, proprietary infant formulas containing lactose, cow’s milk, dairy products, and casein or whey-containing foods; medications with lactose and galactose.

Evaluation of relatives at risk: To allow for earliest possible diagnosis and treatment of at-risk sibs:

  • Perform prenatal diagnosis when the disease-causing GALT mutations in the family are known; or
  • If prenatal testing has not been performed, test the newborn for either the family-specific GALT mutations or erythrocyte GALT enzyme activity.

Genetic counseling. Classic galactosemia and clinical variant galactosemia are 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. Carrier testing for at-risk sibs and prenatal diagnosis for pregnancies at increased risk are an option if the disease-causing GALT mutations in the family are known. If the disease-causing GALT mutations in a family are not known, prenatal testing can rely on assay of GALT enzyme activity in cultured amniotic fluid cells.

Diagnosis

Galactosemia due to deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) may be divided into three clinical/biochemical phenotypes: (1) classic galactosemia; (2) clinical variant galactosemia; and (3) biochemical variant galactosemia. This categorization is based on: residual erythrocyte GALT enzyme activity; the levels of galactose metabolites (e.g., erythrocyte galactose-1-phosphate and urine galactitol) that are observed both off and on a lactose-restricted diet; and, most importantly, the likelihood that the affected individual will develop acute and chronic long-term complications. This categorization allows for proper counseling of the parents of an infant with galactosemia, especially regarding the so-called diet-independent complications.

Classic galactosemia and clinical variant galactosemia are the topics covered in this GeneReview. Patients with these forms of galactosemia will or may exhibit clinical disease. The biochemical variant form of galactosemia is exemplified by the Duarte variant form of galactosemia and is thought by many to not be a real disease [Berry 2012]. The most common mutations that result in the three phenotypes are shown in Table 3 (see Genotype-Phenotype Correlations).

Classic galactosemia and clinical variant galactosemia may be suspected and confirmed in three clinical scenarios:

  • A newborn who is positive on newborn screening (NBS)
  • A newborn with a previously affected sib and/or high-risk ethnicity
  • An infant, child, or adult with signs and/or symptoms suggestive of classic galactosemia or clinical variant galactosemia

Testing

Newborn positive on NBS. Newborn screening utilizes a small amount of blood obtained from a heel prick to quantify:

  • Total content of erythrocyte galactose-1-phosphate and blood galactose concentration

    AND/OR
  • Erythrocyte GALT enzyme activity.

State Newborn Screening (NBS) programs vary as to which of these tests is performed – or, if both are performed, in what sequence. For example, in the New England NBS program, total blood galactose is first measured. The cutoff value for a positive result for galactosemia is a total blood galactose level of 14.5 mg/dL. However, if the value is above 5 mg/dL, an erythrocyte GALT enzyme assay is always performed. If the enzyme activity is below 30 units/hr the test is considered positive for galactosemia even if the total galactose level is between 5 and 14.5 mg/dL.

Classic 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)].

Clinical variant galactosemia will be detected if the enzyme assay is always performed or if the infant has consumed enough lactose and the cutoff value for total galactose is relatively low.

Note: (1) While most infants with classic galactosemia are detected through newborn screening programs, clinicians need to be alert to early signs and remove lactose from the diet and initiate soy-based, dietary therapy while awaiting results of newborn screening and/or diagnostic tests. If classic galactosemia is not treated, sepsis and shock are likely to develop after the first week of life, although deaths have occurred before day eight of life. (2) The newborn with questionable results on newborn screening should continue to be treated with soy-based formula pending definitive results of confirmatory testing.

Following verification of the first positive NBS result, the diagnosis of classic galactosemia or clinical variant galactosemia must be established in a biochemical genetics laboratory. See Cuthbert et al [2008] for a detailed discussion of test methods and clinical interpretation of test results.

The biochemical genetics laboratory test results may yield the following.

In classic galactosemia:

  • Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but usually is >10 mg/dL in the newborn period. When the patient is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
  • Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).

In clinical variant galactosemia:

  • Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the patient is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
  • Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).

The diagnosis of classic galactosemia or clinical variant galactosemia is confirmed in a newborn by identification of reduced erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity (for details see Pathophysiology) and/or biallelic mutations in GALT, the gene encoding galactose-1-phosphate uridyltransferase. Assay activity of galactose-1-phosphate uridyltransferase (GALT) enzyme (EC 2.7.712) in erythrocytes

  • In classic galactosemia, erythrocyte GALT enzyme activity is absent or barely detectable.
  • In clinical variant galactosemia, the erythrocyte GALT enzyme activity may be 1%-10%; however, in certain populations (e.g., as African Americans) with hypomorphic alleles including Ser135Leu/Ser135Leu, erythrocyte GALT enzyme activity may be absent or barely detectable. In contrast, liver GALT enzyme activity is higher, perhaps 10% of control values.

