Clinical characteristics.

The term "galactosemia" refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia (not covered in this chapter). 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 hypergonadatropic hypogonadism or 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 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 uridylyltranserase (GALT) enzyme activity, and/or biallelic pathogenic variants in GALT.

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

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.

Treatment of manifestations: Standard of care in any newborn who is "screen-positive" for galactosemia is immediate dietary intervention while diagnostic testing is under way. Once a diagnosis is confirmed, 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; dietary restrictions on all lactose-containing foods and other dairy products should continue throughout life, although management of the diet becomes less important after infancy and early childhood. 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 and/or developmental pediatrician 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. Stimulation with follicle-stimulating hormone may be useful in producing ovulation in some women.

Prevention of secondary complications: Recommended calcium, vitamin D, and vitamin K intake to help prevent decreased bone mineralization; standard treatment for gastrointestinal dysfunction.

Surveillance: Biochemical genetics clinic visits every three months for the first year of life or as needed depending on the nature of the potential acute complications; every six months during the second year of life; yearly thereafter. Routine monitoring for: the accumulation of toxic analytes (e.g., erythrocyte galactose-1-phosphate and urinary galactitol); cataracts; speech and development; movement disorder; POI; nutritional deficiency; 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 GALT pathogenic variants in the family are known; or
• If prenatal testing has not been performed, test the newborn for either the family-specific GALT pathogenic variants or erythrocyte GALT enzyme activity.

Pregnancy management: Women with classic galactosemia should maintain a lactose-restricted diet during pregnancy.

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. Molecular genetic carrier testing for at-risk sibs and prenatal testing for pregnancies at increased risk are an option if the GALT pathogenic variants in the family are known. If the GALT pathogenic variants in a family are not known, prenatal testing can rely on assay of GALT enzyme activity in cultured amniotic fluid cells.

Scenarios

Establishing the Diagnosis

The diagnosis of classic galactosemia or clinical variant galactosemia is established in a proband by detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltranserase (GALT) enzyme activity, and/or biallelic pathogenic variants in GALT (Table 1).

Molecular genetic testing approaches include single-gene testing:

• Sequence analysis of GALT is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• Targeted analysis for common pathogenic variants can be performed first in individuals of European or African ancestry (see Table 1). This approach is most efficient when testing large numbers of samples (e.g., carrier screening or newborn screening).

Clinical Description

Galactosemia caused by deficiency of the enzyme galactose-1-phosphate uridylyltranserase (GALT) may be divided into three clinical/biochemical phenotypes: (1) classic galactosemia, (2) clinical variant galactosemia, and (3) biochemical variant galactosemia (not covered in this GeneReview; see, for example, Duarte 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.

Genotype-Phenotype Correlations

Significant genotype-phenotype correlations have been noted [Shield et al 2000, Tyfield 2000, Demirbas et al 2019]. 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, employed in the study by Demirbas et al [2019], helps dispel confusion. The most common pathogenic variants 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.)

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

• In the homozygous state, the pathogenic variant interferes with the catalytic reaction. It is associated with increased risks for 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 pathogenic variant, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg pathogenic variant. However, one adult female and one adult male homozygous for the p.Gln188Arg pathogenic variant who had begun normal lactose intake at age three years exhibited no worsening of the underlying classic galactosemia phenotype [Lee et al 2003, Panis et al 2006a].

p.Ser135Leu, 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 heterozygous (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 and a second variant 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;-119_116delGTCA].

• In the homozygous state D₂ erythrocyte GALT enzyme activity is reduced by 50%.
• Compound heterozygotes with D₂ and a pathogenic variant 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 pathogenic variant 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]+[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]+[Gln188Arg] is compared with clinical variant galactosemia caused by the p.[Ser135Leu]+[Ser135Leu] genotype. For example, almost all females with the p.[Gln188Arg]+[Gln188Arg] genotype manifest POI, whereas POI is almost unheard of in African American women with the p.[Ser135Leu]+[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 and 5 mg/dL and urine galactitol levels between 100 and 400 μmol/mmol creatinine, whereas persons with a p.[Ser135Leu]+[Ser135Leu] genotype usually have an erythrocyte galactose-1-phosphate level below 1 mg/dL, and urine galactitol that is below 100 μmol/mmol creatinine and often in the normal range [Saudubray et al 2012, Walter & Fridovich-Keil 2014].
• Persons with biochemical variant galactosemia – for example, compound heterozygotes for c.563A>G (p.Gln188Arg) and D₂ c.[940A>G;-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 300 GALT pathogenic variants 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

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 2014]. 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 p.Ser135Leu/Ser135Leu genotype is 1:20,000 [Henderson et al 2002].

Evaluations Following Initial Diagnosis in the Newborn Period

To establish the extent of disease and needs in an individual diagnosed with classic galactosemia or clinical variant galactosemia, the evaluations summarized in Table 7 are recommended.

Treatment of Manifestations and Complications

An international clinical guideline addressing management has been published [Welling et al 2017] (full text).

Prevention of Primary Manifestations

See Table 8.

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 1,000 IU/day and vitamin K have been recommended [Panis et al 2006b, Batey et al 2013].

• For calcium and vitamin D intake recommendations, see the NIH Osteoporosis and Related Bone Diseases website.
• 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.