Table 1. Summary of Molecular Genetic Testing Used in Classic Galactosemia and Clinical Variant Galactosemia

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency 3
GALTTargeted mutation analysisCommon GALT mutations 4, 5, 687.5% 7, 8
Sequence analysis 9 / mutation scanning 10Sequence variants, including common GALT mutations 4, 5, 6>95% 11
Deletion/duplication analysis 12Exonic or partial gene deletion/duplicationSee footnotes 5 and 13

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Targeted mutation panels often include the common mutations associated with classic galactosemia (p.Gln188Arg, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, c.253-2A>G) [Elsas & Lai 1998], as well as the p.Ser134Leu mutation associated with clinical variant galactosemia and the D2 Duarte (c.[940A>G;c.-119_116delGTCA]) mutation, which is almost always associated with biochemical variant galactosemia (see Genetically Related Disorders).

5. The 5-kb deletion is common in the Ashkenazim (see Molecular Genetics, Pathogenic allelic variants)

6. c.253-2A>G is common in Hispanics.

7. Mutations included in targeted mutation panels may vary by laboratory; detection rates will vary accordingly.

8. In individuals with biochemically confirmed classic galactosemia and clinical variant galactosemia [Elsas & Lai 1998]

9. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

10. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

11. A peer-reviewed publication figure is not available, but the detection rate certainly exceeds 95% [Tyfield et al 1999].

12. Testing that identifies exonic or whole-gene 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.

13. Detection rates may vary among testing laboratories.

Newborn with previously affected sib and/or high risk based on ethnic group. The infant at risk for classic galactosemia or clinical variant galactosemia should be placed on a lactose-free formula at birth pending results of the definitive erythrocyte GALT enzyme activity assay and/or molecular genetic testing.

Note: If both parents are from a high-risk ethnic group (e.g., Irish) and one or both are known carriers or from families with a history of classic galactosemia or clinical variant galactosemia, the diagnostic testing should be performed. The safest course is to place the infant on a lactose-free formula at birth.

Older child or adult with signs/symptoms suggestive of classic galactosemia or clinical variant galactosemia. Children and adults with signs and/or symptoms compatible with GALT enzyme deficiency should have erythrocyte GALT enzyme quantification and GALT molecular genetic testing.

Note: A quick way of providing supportive data at the bedside is to perform a Clinitest® reaction to demonstrate the presence of excess reducing substances, such as galactose in urine. A negative Glucostix® reaction (glucose oxidase-impregnated strip) would further indicate that the excess reducing substance is not glucose.

Clinical Description

Natural History

Classic Galactosemia

Within days of ingesting breast milk or lactose-containing formulas, infants with classic galactosemia develop life-threatening complications including feeding problems, failure to thrive, hypoglycemia, hepatocellular damage, bleeding diathesis, and jaundice (see Table 2). If classic galactosemia is not treated, sepsis with Escherichia coli, shock, and death may occur [Levy et al 1977]. Infants who survive the neonatal period and continue to ingest lactose may develop severe brain damage [Otaduy et al 2006].

Table 2. Frequency of Specific Findings in Symptomatic Neonates with Classic Galactosemia

Finding 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-free diet is provided during the first three to ten days of life, the signs resolve quickly and prognosis is good for prevention of liver failure, Escherichia coli sepsis, and neonatal death. Failure to implement effective newborn screening may have catastrophic consequences such as liver failure [Malone et al 2011].

If the diagnosis of classic 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 poor growth retardation and progressive liver disease are likely. Rare patients may develop vitreous hemorrhages that may produce blindness [Levy et al 1996, Takci et al 2012].

Even with early and adequate therapy, the long-term outcome in older children and adults with classic 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].

Classic galactosemia is associated with extreme variability in chronic complications and/or long-term outcome. Even individuals who have not been sick in the newborn period and who were begun on a lactose-free diet from birth (e.g., those with a prior affected sibling in the family) may manifest language delay, speech defects, learning disabilities, cognitive impairment, and, in females, premature ovarian insufficiency. These problems may manifest as early as age one to two years and – in almost all instances – no findings were present in early infancy that would have predicted eventual brain and ovarian dysfunction. A minority of individuals may exhibit documented neurologic abnormalities including tremor (postural or intentional), cerebellar ataxia, and dystonia. No findings early in the disease course are good predictors of these long-term complications. Overall, the quality of life is reduced in adults with classic galactosemia, and more so when compared to individuals with phenylketonuria (PKU) [Gubbels et al 2011, ten Hoedt et al 2011, Hoffmann et al 2012].

Outcome and the "disease burden" can be predicted based on the level of erythrocyte 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 (available on a research basis only) 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. To summarize, the data on long-term outcome indicate that complications involving the nervous system and ovary do not correlate with any of the well-known biochemical variables (e.g., erythrocyte galactose-1-phosphate levels); furthermore, manifestations of one or more of these complications vary even among individuals with the same genotype associated with classic galactosemia (see Table 3) [Doyle et al 2010, Schadewaldt et al 2010, Hoffmann et al 2011, Krabbi et al 2011, Coss et al 2012, Waisbren et al 2012].