Some affected individuals may develop gastrointestinal dysfunction such as chronic constipation. For those with severe symptoms, evaluation by a gastroenterologist may be considered [Shaw et al 2017].

Surveillance

See also the management guidelines published by Welling et al [2017] (full text).

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

Prenatal testing of a fetus at risk. When the pathogenic variants causing classic galactosemia or clinical variant galactosemia in the family are known, prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to allow for institution of treatment at birth.

Newborn sib. 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 and/or genetic testing (if the familial pathogenic variants in the family are known) 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

Affected females. Women with classic galactosemia or clinical variant galactosemia should be on a lactose-restricted diet during pregnancy.

Carrier females. There is no evidence that the outcome of children with classic galactosemia or clinical variant galactosemia is improved if their mothers (who are obligate carriers) were on a lactose-restricted diet during pregnancy. Therefore, unaffected pregnant women who are heterozygous for a pathogenic variant in GALT (carrier females) do NOT require a lactose-restricted diet during pregnancy.

Therapies Under Investigation

Research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 1-2 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-1-phosphate are under investigation using small inhibitors of the GALK enzyme [Tang et al 2010]. While 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 that expresses an ARHI (DIRAS3) signal is needed to test the hypothesis that ARHI gene expression plays a role in phenotypic expression of disease and to determine whether inhibition of galactose-1-phosphate production limits or abrogates the "human phenotype."

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 (i.e., presumed to be carriers of one GALT pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GALT pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.

Sibs of a proband

• If both parents are known to be heterozygous for a GALT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.

Offspring of a proband

• The offspring of an individual with classic galactosemia or clinical variant galactosemia are obligate heterozygotes (carriers) for a pathogenic variant 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. Each sib of the proband's parents is at a 50% risk of being a carrier of a GALT pathogenic variant.

Carrier Detection

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

Biochemical genetic testing. Carrier testing is done by measuring erythrocyte GALT enzyme activity. Erythrocyte GALT enzyme activity is:

• ~50% of control values in carriers of classic galactosemia;
• ~50% of control values in carriers of p.Ser135Leu-related clinical variant galactosemia; this will be different with other clinical variant galactosemia-causing pathogenic variants, 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/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once both GALT pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for classic galactosemia or clinical variant galactosemia are possible.

Prenatal testing (or preimplantation genetic testing) using molecular genetic testing is preferred over enzyme analysis.

Biochemical testing. Analysis of GALT enzyme activity and molecular diagnosis rely on cells obtained by chorionic villus sampling or amniocentesis.

Note: 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.

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

Molecular Pathogenesis

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.

Galactose 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.

Galactose-1-phosphate then 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 brain cells and subsequently, pseudotumor cerebri.

Figure 2.

Galactose metabolism, GALT deficiency

Since individuals 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 the 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 central nervous system insult is secondary to myo-inositol deficiency [Berry 2011].

Mechanism of disease causation. Loss of function

Author Notes

Gerard T Berry is the Harvey Levy Chair in Metabolism at the Boston Children's Hospital and Professor of Pediatrics at the Harvard Medical School. He is the Director of Metabolism Program at Boston Children's Hospital and the Director of the Harvard Medical School Biochemical Genetics Training Program. He is a member of the Broad Institute of Harvard and MIT. He was the recipient of the 2004 Emmanuel Shapiro Society for Inherited Metabolic Disorders (SIMD) Award. As a member of the SIMD Board of Directors, Dr Berry is the SIMD President Elect. He is the co-chair of the Undiagnosed Disease Network (UDN) metabolomics working group. Dr Berry has established an international center for galactosemia at Boston Children's Hospital. His research has been in both the clinical and basic science spheres. The Berry laboratory has been heavily involved in stable isotope breath testing and whole-body galactose modeling in patients with galactosemia. He created new accurate methods to quantify GALT, GALK, and GALE enzyme activities using LC-MS/MS methodology. More recently his laboratory has turned to studying human induced pluripotent stem (IPS) cells generated from blood and fibroblasts of individuals with galactosemia. He is using synthetic cortical neurons derived from IPS cells, as well as human organoids, to study the mechanisms of central nervous system dysfunction and cell death in galactosemia.

Acknowledgments

I thank the Galactosemia Foundation for their many years of support of this work, all of my colleagues and co-investigators, and the patients and families who have contributed so much and participated in the various research studies.

Author History

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

Revision History

• 11 March 2021 (ma) Comprehensive update posted live
• 9 March 2017 (ma) Comprehensive update posted live
• 3 April 2014 (me) Comprehensive update posted live
• 26 October 2010 (me) Comprehensive update posted live
• 27 September 2007 (me) Comprehensive update posted live
• 2 May 2005 (me) Comprehensive update posted live
• 27 March 2003 (me) Comprehensive update posted live
• 4 February 2000 (me) Review posted live
• 31 August 1999 (le) Original submission

Published Guidelines / Consensus Statements

• Welling L, Bernstein LE, Berry GT, Burlina AB, Eyskens F, Gautschi M, Grünewald S, Gubbels CS, Knerr I, Labrune P, van der Lee JH, MacDonald A, Murphy E, Portnoi PA, Õunap K, Potter NL, Rubio-Gozalbo ME, Spencer JB, Timmers I, Treacy EP, Van Calcar SC, Waisbren SE, Bosch AM; Galactosemia Network (GalNet). International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. Available online. 2017. Accessed 3-24-22.

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