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 individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%. A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [Robertson & Singh 2000, Webb et al 2003]. Speech defects are heterogeneous, involving both central defects and motor abnormalities, and evolve with time [Potter et al 2013].

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. Adults manifest tremors, dysarthria, cerebellar ataxia and dystonia [Waisbren et al 2012, Rubio-Agusti et al 2013].

Gonadal function. Of 47 girls and women, 81% had signs of premature ovarian insufficiency (POI). 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 2 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 galactose-1-phosphate concentration is greater than 3.5 mg/dL during therapy; and
  • 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. However, the literature has few reports of males with classic galactosemia who have fathered a child [Panis et al 2006a, Gubbels et al 2013]. There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [Gubbels et al 2013].

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 low 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 between treatment and outcome 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 than males 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 galactose-1-phosphate 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 [Schadewaldt et al 2010].

Clinical Variant Galactosemia

Individuals with variant forms of galactosemia may have some aspects of classic galactosemia, including early cataracts, liver disease, mild intellectual disability with ataxia, and growth retardation [Fridovich-Keil et al 2011]. Clinical variant galactosemia can result in life-threatening complications in untreated infants including feeding problems, failure to thrive, hepatocellular damage (including cirrhosis), and bleeding.

Clinical variant galactosemia is exemplified by the disease that occurs in African Americans and native Africans in South Africa with a Ser135Leu/Ser135Leu genotype. Neonates with clinical variant galactosemia may be missed with newborn screening (NBS) as the hypergalactosemia is not as marked as in classic galactosemia and breath testing is normal [Crushell et al 2009].

If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications are usually prevented.

To the best of current knowledge, African Americans with clinical variant galactosemia and adequate early treatment do not develop long-term complications including POI.

Pathophysiology

The GALT enzyme catalyzes the conversion of galactose-1-phosphate and UDPglucose to UDPgalactose and Glu-1-P in a two-step process termed a ping-pong or bi-bi molecular reaction (Figure 1):

Figure 1

Figure

Figure 1. GA lactose metabolism, the Leloir pathway

1.

UDPglucose binds to the active site and glucose-1-phosphate is released, leaving UMP covalently linked to the enzyme.

2.

Then, galactose-1-phosphate lands at the active site, engages the bound UMP, and following cleavage of the phosphonium bond, UDP galactose is released.

When GALT enzyme activity is deficient, galactose-1-phosphate, galactose, and galactitol accumulate (Figure 2). Galactose is converted to galactitol in cells and produces osmotic effects including swelling of lens fibers that may result in cataracts. The same process has been hypothesized to produce swelling of neurons and subsequently, pseudotumor cerebri.

Figure 2

Figure

Figure 2. Galactose metabolism, GALT deficiency

Since patients with classic galactosemia who are prospectively treated may manifest all of the so-called chronic diet-independent complications and since the amniotic fluid of affected fetuses contains high levels of galactitol and cord blood of affected newborns contains elevated levels of erythrocyte galactose-1-phosphate, one must consider whether the long-term complications of GALT enzyme deficiency are due to prenatal toxicity [Komrower 1982]. One hypothesis is that the prenatal CNS insult is secondary to myo-inositol deficiency [Berry 2011].

Genotype-Phenotype Correlations

Significant genotype-phenotype correlations have been noted [Shield et al 2000, Tyfield 2000]. Although the GALT genotype informs prognosis [Guerrero et al 2000, Webb et al 2003], some confusion about genotype-phenotype correlations appears to have resulted from the variability of the manifestations and severity of the chronic complications of classic galactosemia.

Use of the galactosemia classification system in Table 3 helps dispel confusion. The most common mutations that result in the three galactosemia phenotypes – classic, clinical variant, and biochemical variant – are shown in Table 3. (See Diagnosis and Genetically Related Disorders for definitions.)

Table 3. GALT Genotypes and Biochemical/Clinical Phenotypes

Classic Galactosemia
(Alias 1)
Clinical Variant Galactosemia
(Alias 1)
Biochemical Variant Galactosemia
(Alias 1)
p.[Gln188Arg]+[p. Gln188Arg]
(Q188R/Q188R)
p.[Ser135Leu]+[Ser135Leu]
(S135L/S135L) 2
c.[940A>G; c.-16_119delGTCA]
(4bp 5' del + N314D/Q188R) 3
p.[Lys285Asn]+[Lys285Asn]
(K285N/K285N)
p.[Leu195Pro]+[Leu195Pro]
(L195P/L195P)
(Δ5.2 kb del/ Δ5.2 kb del) 4

1. Variant designation that does not conform to current naming conventions

2. The original identification of the Ser135Leu mutation was exclusively in African Americans; however, it is present on occasion in infants without known African American heritage.

3. Known as “Duarte variant galactosemia” or the “Duarte D2 variant”

4. See Table 5, footnote 4.

p.Gln188Arg. Approximately 70% of the alleles in persons with GALT deficiency from the white population of northern European ethnicity have a substitution of an arginine for a glutamine at amino acid position 188 (p.Gln188Arg).

In the homozygous state, the mutation interferes with the catalytic reaction. It is associated with increased risks for premature ovarian insufficiency (POI) and childhood apraxia of 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. However, one adult male homozygous for the p.Gln188Arg mutation who had begun normal lactose intake at age three years had no known clinical deficits [Panis et al 2006a].

p.Ser135Leu. 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 the homozygous state have a good prognosis. Generally, these individuals are not prone to E. coli sepsis in the neonatal period or chronic complications (i.e., speech disorder, POI, and intellectual disability) when treated from infancy [Lai et al 1996].

Data are limited on outcome in persons who are compound heterozygotes (p.[Ser135Leu];[Gln188Arg]); however, they appear to have fewer complications than individuals with the genotype p.[Gln188Arg]+[p.Gln188Arg], associated with classic galactosemia.

p.Asn314Asp. The Duarte (D2) variant is the allele in which an aspartate is substituted for asparagine at residue 314 (p.Asn314Asp) and a second mutation in cis configuration – a 4-bp deletion in the promoter region (c.-119_116delGTCA) – results in reduced erythrocyte GALT enzyme activity. The D2 allele designation is c.[940A>G; c.-119_116delGTCA].

In the homozygous state D2 erythrocyte GALT enzyme activity is reduced by 50%.

Compound heterozygotes with D2 and a mutation associated with classic galactosemia have a good prognosis [Langley et al 1997, Lai et al 1998].

However, compound heterozygosity for D2 (Duarte) and D1 (LA variant) is known to occur. The D1 allele has a p.Leu218Leu in cis configuration with the p.Asn314Asp mutation p.[Leu218Leu;Asn314Asp] which confers “superactivity” (i.e., heterozygotes have ~117% erythrocyte GALT activity while homozygotes display ~134% activity).

Other. Substitution of an asparagine for a lysine at position 285 (p.Lys285Asn) is prevalent in southern Germany, Austria, and Croatia; it is associated with a poor prognosis for neurologic and cognitive function in either the homozygous state or compound heterozygous state with p.Gln188Arg and is considered classic galactosemia.

Other compound heterozygotes (e.g., p.[Gln188Arg]+[p.Arg333Gly]) have a good long-term outcome [Ng et al 2003].

  • A clear genotype-phenotype correlation is seen when classic galactosemia with genotypes such as p.[Gln188Arg]+[p. Gln188Arg] is compared with clinical variant galactosemia caused by the p.[Ser135Leu]+[p.Ser135Leu] genotype. For example, almost all females with the p.[Gln188Arg]+[p.Gln188Arg] genotype manifest POI, whereas POI is almost unheard of in African American women with the p.[Ser135Leu]+[p.Ser135Leu] genotype. A critical unanswered question is how much residual GALT enzyme activity in target tissues there must be to eliminate chronic diet-independent complications. To illustrate, cryptic residual GALT enzyme activity may be a potential modifier of scholastic outcome in school-age children [Ryan et al 2013].
  • While on a lactose-restricted diet, persons with classic galactosemia display erythrocyte galactose-1-phosphate levels between 1 to 5 mg/dL and urine galactitol levels between 100 to 400 μmol/mmol creatinine, whereas persons with a p.[Ser135Leu]+[p.Ser135Leu] genotype usually have an erythrocyte galactose-1-phosphate level <1 mg/dL, and urine galactitol that is <100 μmol/mmol creatinine and often in the normal range [Saudubray et al 2012, Fridovich-Keil & Walter 2014].
  • Persons with biochemical variant galactosemia – for example, compound heterozygotes for c.563A>G (p.Gln188Arg) and D2 c.[940A>G; c.-119_116delGTCA] genotype – differ from those with either classic galactosemia or clinical variant galactosemia; they generally exhibit no signs and symptoms of disease, only biochemical perturbations.

Note: Many of the more than 250 GALT mutations have been identified following newborn screening with little or no long-term follow-up data. In these instances, the term classic galactosemia should be applied with caution or not at all. It would be inappropriate to counsel new parents that their infant will develop one or more of the chronic complications seen in galactosemia without supportive data.

Nomenclature

The genetic hypergalactosemias

1.

Galactokinase deficiency secondary to mutations in GALK

2.

UDP galactose 4′-epimerase deficiency secondary to mutations in GALE

3.

Galactose-1-phosphate uridyltransferase deficiency secondary to mutations in GALT

a.

Classic galactosemia

i.

Severe GALT enzyme deficiency with absent or barely detectable activity in erythrocytes and liver

ii.

Also known as G/G and carriers as G/N

b.

Clinical variant galactosemia

i.

1-10% residual GALT enzyme activity in erythrocytes and/or liver

c.

Biochemical variant galactosemia

i.

15-33% residual GALT enzyme activity in erythrocytes

ii.

Includes the D2 Duarte biochemical variant state also known as G/N

Prevalence

Based on the results of newborn screening programs, the prevalence of classic galactosemia is 1:48,000 [National Newborn Screening and Genetics Resource Center 2013]. However, when erythrocyte GALT enzyme activity <5% of control activity and erythrocyte galactose-1-phosphate concentration >2 mg/dL are used as diagnostic criteria, some newborn screening programs record a prevalence of 1:10,000 [Bosch et al 2005].

The frequency of classic galactosemia in Ireland is 1:16,476 [Coss et al 2013].

While it is not possible to provide prevalence data for clinical variant galactosemia, the estimated prevalence of the Ser135Leu/Ser135Leu genotype is 1:20,000 [Henderson 2002].

Differential Diagnosis

Infectious diseases, obstructive biliary disease including Alagille syndrome, progressive familial intrahepatic cholestasis (Byler disease) and citrin deficiency, hereditary fructose intolerance, tyrosinemia type 1, and other metabolic diseases including Neimann-Pick Disease Type C are in the differential diagnosis for neonatal hepatotoxicity.

Note: Establishing the diagnosis of sepsis does not exclude the possibility of galactosemia, as sepsis, particularly E. coli sepsis, occurs commonly in infants with classic 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 erythrocyte GALT enzyme activity and do not accumulate erythrocyte galactose-1-phosphate. The cataracts are caused by accumulation of galactose in lens fibers and its reduction to galactitol, an impermeant alcohol that results in increased intracellular osmolality and water imbibition. Other individuals with GALK deficiency develop CNS disease. Detection of reduced GALK enzyme activity is diagnostic. Biallelic 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.

Epimerase deficiency galactosemia (UDP-galactose 4-epimerase (GALE) deficiency) should be considered in individuals who have liver disease, failure to thrive, and elevated erythrocyte galactose-1-phosphate concentrations but normal erythrocyte GALT enzyme activity. To date, only eight individuals have been reported with this severe phenotype. In contrast, most individuals with GALE deficiency have a benign peripheral form and do not manifest disease: they are healthy newborns with a positive newborn screen, increased erythrocyte galactose-1-phosphate, and normal erythrocyte GALT enzyme activity. Detection of reduced GALE enzyme activity is diagnostic. Biallelic mutations in GALE are causative. GALE deficiency has an estimated prevalence of 1:23,000 in Japan and an unknown prevalence in other populations.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis in the Newborn Period

To establish the extent of disease and needs in a newborn diagnosed with classic galactosemia or clinical variant galactosemia, the following evaluations are recommended [Walter et al 1999]:

  • Consultation with a specialist in biochemical genetic disorders
  • Measurement of erythrocyte galactose-1-phosphate concentration and urinary galactitol as a baseline for monitoring the effect of treatment (see Prevention of Primary Manifestations).
  • Neurologic examination and brain MRI as needed
  • Ophthalmologic examination, including slit lamp examination for cataracts
  • If applicable, evaluation for hepatocellular disease, especially in patients with late-treated disease who may be at risk for cirrhosis

Treatment of Manifestations and Complications

See Prevention of Primary Manifestations for information on dietary intervention. Lactose restriction reverses liver disease in newborns who already have hepatocellular disease.

Ophthalmologic treatment. Cataract surgery may need to be performed in the first year of life, especially in the rare cases where failure to perform NBS has resulted in delayed diagnosis.

Speech treatment. Patients with childhood apraxia of speech and dysarthria require therapy by a speech expert until the complication has been brought under control. This may require years of intense therapy.

Developmental treatment. Developmental examination by a psychologist at age one year, followed by the psychologist working closely with the speech therapist and treating physician to map out a treatment plan and evaluation scheme tailored to each child. Individual education plan and/or professional help with learning skills and special classrooms may be needed depending on the timing of the clinical manifestations and the nature of the complications which may be quite variable, even for children with the same genotype.

Premature ovarian insufficiency (POI) treatment. While biochemical/endocrine tests may indicate POI during early infancy, females do not usually exhibit signs of POI until there is delayed pubertal development or primary or secondary amenorrhea. Therefore, during pubertal development or adolescence females should be referred to a pediatric endocrinologist for consultation. When appropriate, the patient should be seen by an obstetrician-gynecologist who specializes in adolescent services and/or infertility.

Estrogen and progesterone may need to be given in a minority of instances to promote pubertal development or more likely when secondary amenorrhea occurs.

There is controversy as to whether females should be given estrogen and progesterone early in adolescence to retard “oocyte wastage” and whether more aggressive treatment plans (similar to those used in oncology) should be employed in adolescents. In this regard, the autonomy of the patient must be respected and her ability to reason taken into consideration. It is important that hospital ethics boards be involved in any decision making and patients be treated on an individual basis.

The consideration of ovarian biopsy with oocyte preservation for future use in females with classic galactosemia and POI is controversial. If this type of procedure (which is becoming more common for females undergoing cancer chemotherapy) is being considered, consultation with the hospital ethics committee is recommended.

Fertility is possible for certain patients with classic galactosemia. Therefore, adults should be afforded this opportunity and helped to secure consultation with an obstetrician-gynecologist who specializes in infertility and who will promote conception.

Infertility. Because of the ovarian dysfunction, 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 in some instances may be potentially treatable by exogenous pharmacologic stimulation by gonadotropic hormones [Rubio-Gozalbo et al 2010].

Prevention of Primary Manifestations

Classic Galactosemia and Clinical Variant Galactosemia

Dietary intervention. Immediate dietary intervention is indicated in infants whose erythrocyte GALT enzyme activity is ≤10% of control activity and whose erythrocyte galactose-1-phosphate concentration is >10 mg/dL.

Because 90% of the newborn’s carbohydrate source is lactose and human milk contains 6%-8% lactose, cow’s 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 lactose (e.g., Isomil® or Prosobee®). Such soy formulas contain sucrose, fructose, and galactose-containing oligosaccharides that cannot be hydrolyzed in the small intestine.

Elemental formulas that contain small amounts of galactose such as Alimentum®, Nutramigen®, and Pregestimil® made with casein hydrolysates have been employed in the past without obvious side effects. A formula (Neocate®) that is free of both free and bound galactose has been used without any side effects [Zlatunich & Packman 2005].

Dietary restrictions on all lactose-containing foods including cow’s milk and other dairy products 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 infancy [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. Until more prospective evidence-based medicine studies have been performed with a large number of subjects, parents should be educated about the lifelong need for dietary restriction of cow’s milk and dairy products.

Concentration of erythrocyte galactose-1-phosphate can be used to monitor the effectiveness of therapy. Exogenous galactose restriction notwithstanding, galactose-1-phosphate levels in individuals with classic galactosemia remain elevated (1-5 mg/dL; normal: <1 mg/dL).

Biochemical Variant Galactosemia

Expert opinion and anecdotal information suggest that Duarte variant galactosemia, the most prevalent form of biochemical variant galactosemia, does not result in clinical disease. However, supporting studies are limited to relatively small samples; no prospective long-term evidence-based medicine study has confirmed that individuals with the D2 c.[940A>G; c.-16_119delGTCA] genotype exhibit no disease with or without dietary intervention.

Prevention of Secondary Complications

Because bone mineral density in children and adults with classic galactosemia and clinical variant galactosemia may be diminished, supplements of vitamin D in excess of 1000 IU/day and vitamin K have been advocated [Panis et al 2006b, Batey et al 2013].

For calcium and vitamin D intake for patients with classic and clinical variant galactosemia, see the recommended dietary allowances and adequate intakes (pdf) from the Institute of Medicine. Additional dietary reference intake tables are available here.

If routine follow-up visits with a dietitian knowledgeable about metabolic disorders have verified that calcium and vitamin D intake are adequate for age and if plasma 25-hydroxyvitamin D is within the normal range but bone mineral density is decreased, consultation with a pediatric and/or adult endocrinologist may be warranted.

Surveillance

Affected individuals should be routinely monitored [Walter et al 1999].

Patients with classic galactosemia and clinical variant galactosemia should be monitored routinely for the accumulation of analytes including:

  • Erythrocyte galactose-1-phosphate. Concentrations <5 mg/dL are considered within the therapeutic range.
    Note: Erythrocyte galactose-1-phosphate is a good way to evaluate for acute ingestion of galactose.
  • Urinary galactitol (a product of an alternate pathway for galactose metabolism). Values >78 mmol/mol creatinine are abnormal.
    Note: Urinary galactitol is often not affected by acute dietary ingestion of galactose

If sudden increases in either erythrocyte galactose-1-phosphate or urinary galactitol are detected, dietary sources of excess galactose should be sought or evaluation undertaken for other causes.

Schedule for Patients with Classic or Clinical Variant Galactosemia

Biochemical genetics clinic visits

  • Every three months for the first year of life or as needed depending on the nature of potential acute complications
  • Every six months during the second year of life
  • Yearly thereafter

Note: Patients with biochemical variant galactosemia such as those with the D2 Duarte c.[940A>G; c.-16_119delGTCA] genotype are encouraged to return to the clinic once a year to monitor the clinical state even if they are not on diet therapy.

Metabolic dietician clinic visits. As above, plus interim visits and phone consultations as necessary

Biochemical testing

  • Measure erythrocyte galactose-1-phosphate level at each clinic visit and as needed. For example, introduction of a new food such as a soy derivative with a relatively high content of free galactose may necessitate a series of erythrocyte galactose-1-phosphate measurements to verify that ingestion does not affect metabolic control.
  • Urine galactitol levels may also be obtained at the clinic visits, although few facilities perform this test. With daily consumption of galactose, urine levels may rise; however, unlike erythrocyte galactose-1-phosphate and plasma galactose, urine galactitol levels usually do not provide insight into acute and transient effects of galactose intake.

Ophthalmologic evaluations. The timing of follow-up examinations depends on the presence or absence of neonatal cataracts. If absent, an examination may be performed at age one year, age five years, and during adolescence. Note: It is very unusual for a patient with classic galactosemia to present after early infancy with cataracts, as cataract development probably requires significant intake of cow’s milk and dairy products.

Speech evaluations

  • An evaluation by a speech expert is recommended for all children at age 18 months.
  • If the initial evaluation does not reveal a diagnosis of a speech or language disorder, the child should be reevaluated every three to 12 months during infancy and early childhood depending on the assessments performed by the developmental specialists and physicians.

Developmental evaluations. Patients should undergo a developmental examination by a psychologist at age one year and thereafter every one to three years depending on the extent of delay in one or more spheres of development.

Evaluations for premature ovarian insufficiency (POI)

  • Measure plasma estradiol, FSH, and LH in females at age one year, age two years, and during puberty.
  • Further testing and its timing depend on pubertal status and the presence or absence of primary or secondary amenorrhea and its treatment.

Evaluations for osteopenia

  • Measure plasma calcium, phosphorous, 25-hydroxyvitamin D on a yearly basis and as needed.
  • Because decreased bone mineral density is prevalent in patients with classic galactosemia, a DXA scan is recommended for surveillance at age six years, during puberty, through adolescence, and then every five years during adult life.
  • Routine metabolic dietetic visits should verify that calcium and vitamin D intake is adequate for age, and that plasma 25-hydroxyvitamin D is within the normal range. Even so, bone mineral density may be decreased in certain patients for reasons that are not understood. Under these circumstances, consultation with a pediatric and/or adult endocrinologist may be warranted.

Agents/Circumstances to Avoid

The following should be avoided:

  • Breast milk, proprietary infant formulas containing lactose, cow’s milk, dairy products, and casein or whey-containing foods
  • Lactose- or galactose-containing drug preparations
  • Medicines that contain lactose (tablets, capsules, sweetened elixirs), especially during infancy

Evaluation of Relatives at Risk

When the disease-causing mutations of classic galactosemia and clinical variant galactosemia in the family are known, prenatal diagnosis of fetuses at risk may be performed via amniocentesis or CVS to allow for institution of treatment at birth.

If prenatal testing has not been performed, each at-risk newborn sib should be treated from birth and screened for classic galactosemia or clinical variant galactosemia using the erythrocyte GALT enzyme assay to allow for earliest possible diagnosis. 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.

Pregnancy Management

No data support that the outcome of children with classic galactosemia or clinical variant galactosemia is improved when their mothers (who are obligate carriers) were on a lactose restricted diet during pregnancy.

Therapies Under Investigation

Research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 1.0-2.0 g/day [Berry et al 1995, 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-1-phosphate are under investigation using small inhibitors of the GALK enzyme [Tang et al 2010]. In vitro studies of GALT enzyme-deficient human fibroblasts demonstrated proof of concept, it is yet to be performed in an animal model. The GALT knockout mice generated by Leslie et al [1992] do not express the human phenotype of galactosemia and except for polyuria due to hypergalactosemia and hypergalactosuria are largely without disease. As mice have lost ARHI (DIRAS3) during evolution [Lai et al 2008, Rubio-Gozalbo et al 2010, Tang et al 2010], a GALT enzyme-deficient mouse model is needed that expresses an ARHI (DIRAS3) signal to test the hypothesis that ARHI gene expression plays a role in phenotypic expression of disease, and whether inhibition of galactose-1-phosphate production limits or abrogates the “human phenotype.”

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Classic galactosemia and clinical variant galactosemia are 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 classic galactosemia or clinical variant 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 chance of his/her being a carrier is 2/3.

Offspring of a proband

  • The offspring of an individual with classic galactosemia or clinical variant galactosemia are obligate heterozygotes (carriers) for a disease-causing mutation in GALT.
  • If one parent has classic galactosemia or clinical variant galactosemia and the other parent is a carrier, each child has a 50% chance of being a heterozygote and a 50% chance of having classic galactosemia or clinical variant 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

Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Molecular genetic testing. Carrier testing for at-risk family members is possible if the GALT disease-causing mutations have been identified in the family.

Biochemical genetic testing

  • Carrier testing is done by measuring erythrocyte GALT enzyme activity, which is approximately 50% of control values in carriers of classic galactosemia or clinical variant galactosemia when the mutation is Ser135Leu.
  • This will be different with other mutations associated with clinical variant galactosemia which in the homozygous state result in 1-10% residual erythrocyte GALT enzyme activity.

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, clarification of carrier status, and discussion of the availability of prenatal 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 risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for fetuses at 25% risk for classic galactosemia or clinical variant galactosemia using either GALT enzyme activity or molecular genetic testing (if both disease-causing GALT mutations in the family are known) [Elsas 2001]. Prenatal testing using molecular genetic testing is preferred over enzyme analysis.

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 to 18 weeks' gestation.

Note: (1) When a fetus has classic galactosemia or clinical variant galactosemia, amniotic fluid concentration of galactitol is elevated in the late third trimester and has been used in the past for prenatal testing. (2) 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, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the GALT disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Galactosemia Support Group (GSG)
    31 Cotysmore Road
    Sutton Coldfield West Midlands B75 6BJ
    United Kingdom
    Phone: +44 0121 378 5143
    Email: sue@galactosaemia.org
  • National Library of Medicine Genetics Home Reference
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • The Galactosemia Foundation
    P.O. Box 2401
    Mandeville LA 70471
    Phone: 866-900-7421
    Email: president@galactosemia.org
  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Classic Galactosemia and Clinical Variant Galactosemia: Genes and Databases

Data 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 Classic Galactosemia and Clinical Variant Galactosemia (View All in OMIM)

230400GALACTOSEMIA
606999GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE; GALT

Gene structure. 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." For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 250 GALT mutations 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 4. The frequency of the five most common GALT mutations in diverse ethnic groups was reported by Suzuki et al [2001].

A GALT 5-kb deletion is common in persons of Ashkenazi Jewish background [Coffee et al 2006]. The 5-kb deletion allele is a complex deletion that involves a 3163-nucleotide 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 5-kb complex deletion is detectable by MLPA.

Table 4. Prevalence of GALT Mutant Alleles in 284 Individuals from the US with Classic Galactosemia

MutationNumber of AllelesPercent of Total
p.Gln188Arg28049%
p.Ser135Leu407%
p.Lys285Asn204%
p.Leu195Pro112%
p.Tyr209Cys51%
5-kb deletion 171%
p.Asn314Asp14125%
Other6411%
TOTAL568100%

Adapted from Elsas & Lai [1998]

1. See Table 5, footnote 4.

Table 5. GALT Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.404C>Tp.Ser135LeuNM_000155​.2
NP_000146​.2
c.512T>Cp.Phe171Ser
c.563A>Gp.Gln188Arg
c.584T>Cp.Leu195Pro
c.607G>Ap.Glu203Lys
c.626A>Gp.Tyr209Cys
c.855G>Tp.Lys285Asn
c.[940A>G; c.-119_116delGTCA] 2p.Asn314Asp; effect on promoter mutation
c.997C>Gp.Arg333Gly
c.253-2A>G
(IVS2-2A>G) 3
--
(Δ5kb) or (5kbdel) 4, 5--

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. The Duarte D2 variant allele with two variants in cis configuration

3. Seen in persons of Hispanic heritage

4. 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 Ashkenazi Jewish ethnicity

Normal 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 UDPgalactose and the free GALT enzyme.

Abnormal gene product

  • The mutation p.Gln188Arg prevents formation of a GALT-UMP intermediate.
  • 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 benign variant has been proposed to account for increased activity in the LA variant [Langley et al 1997]. The LA variant (D1) in codon 218 is p.Leu218Leu (c.652C>T). Note: Because the amino acid does not change, the correct designation is p.=.
  • The Duarte D2 variant is a deletion in the E-box, a carbohydrate response element that reduces GALT gene expression [Elsas et al 2001].

References

Published Guidelines/Consensus Statements

  1. National Newborn Screening and Genetics Resource Center. National newborn screening status report. Available online. 2013. Accessed 7-8-14.

Literature Cited

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Suggested Reading

  1. Berry GT, Elsas LJ. Introduction to the Maastricht workshop on galactosemia: lessons from the past and new directions in galactosemia. J Inherit Metab Dis. 2011;34:249–55. [PubMed: 21116719]
  2. Berry GT, Walter JH. Disorders of galactose metabolism. In: M. Saudubray, G. van der Berghe, J.H. Walter, eds. Metabolic Diseases – Diagnosis and Treatment. 5 ed. New York, NY: Springer-Verlag, Inc; 2012:141-50.
  3. Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. 2006;29:516–25. [PubMed: 16838075]
  4. Waisbren SE, Potter NL, Gordon CM, Green RC, Greenstein P, Gubbels CS, Rubio-Gozalbo E, Schomer D, Welt C, Anastasoaie V, D’Anna K, Gentile J, Guo C-Y, Hecht L, Jackson R, Jansma BM, Li Y, Lip V, Miller DT, Murray M, Power L, Quinn N, Rohr F, Shen Y, Skinder-Meredith A, Timmers I, Tunick R, Wessel A, Wu B-L, Levy H, Elsas L, Berry GT. The adult galactosemic phenotype. J Inherit Metab Dis. 2012;35:279–86. [PMC free article: PMC3641771] [PubMed: 21779791]

Chapter Notes

Author History

Gerard T Berry, MD, FFACMG (2014-present)
Louis J Elsas II, MD, FFACMG; University of Miami (1999-2014)

Revision History

  • 3 April 2014 (me) Comprehensive update posted live
  • 26 October 2010 (me) Comprehensive update posted live
  • 27 September 2007 (me) Comprehensive update posted to live Web site
  • 2 May 2005 (me) Comprehensive update posted to live Web site
  • 27 March 2003 (me) Comprehensive update posted to live Web site
  • 4 February 2000 (me) Review posted to live Web site
  • 31 August 1999 (le) Original submission
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